Redhill Biopharma - 20-F annual report

TABLE OF CONTENTS

​

​

​

​

​

We have included important factors in the cautionary statements included in this Annual Report, particularly in “Item 3. Key Information – Risk Factors”, that we believe could cause actual results or events to differ materially from the forward-looking statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make. No forward-looking statement is a guarantee of future performance.

You should read this Annual Report completely and with the understanding that our actual future results may be materially different from what we expect. The forward-looking statements in this Annual Report represent our views as of the date

of this Annual Report. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this Annual Report.

​

Summary of Risk Factors

The following is a summary of some of the principal risks we face. The list below is not exhaustive, and investors should read the “Risk Factors” section included in “Item 3. Key Information – Risk Factors” in full.

​

ITEM 1.          IDENTITY OF DIRECTORS, SENIOR MANAGEMENT AND ADVISERS

Not applicable.

​

ITEM 2.          OFFER STATISTICS AND EXPECTED TIMETABLE

Not applicable.

​

ITEM 3.          KEY INFORMATION

A.          [Reserved]

B.          Capitalization and Indebtedness

Not applicable.

C.          Reasons for the Offer and Use of Proceeds

Not applicable.

D.          Risk Factors

You should carefully consider the risks we describe below, in addition to the other information set forth elsewhere in this Annual Report, including our financial statements and the related notes beginning on page F-1, before you decide to buy our securities. The risks and uncertainties described below in this Annual Report for the year ended December 31, 2025, are not the only risks facing us. We may face additional risks and uncertainties not currently known to us or that we currently deem to be immaterial. Any of the risks described below or incorporated by reference in this Form 20-F, and any such additional risks, could materially adversely affect our reputation, business, financial condition or results of operations. In such case, you may lose all or part of your original investment.

Risks Related to Our Business

Our financial statements include a going concern reference. We will need to raise significant additional capital to finance our losses and negative cash flows from operations, and if we were to fail to raise sufficient capital on favorable terms, we may need to cease operations. Management has substantial doubt about our ability to continue as a going concern.

Our consolidated financial statements have been prepared on a going concern basis, which contemplates the realization of assets and the satisfaction of liabilities in the normal course of business. During the year ended December 31, 2025, our net cash used in operating activities was $9.7 million leaving a cash balance of $4.1 million as of December 31, 2025. Because we do not have sufficient resources to fund our operations for the next twelve months from the date of this filing, management has substantial doubt about our ability to continue as a going concern. We have determined that the Company’s available cash on December 31, 2025 is not sufficient to fund our operations and satisfy our payment obligations for a period exceeding one year from the date of this Annual Report. Our operational costs include payment of pre-closing liabilities relating to Movantik^®, which our subsidiary, RedHill U.S., retained under our agreement with HCR Collateral Management, LLC (“HCRM”) for the extinguishment of all our debt obligations under the Credit Agreement, dated February 23, 2020, as amended (the “Credit Agreement”) in exchange for the transfer of our rights in Movantik^® to an affiliate of HCRM. As of December 31, 2025, estimated remaining pre-closing liabilities relating to Movantik^® were approximately $1.5 million, substantially all of which are included in the allowance for deductions from revenue and accrued expenses and other liabilities balances in the consolidated statements of financial position. In addition, we assumed obligations under the Global Termination Agreement with Movantik Acquisition Co., Valinor Pharma, LLC, and HCR Redhill SPV, LLC (the “Global Termination Agreement”). As of December 31, 2025, our estimated obligations relating to this agreement were $5.7 million which are included in accrued expenses and other  liabilities in the consolidated statements of financial position. See “Item 5. Operating and Financial Review and Prospects – B. Liquidity and Capital

Resources – Term Loan Facility”. In addition, as of the reporting date, we have  significant amounts of obligations related to allowance for deductions from revenues and other liabilities that are past due, including certain obligations that are materially overdue. We are actively engaging with various counterparties in an effort to reach structured payment arrangements. To date, we have finalized formal agreements with a limited number of counterparties to reschedule payments over a period of up to 24 months, however, if we are unable to comply with such agreements, we could incur additional costs or penalties. No other formal agreements have been finalized to date with respect to the remaining counterparties, and there can be no assurance such arrangements will be achieved. Any default on our obligations or defaults on our restructuring arrangements could result in legal proceedings against us, imposition of additional costs or penalties, and could materially adversely affect our business, financial condition, and results of operations. The consolidated financial statements do not include any adjustments relating to the recoverability and classification of asset amounts or the classification of liabilities that might be necessary should we be unable to continue as a going concern.

We also anticipate that significant additional expenditures will be necessary to develop and expand our business before significant positive operating cash flows can be achieved, and we expect losses and negative cash flows to continue for the foreseeable future. Our ability to continue as a going concern is dependent upon our ability to raise significant additional capital to finance our losses and negative cash flows from operations and to ultimately achieve sustainable revenues and profitable operations. If we were to fail to raise sufficient capital or on favorable terms, we may need to cease operations. There are no assurances that we will be able to raise significant additional capital on terms favorable to us or at all, particularly given the current difficult conditions in the capital markets and very low market capitalization which makes it more difficult to raise significant amounts of capital. Even if we are able to obtain additional financing, it may cause substantial dilution for our shareholders. If we are unsuccessful in achieving sufficient commercial sales of our products or in raising sufficient capital, we will need to reduce activities and curtail or cease operations.

In addition, our business plan and our ability to continue as a going concern is largely dependent on our ability to defer payments we owe to the following year. However, except as noted above, we do not currently have any formal payment plans in place and there can be no assurance that any counter-party to whom we owe payments will agree to such payment deferrals. Actual payment schedules could differ significantly and adversely from our current contemplated payment schedules, which may have a material adverse effect on our ability to continue to operate as a going concern.

Following our 2023 sale of our rights to Movantik®, our revenue, market share and opportunities in certain markets, and the size and scope of our business were reduced. We may never achieve the levels of revenue we achieved through Movantik®, and we continue to bear significant legacy liabilities relating to our former Movantik® business. These factors could have a material adverse effect on our ability to operate as a going concern.

Following the consummation of our sale of our rights to Movantik^® in February 2023, our revenue generated from Movantik^® sales was eliminated and our business’ size and scope, market share and opportunities in certain markets, and our ability to compete in certain markets and therapeutic categories were substantially reduced. Our ability to realize any value from Movantik^® beyond its price in an asset sale was permanently lost. Additionally, following the sale of our rights to Movantik^®, we lost our primary revenue source and our ability to operate as a financially viable commercial business has been significantly more difficult. We also lost economies of scale in our commercial operations that we were able to benefit from by having Movantik^® as a core commercial product. As a result, we downsized our commercial operations and took other steps to better align our expenses and revenues, which adversely affected our ability to sell Talicia^®. This could have a material adverse effect on our ability to continue to operate as a going concern.  In addition, in the event we are not able to achieve sufficient levels of revenues, we may need to further downsize, or even shut down our commercial operations, which could cause us to incur additional costs and expenses, including severance expenses, and make it more difficult to sell commercial products in the future. See “Item 6. Directors, Senior Management and Employees – B. Compensation – Change in Control Retention Plan and Agreements; Severance Arrangements.”

In addition, we continue to bear significant pre-closing liabilities and other obligations relating to our former Movantik® business, including obligations under the Global Termination Agreement, which continue to materially affect our liquidity position.

Our current working capital is not sufficient to complete the research and development with respect to any or all of our therapeutic candidates or commercializing products that we may commercialize or promote in the future. We will need to raise significant additional capital to achieve our strategic objectives and to execute our business plans. Our failure to raise sufficient capital or on favorable terms would significantly impair our ability to fund the further development of our therapeutic candidates, or the products we may commercialize or promote in the future, support our strategic collaborations and investments, attract development or commercial partners or retain key personnel, and to fund operations.

As of December 31, 2025, we had cash, cash equivalents, short-term investments and restricted cash of approximately $4.1 million, and as of December 31, 2024, we had cash, cash equivalents and short-term investments of approximately $4.8 million. We have funded our operations primarily through public and private offerings of our securities, strategic investments, and the Global Termination Agreement. We will need to raise significant additional capital to achieve our strategic objectives of completing the research and development with respect to any or all of our therapeutic candidates, commercializing products that we may commercialize or promote in the future and acquiring, in-licensing and developing therapeutic candidates including advancing our pipeline and acquiring, in-licensing and developing therapeutic candidates. Following the transfer of the Talicia Business to Talicia Holdings Inc. (“Talicia Holdings”), we no longer directly commercialize Talicia^®. Net revenues from U.S. sales of Talicia^® are received at the level of Talicia Holdings and are shared equally between Talicia Holdings and Cumberland pursuant to the Exclusive Joint Commercialization Agreement. Any benefit to us depends on Talicia Holdings’ performance, its cash position and our 70% equity interest therein.

We plan to fund our future operations through potential out-licensing of our therapeutic candidates and commercialization of in-licensed or acquired products. However, we will also need to raise significant additional capital through equity or debt financings or non-dilutive sources, including government grants in order to fund our future operations.

We are not yet certain of the financial impact of our development activities and our interest in Talicia Holdings, and the amounts we raise may not be sufficient to complete the research and development of all of our therapeutic candidates.

Our business is not yet profitable. As we plan to continue expending funds to advance and develop our therapeutic candidates, pursue strategic transactions, and potentially acquire additional products and therapeutic candidates and expand our efforts in research and development, we will need to raise significant additional capital in the future through equity or debt financing, non-dilutive financing or pursuant to development  or strategic collaborations  with third parties with respect to particular therapeutic candidates and commercial products approved for sale in the U.S. However, we cannot be certain that we will be able to raise capital on commercially reasonable terms or at all, or that our actual cash requirements will not be greater than anticipated.

​

We may have difficulty raising needed capital or securing development or commercialization partners in the future as a result of, among other factors, present and future market conditions, the low trading volume of the ADSs, the very low market capitalization of our company which makes it more difficult to make large capital raises, limitations pursuant to General Instruction I.B.5 of Form F-3 and the resulting need to potentially have to raise capital via Form F-1, which may be less appealing to investors and less favorable to us, the need to potentially have to increase our authorized share capital in order to raise amounts sufficient to carry out our business plan, which would be subject to shareholder approval that may not be obtained, unsuccessful commercialization of Talicia^® by our strategic partner or products that we may commercialize or promote in the future, as well as the inherent business risks associated with our Company, products that we may commercialize or promote in the future and our therapeutic candidates. In addition, our ability to raise capital would be adversely affected if we are not able to regain and maintain compliance with Nasdaq’s continued listing requirements. Any financing may also involve significant dilution to our shareholders. We have completed financings in the past which resulted in significant dilution to our shareholders, and we may complete additional financings in the future with similar dilutive effects to our shareholders. To the extent we are able to generate meaningful revenues from Talicia^® through Talicia Holdings and any future commercial products, we may still need to raise capital because the share of profit from Talicia Holdings and any future commercial products may not be sufficient to cover all of our operating expenses. However, the limitations noted above may make future financings difficult or impossible and force us to seek alternative sources of capital such as strategic transactions, licenses, and grants, all of which take a significant amount of time and may not yield the capital we need on favorable terms, if at all. In addition, global and local economic conditions may make it more difficult for us to raise needed capital or secure a development or commercialization partner in the future and may impact our liquidity. If we are unable to obtain sufficient future financing, we will need to reduce activities and curtail or cease operations.

If Talicia Holdings fails to sustain its operations, or fulfill its commitments, we may not successfully continue the commercialization of Talicia^®.

We entered into a collaboration with Cumberland to jointly commercialize Talicia^® in the U.S. through Talicia Holdings Inc. We expect our future success will significantly depend upon our ability to successfully commercialize Talicia^® together with Cumberland. We may not successfully continue the commercialization of Talicia,^® together with Cumberland through Talicia Holdings and our products may not be, or continue to be, commercially successful for various reasons, including but not limited to:

Physicians, various other healthcare providers, patients, payors or the medical community, in general, may be unwilling to accept, utilize or recommend Talicia^®. If we and Cumberland are unable, either on our own or through third parties, to manufacture, commercialize or market Talicia^®, we may not achieve or continue to achieve market acceptance or generate meaningful revenues from Talicia^®. Furthermore, our success depends on obtaining reimbursement to patients for our products and there is no guarantee we will be able to secure commercial or government coverage for any of our products. There is significant pressure within the U.S. healthcare reimbursement system to reduce costs of prescription drugs which could adversely affect us.

In addition, in order to support our development product portfolio, we will need to achieve revenues from sales of Talicia^® consistent with our business expectations, which may prove more difficult than currently expected. Our reputation, business, financial condition and results of operations may be materially adversely affected by any failure to meet such expectations.

We are actively pursuing and in discussions with multiple parties regarding strategic business transactions. There is no assurance that our discussions will result in any strategic business transactions.

We are actively pursuing and in discussions with multiple parties regarding strategic business transactions. The success of any such strategic business transactions is subject to various uncertainties, including but not limited to, market and other conditions, negotiations with potential buyers, regulatory approvals, and other factors beyond our control. There is no assurance that our discussions will result in any strategic business transactions. If we are unable to successfully complete strategic business transactions on favorable terms to us, or at all, our ability to strengthen our balance sheet and enhance our strategic focus could be impacted and could have a material adverse effect on our ability to continue to operate as a going concern.

Even if we are able to complete a strategic business transaction, any such strategic business transaction may require us to incur non-recurring or other charges, increase our expenditures, pose significant integration or implementation challenges or disrupt our management or business. These transactions could entail numerous operational and financial risks, including exposure to unknown liabilities, incurrence of substantial debt or dilutive issuances of equity securities to pay transaction consideration or costs, higher than expected collaboration, acquisition or integration costs, write-downs of assets or goodwill or impairment charges, increased amortization expenses, difficulty and cost in facilitating the collaboration or combining the operations and personnel of any acquired business, impairment of relationships with key suppliers, manufacturers or customers of any acquired business due to changes in management and ownership and the inability to retain key employees of any acquired business.

Accordingly, although there can be no assurance that we will undertake or successfully complete any transactions of the nature described above, any transactions that we do complete may be subject to the foregoing or other risks and have a material adverse effect on our business, results of operations, financial condition and prospects. Conversely, any failure to enter any collaboration or other strategic transaction that would be beneficial to us could delay and make more expensive the development and potential commercialization of our therapeutic candidates and have a negative impact on the competitiveness of any therapeutic candidate that reaches market.

Our management conducted an evaluation of the effectiveness of our internal control over financial reporting and concluded that our internal control over financial reporting was not effective as of December 31, 2025. As a result, shareholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of the ADSs.

Effective internal controls over financial reporting are necessary for us to provide reliable financial reports and, together with adequate disclosure controls and procedures are designed to prevent fraud. Our management is required to assess the effectiveness of our internal controls and procedures and disclose changes in these controls on an annual basis.

Any failure to implement required new or improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations. In addition, any testing by us conducted in connection with any applicable requirements of Section 404 may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our financial statements or identify other areas for further attention or improvement. Inferior internal controls could also cause investors to lose confidence in our reported financial information, which could have a negative effect on the trading price of the ADSs.

Our management conducted an evaluation of the effectiveness of our internal control over financial reporting and concluded that our internal control over financial reporting was not effective as of December 31, 2025. A material weakness in internal control over financial reporting was previously identified in 2022 and disclosed in our Annual Reports on Form 20-F for the year ended December 31, 2022, 2023 and 2024  relating to lack of sufficient controls which impacted the calculation of allowance for deductions from revenues, and such material weakness had not yet been sufficiently remediated as of December 31, 2025. We lacked enough financial reporting personnel with an appropriate level of knowledge, experience, and training commensurate with our financial reporting requirements. This control deficiency contributed to the fact that not all data and information available to us was taken into consideration when making the calculation. While we have implemented a remediation plan, as of December 31, 2025, we were not yet able to conclude that such material weakness had been fully remediated. We continue to monitor and assess our internal control environment, and no assurance can be given that significant deficiencies or other material weaknesses will not be identified in the future or that we will be able to remediate such significant deficiencies or other material weaknesses in a timely matter or at all.

Implementation of remediation measures requires validation and testing of the design and operating effectiveness of internal control over a sustained period of financial reporting prior to reaching a determination that the material weakness have been remediated. As we continue to validate and test our internal control over financial reporting, we may determine that additional measures or modifications to the remediation plan are necessary or appropriate. If the steps we take do not remediate the material weaknesses in a timely manner, there could continue to be a reasonable possibility that these control deficiencies or others could result in a material misstatement in our financial statements. Additionally, if significant deficiencies or other material weaknesses are identified in our internal control over financial reporting that we cannot remediate in a timely manner, investors and others may lose confidence in the reliability of our financial statements and the trading price of our securities and ability to obtain any necessary equity or debt financing could suffer. The material weaknesses will not be considered remediated until we have completed implementing the necessary controls and ensured their applicability.

We have made, and will continue to make, changes in these and other areas. In any event, the process of determining whether our existing internal controls are compliant with any applicable requirements under Section 404 and sufficiently effective has required and will continue to require the investment of substantial time and resources, including by our chief financial officer and other members of our senior management. As a result, this process may continue to divert internal resources and may take a significant amount of time and effort to complete. In addition, we cannot predict the outcome of this process and whether we will need to implement remedial actions in order to implement effective controls over financial reporting. The determination of whether or not our internal controls are sufficient and any remedial actions required could result in us incurring additional costs that we did not anticipate, including the hiring of outside consultants. We may also fail to complete our evaluation, testing and any required remediation needed to comply with any applicable requirements under Section 404 in a timely fashion. Irrespective of compliance with any applicable requirements under Section 404, any additional failure of our internal controls could have a material adverse effect on our stated results of operations and harm our reputation. As a result, we may experience higher than anticipated operating expenses, as well as higher independent auditor fees during and after the implementation of these changes. If we are unable to implement any of the required changes to our internal control over financial reporting effectively or efficiently or are required to do so earlier

than anticipated, it could adversely affect our operations, financial reporting or results of operations and could result in an adverse opinion on internal controls from our independent auditors.

Furthermore, if we are unable to certify that our internal control over financial reporting is effective and in compliance with any applicable requirements under Section 404, we may be subject to sanctions or investigations by regulatory authorities, such as the SEC or stock exchanges, and we could lose investor confidence in the accuracy and completeness of our financial reports, which could hurt our business, the price of the ADSs and our ability to access the capital markets.

We have a history of operating losses. We may continue to incur significant losses in the coming years.

We have incurred operating losses in each fiscal year since inception, principally as a result of research and development, selling, marketing, and business development, and general and administrative expenses in support of our operations, and we may continue to incur operating losses for the immediate future. We experienced net loss of approximately $0.4 million in 2025, net loss of approximately $8.3 million in 2024, and net income of approximately 23.9 million in 2023. As of December 31, 2025, we had an accumulated deficit of approximately $413.8 million. Our ability to generate sufficient revenues to sustain our business operations in accordance with our plan and to achieve profitability depends mainly upon our ability, together with Cumberland, to successfully commercialize or promote Talicia^® and, alone and/or with others, products that we may acquire or for which we may acquire commercialization rights in the future, develop our therapeutic candidates, obtain the required regulatory approvals in various territories. We may be unable to achieve any or all of these goals with regard to Talicia^®, our therapeutic candidates or products we may commercialize or promote in the future. As a result, we may never achieve sufficient revenues to sustain our business operations in accordance with our plan or be profitable.

Most of our therapeutic candidates are in late-stage clinical development. All of our therapeutic candidates will likely require successful additional clinical and non-clinical trials before we can obtain the regulatory approvals in order to initiate commercial sales of them, if at all. We plan to further fund our future operations through commercialization and out-licensing of our therapeutic candidates, commercialization of in-licensed or acquired products and raising significant additional capital through equity or debt financing or through non-dilutive financing, including government grants. Our current cash resources are not sufficient to complete the research and development of any or all of our therapeutic candidates and to fully support our commercial operations until generation of sustainable positive cash flows. We expect that we will incur additional losses as we continue to focus our resources on advancing the development of our therapeutic candidates, as well as advancing our commercial operations, based on a prioritized plan that may result in negative cash flows from operating activities.

Our capital requirements are subject to numerous risks.

Our long-term capital requirements are expected to depend on many potential factors, including but not limited to:

We have limited experience achieving regulatory approval or out-licensing our therapeutic candidates, making it difficult to evaluate our business and prospects.

Talicia^® is our first and only product that was developed internally and approved for marketing by the FDA. We have limited experience in commercializing products and achieving regulatory approval or out- licensing our therapeutic candidates. Consequently, any predictions about our or Talicia Holdings’ future performance may not be accurate, and we and Talicia Holdings may not be able to fully assess our ability to commercialize Talicia^® or ones we may acquire or develop in the future, complete the development or obtain regulatory approval for our current and future therapeutic candidates or obtain regulatory approvals, reimbursement by third-party payors, achieve market acceptance or competitive pricing of Talicia^® or products that we may commercialize or promote in the future.

We have ceded significant control over the U.S. commercialization of Talicia^®.  We are dependent in significant part on Cumberland’s performance, and we are dependent on joint decision-making with Cumberland for the successful commercialization of Talicia^® in the U.S. and globally, which may result in disagreements, deadlocks, delays or outcomes that are not in our best interests.

We entered into a collaboration with Cumberland to jointly commercialize Talicia^® in the U.S. through Talicia Holdings, pursuant to which we sold a 30% equity interest in Talicia Holdings to Cumberland. Our future revenues and related cash flows from Talicia^® in the U.S., and our ability to realize the anticipated benefits of this arrangement, depends in significant part on Cumberland’s performance and on our ability to successfully manage a jointly controlled commercialization structure. If Cumberland does not perform its obligations satisfactorily, including by failing to fund its share of operations and development activities, and we do not successfully manage the commercialization structure, commercialization of Talicia^® in the United States and globally and our business, financial condition and results of operations may be adversely affected.

Pursuant to the collaboration arrangements, Talicia^® will be jointly commercialized in the United States through a joint committee (“Joint Committee”) with equal representation and joint decision-making authority over key matters, including commercialization strategy, pricing, contracting, sales and marketing activities. Although we believe joint governance is expected to align incentives, it may also require consensus on significant decisions. We and Cumberland may have different and inconsistent business objectives, operating priorities, risk tolerances, constraints on resources, views on pricing and contracting, and preferences with respect to promotional strategy, compliance approaches, and market access initiatives, especially in times of economic uncertainty. Disagreements may delay or prevent decisions, cause commercial opportunities to be missed, or result in a compromise position that is less effective than a unified strategy. If disputes arise, available dispute resolution mechanisms (if any) may be time-consuming, costly, disruptive to commercialization efforts and may not yield results favorable to us. Any such disagreements or deadlocks could materially adversely affect the commercialization of Talicia^® in the United States and globally and our business, financial condition and results of operations.

The division of responsibilities between Talicia Holdings and Cumberland increases operational and supply chain risks, and failures in coordination could disrupt commercialization.

Under the Exclusive Joint Commercialization Agreement with Cumberland, Talicia Holdings will oversee market access, marketing, regulatory approvals and medical affairs activities, as well as manufacturing, quality and supply of Talicia^®, bearing the related cost of goods sold. Cumberland will oversee trade operations and distribution and fund significant commercialization activities approved by the Joint Committee. The success of the U.S. commercialization effort depends on effective coordination across these functions. Operational failures by either party, or failures to coordinate effectively, may result in inventory shortages, excess inventory, product returns, disruptions in distribution, delays in contracting and payer coverage, inconsistent messaging to customers, operational or compliance errors, or increased expenses. Because Talicia Holdings bears the cost of goods sold, any manufacturing, quality or supply inefficiencies, delays, or cost increases could disproportionately impact our financial results. In addition, if manufacturing or supply disruptions occur at the same time that demand is increased through Cumberland’s promotional efforts, the collaboration could be unable to capture market opportunities, which could reduce revenues and damage relationships with customers and distributors.

Our minority sale of Talicia Holdings and joint control structure may limit our ability to unilaterally determine strategy for Talicia^® in the United States and globally, restructure Talicia Holdings, or pursue certain strategic transactions.

By selling a 30% equity interest in Talicia Holdings and agreeing to joint governance arrangements, we reduced our unilateral control over Talicia Holdings and certain strategic and operational decisions relating to Talicia^® in the United States and globally. Under the organizational documents of  Talicia Holdings and related agreements, Cumberland has approval rights, board representation, information rights, transfer restrictions, rights of first refusal or other rights that could restrict or delay our ability to cause Talicia Holdings to take certain actions, including entering into additional collaboration arrangements, changing commercialization strategy, incurring indebtedness, making certain capital expenditures, or engaging in mergers, acquisitions, sales of assets or other strategic transactions involving Talicia Holdings or Talicia^® in the U.S. or globally Even where we retain majority ownership, joint decision-making may limit our flexibility to respond quickly to market conditions or to implement changes we believe are necessary.

The structure of our arrangements with Cumberland may create conflicts of interest and may increase the risk of disputes regarding commercialization strategy, budgets, and interpretation of contractual requirements.

The collaboration contemplates that Cumberland will fund significant commercialization activities approved by the Joint Committee and that the parties will jointly oversee pricing, contracting and commercial strategy. Disputes could arise over the scope of Joint Committee authority, what expenses are required or reimbursable, whether particular plans were properly approved, and how costs and responsibilities should be allocated. Disputes could also arise over the use of third parties, vendors, subcontractors and other commercial partners, including whether certain arrangements require consent. Such disputes could result in reduced spending, delays in commercialization initiatives, interruption of operations, or litigation or arbitration, any of which could negatively affect the commercialization of Talicia^® and our results of operations.

If the collaboration is terminated, not renewed or otherwise fails, we may incur substantial costs and face significant delays in maintaining U.S. commercialization of Talicia^® and our business could be materially adversely affected.

The collaboration with Cumberland may be subject to termination or non-renewal in accordance with its terms, including in connection with certain breaches or other events. If the collaboration is terminated or otherwise fails, we may need to assume responsibilities currently performed by Cumberland, including U.S. sales efforts and trade operations, or identify and transition to a replacement partner. Transitioning commercialization activities could be time-consuming and expensive. We may need to engage third parties on less favorable terms, and could lead to reduced Talicia^® revenues in the United States. In addition, the existence of a minority equity owner in Talicia Holdings may complicate or delay a transition. Any transition following termination or non-renewal could require significant management attention and may divert time and attention from other strategic priorities, which could impair our ability to execute our business plan.

If we or subsidiaries, collaborators and affiliates are unable to maintain and train an effective commercial infrastructure, including sales and marketing infrastructure, including through subsidiaries, collaborators and affiliates, or maintain compliant and adequate commercial capabilities, we will not be able to successfully commercialize and grow Talicia^® and any products we may commercialize or promote in the future.

We and our employees, including our contractors, subsidiaries, collaborators and affiliates must comply with applicable regulatory requirements and restrictions relating to marketing and advertising. If we or our subsidiaries, collaborators or affiliates are unable to maintain compliant and adequate sales and marketing capabilities, including training new sales personnel (including sales contractors) regarding applicable regulatory requirements and restrictions, we may not be able to increase our product revenue, may generate increased expenses, and may be subject to regulatory investigations and enforcement actions.

Our commercial efforts, including our sales and marketing efforts and those of our subsidiaries, collaborators and affiliates, must comply with various laws and regulations. Under applicable FDA marketing regulations, prescription drug promotions must be consistent with and not contrary to labeling, present “fair balance” between risks and benefits, be truthful and not false or misleading, be adequately substantiated (when required), and include adequate directions for use. Additionally, our marketing activities and those of our subsidiaries, collaborators and affiliates may be subject to enforcement by the Federal Trade Commission, state attorneys general, and consumer class-action liability if we engage in any practices that appear misleading or deceptive to the applicable agencies or consumers. Our sales and marketing practices and those of our subsidiaries, collaborators and affiliates must also comply with federal and state anti-kickback statutes and other applicable healthcare laws, the violation of which can result in civil and criminal liability and other penalties.

In addition to the requirements applicable to approved drug products, we may also be subject to enforcement action in connection with any promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, may not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the therapeutic candidate.

If the FDA investigates our or our subsidiaries’, collaborators’ and affiliates’ marketing and promotional materials or other communications and finds that any of our current or future commercial products are being marketed or promoted in violation of the applicable regulatory restrictions, we and our subsidiaries, collaborators and affiliates could be subject to FDA enforcement action. Any enforcement action (or related lawsuit, which could follow such action) brought against us or our subsidiaries, collaborators or affiliates in connection with alleged violations of applicable drug promotion requirements, or prohibitions, could have an adverse effect on our reputation, business, financial condition or results of operations, as well as the reputation of any approved drug products we or our subsidiaries, collaborators and affiliates may commercialize or promote in the future. In addition, we may also be reliant on third parties’ compliance with such regulations.

Moreover, laws and regulations covering commercialization activities in the pharmaceutical industry are constantly changing, and we will need to continually update and adjust our policies and sales and marketing and commercialization activities to meet legal and regulatory requirements. Our ability and the ability of our subsidiaries, collaborators and affiliates to comply with legal and regulatory requirements at any time in time does not guarantee we will continue to be able to comply in the future.

In addition to complying with applicable laws and regulations covering commercialization activities in the pharmaceutical industry, we and our subsidiaries, collaborators and affiliates must also comply with various contractual terms governing our use of third-party intellectual property in our commercialization materials.

In order to maintain and potentially increase our commercialization capabilities in the U.S. and outside the U.S., we and our subsidiaries, collaborators and affiliates may need to maintain and potentially expand, among others, our development, regulatory, manufacturing, sales and marketing capabilities, and to maintain or potentially increase our personnel to accommodate sales. We may experience difficulties in managing this growth and integrating new personnel.

To maintain and potentially increase our own commercialization capabilities in the U.S. and outside the U.S. we and our subsidiaries, collaborators and affiliates may need to expand, among others, our and their development, regulatory, manufacturing, sales and marketing capabilities, and to maintain or potentially increase our personnel to accommodate sales. We and our subsidiaries, collaborators and affiliates may not be able to secure or retain personnel, organizations or vendors that are adequate in number or expertise to successfully and lawfully market and sell our products in the U.S. or outside the U.S. If we or our subsidiaries, collaborators or affiliates are unable to maintain or expand our or their sales and marketing capabilities, train our or their sales force or contractors effectively or provide any other capabilities necessary to commercialize products, we and our subsidiaries, collaborators and affiliates may need to contract with third parties to market and sell our products, which, if we are able to sell our products, could have an adverse effect on our financial condition and our results of operations.

We and our subsidiaries, collaborators or affiliates may also have difficulty in integrating into our existing U.S. operations sales and other commercial personnel or contractors that we may hire or engage to support the commercialization of Talicia^®. Sales personnel or contractors’ productivity may decrease as new, less experienced sales personnel or contractors are hired who are not yet familiar with Talicia^® and any future commercial products. In addition, we and our subsidiaries, collaborators and affiliates may be exposed to greater regulatory and compliance risks with an expanded sales force and activities to the extent applicable.

Future growth may impose significant added responsibilities on members of management, including the need to identify, recruit, maintain, motivate and integrate additional employees or contractors. See “– Our business could suffer if we are unable to attract and retain key personnel and additional highly qualified personnel” below. In addition, management may have to divert a disproportionate amount of its attention away from running our day-to-day activities and devote a substantial amount of time to managing these growth activities.

Any collaborative arrangements that we have established or may establish may not be successful, or we may otherwise not realize the anticipated benefits from these collaborations, including commercialization of Talicia^®. We do not control third parties with whom we have or may have collaborative arrangements, and we rely on such third parties to achieve results which may be significant to us. In addition, any current or future collaborative arrangements may place the commercialization of Talicia^® or products that we may commercialize or promote in the future or the development of our therapeutic candidates outside our control and may require us to relinquish important rights or may otherwise be on terms unfavorable to us.

Each of our collaborative arrangements requires us to rely on external consultants, advisors, and experts for assistance in several key functions, including clinical development, manufacturing, regulatory, market research, intellectual property, and commercialization. We do not control these third parties, but we rely on such third parties to achieve results, which may be significant to us. With respect to RHB-102, we rely on Hyloris Pharmaceuticals NV (“Hyloris”), the party responsible for, among other things, the development, manufacture, registration and commercialization of the product with respect to the territories granted to Hyloris under our exclusive license agreement with Hyloris, dated as of February 25, 2025.  With respect to Talicia^® outside the U.S., we rely on Recipharm Strängnäs AB (“Recipharm”) and other contracting parties for the manufacture of Talicia^® and its components, and we rely on Gaelan Medical Trade LLC (“Gaelan Medical”) to obtain necessary approvals and commercialize Talicia^® in the United Arab Emirates (“UAE”) and other Middle East markets. With respect to Talicia^® in the U.S., we rely on Cumberland to jointly commercialize Talicia^® in the United States through our U.S. subsidiary, Talicia Holdings.

​

Relying upon collaborative arrangements to commercialize Talicia^® and any other products that we may commercialize or promote in the future and to develop our therapeutic candidates, subject us to a number of risks, including but not limited to the following:

​

In addition, our reliance upon our partners in connection with commercial activities subjects us to a number of additional risks, including but not limited to, the following:

If any of these or other scenarios materialize, they could have an adverse effect on our reputation, business, financial condition or results of operations.

If we acquire products, technologies, companies or businesses that own rights to, or otherwise acquire commercialization and related rights to, products, such transactions could result in additional costs, integration or operating difficulties, dilution and other adverse consequences. Such acquired products, technologies or businesses that own rights to products may not achieve commercial success or further establish our marketing and commercialization capabilities or those of our subsidiaries, collaborators and affiliates.

Part of our strategy is to identify and acquire rights to products that have been cleared or approved for marketing in the U.S. or elsewhere, and in particular, those with a therapeutic focus on GI, infectious diseases and oncology or with therapeutic activities which are overlapping or complementary to our existing commercial activities. Management has evaluated, and expects to continue to evaluate, a wide array of potential strategic acquisitions. From time to time, management may engage in discussions regarding potential acquisitions or licensing of rights to certain products that management believes are important to our business. Any one of these transactions could have a material effect on our reputation, business financial condition or results of operations. In connection with these acquisitions or licensing transactions, we may:

In addition, the process of integrating an acquired product, technology, company or business may create operating difficulties and expenditures and pose numerous additional risks to our operations, including:

If any of the above events (or more) occur, or if we cannot effectively manage or respond to such events following one or more acquisitions, they may have a material adverse effect on our reputation, business, results of operations or financial condition.

Moreover, there can be no assurance that we will accurately or consistently identify products approved or cleared for marketing that will achieve commercial success, that we will be able to successfully acquire or commercialize such products or that such acquisitions would further establish our marketing and commercialization capabilities or those of our subsidiaries, collaborators and affiliates.

Maintaining and potentially expanding our commercial infrastructure in the U.S., is a significant undertaking that requires substantial financial and managerial resources, and we and subsidiaries, collaborators and affiliates may encounter setbacks or may not be successful in our efforts.

Maintaining and potentially expanding the necessary commercial capabilities is competitive and time-consuming, and the commercialization of Talicia^® requires a significant expenditure of operating, financial and management resources. Even with those investments, we, through Talicia Holdings, may not be able to effectively commercialize Talicia^®, or we and Talicia Holdings and other subsidiaries, collaborators and affiliates may incur more expenditures than anticipated in order to maximize our or their sales of Talicia^® or other future commercial products. We cannot guarantee that we or our subsidiaries, collaborators and affiliates will be able to maintain or expand our or their sales, marketing, distribution, and market access capabilities and enter into and maintain any agreements necessary for commercialization with payors and third-party providers on acceptable terms, if at all. If we and subsidiaries, collaborators and affiliates are unable to maintain or expand such capabilities, either on our own or by entering into agreements with others, or are unable to do so in an efficient manner or on a timely basis, we will not be able to maximize the commercialization of Talicia^® or products that we may commercialize or promote in the future, which would adversely affect our reputation, business, financial condition or results of operations.

Even if the commercialization of Talicia^® and any future commercial products is successful, we may fail to further our business strategy as anticipated or to achieve anticipated benefits and success. Talicia Holdings may incur higher than expected costs in connection with the commercialization of Talicia^®, and we may encounter general economic or business conditions that adversely affect these products.

In addition, if we or our subsidiaries, collaborators and affiliates incur higher than expected costs in connection with the commercialization of Talicia^® and any future commercial products, we or they may need to reduce or terminate our commercial activities, which may have a material adverse effect on our reputation, business, financial condition or results of operations.

We have a limited history of independently commercializing products that we developed and for which we obtained regulatory approval, such as Talicia^®, and a limited history of commercializing products in the U.S. Due to our limited experience, we may have difficulty commercializing Talicia^® if our commercialization agreement with Cumberland is not successful or promoting or commercializing any products for which we may obtain FDA approval or to which we may acquire commercialization or promotion rights in the future.

Compared to competitors in the industry, we have relatively limited experience marketing and selling products in the U.S. In particular, we have limited experience in commercializing products that we developed and for which we obtained regulatory approval, such as Talicia^®. Talicia^® is the first product that we are commercializing that we developed and for which we obtained regulatory approval. In October 2025, Talicia Holdings and Cumberland entered into a five-year Exclusive Joint Commercialization Agreement for Talicia^® in the U.S. pursuant to which the parties will jointly commercialize Talicia^® in the U.S.  If this agreement is not successful, our limited experience in commercializing products may materially increase our marketing and sales expenses or cause us to be ineffective in our efforts to commercialize on our own.

Our prior experience promoting and commercializing several other commercial products in the U.S. that we no longer commercialize or promote was limited and brief.

There can be no assurance Talicia Holdings will successfully commercialize Talicia^® or that we or our subsidiaries, collaborators and affiliates will successfully commercialize any products we may commercialize or promote in the future.

In addition, many companies, both public and private, including well-known pharmaceutical companies and smaller niche-focused companies, are currently selling, marketing and distributing drug products that directly compete with Talicia^® and therapeutic candidates that we may seek to commercialize in the future. Many of these companies have significantly greater financial capabilities, marketing, and sales experience and resources than us and our subsidiaries, collaborators and affiliates. As a result, our competitors may be more successful than we or our subsidiaries, collaborators and affiliates are in commercializing products, and we may not be able to generate sufficient revenue to achieve or sustain profitability.

Our failure to accurately forecast demand for Talicia^® and any future commercial products, or to quickly adjust to forecast changes, could adversely affect our business and financial results.

Market uncertainty makes it difficult for us to accurately forecast future commercial product demand. Talicia Holdings will be setting target levels for the manufacture of Talicia^® and any future commercial products in advance of purchases based upon our forecasts of commercial product sales.

If our forecasts exceed demand, Talicia Holdings could experience excess inventory of APIs or of Talicia^® and any future commercial products, which can increase the inventory costs and result in obsolete inventory. Alternatively, if demand exceeds the forecasts, this may cause a shortage of commercial products, or the APIs used in our products, which could result in an inability to satisfy demand for Talicia^® and any future commercial products and a resulting material loss of market share and potential revenue. A failure to accurately predict the level of demand for Talicia^® and any future commercial products could adversely affect revenues and net income.

In addition, some of our and our subsidiaries’, collaborators’ and affiliates’ suppliers may require extensive advance notice of our and their requirements in order to produce APIs or commercial products in the quantities desired. Long lead times may require us and our subsidiaries, collaborators and affiliates to place orders far in advance of the time when the commercial products will be offered for sale, and limitations on our and our subsidiaries’, collaborators’ and affiliates’ flexibility to change such orders may not only make it difficult for us to accurately forecast demand for Talicia^® and any future commercial products, but also expose us to risks relating to shifts in consumer demand and trends and adversely affecting our operating results.

If third parties do not manufacture, our therapeutic candidates, upon approval, if any, or products we may commercialize or promote in the future in sufficient quantities, within the required timeframes, at an acceptable cost and in accordance with applicable quality standards and other regulatory requirements, the commercialization of Talicia^® or products we may commercialize or promote in the future may be adversely affected, or clinical development of our therapeutic candidates.

We and our subsidiaries, collaborators and affiliates do not currently own or operate manufacturing facilities. We and our subsidiaries, collaborators and affiliates rely on, and expect to continue to rely on, third parties to manufacture commercial quantities of Talicia^® and products that we may commercialize or promote in the future and clinical quantities of our therapeutic candidates. We and Talicia Holdings currently rely on Recipharm and other contracting parties to provide sufficient quantities of Talicia^® in the required timeframe. For example, Talicia Holdings, relies on various third parties to satisfy its supply requirements and there is no guarantee they will be able to do so successfully or in a timely manner. Talicia Holdings’ reliance on third parties includes its reliance on them for quality assurance related to regulatory compliance. Our and our subsidiaries’, collaborators’ and affiliates’current and anticipated future reliance upon others for the manufacture of our therapeutic candidates and any products that we and our subsidiaries, collaborators and affiliates may commercialize or promote may adversely affect our future operations and our  and our subsidiaries’, collaborators’ and affiliates\ ability to commercialize Talicia^® and any products that we may commercialize or promote on a timely and competitive basis, and to develop therapeutic candidates.

We and our subsidiaries, collaborators and affiliates may not be able to maintain our or their existing or future third-party manufacturing arrangements on acceptable terms, if at all. If for some reason our manufacturers or the manufacturers of our subsidiaries, collaborators and affiliates do not perform as agreed or expected or terminate or fail to renew the agreements for any reason, we or our subsidiaries, collaborators and affiliates may be required to replace them, in which event we and our subsidiaries, collaborators and affiliates may incur added costs and delays in identifying, engaging, qualifying under applicable regulatory requirements and training any such replacements and entering into agreements with

such replacements on acceptable terms. In addition, our  and our subsidiaries’, collaborators’ and affiliates’ ability to enter into such alternative arrangements within a reasonable period of time, if at all, may be contractually limited by the terms of the manufacturing agreements existing at that time. Obtaining the necessary FDA or other regulatory approvals or other qualifications required for changes in manufacturing sites, methods or processes under applicable regulatory requirements could result in a significant interruption of supply. In the case of the manufacturer of Talicia^®, in particular, the delay in identifying, engaging, qualifying and training its replacement may be extended, leading to a significant interruption of supply. Any such additional costs and delays may adversely impact our or our subsidiaries’, collaborators’ and affiliates’ ability to obtain regulatory clearances and approvals for our therapeutic candidates or any product we may commercialize or promote or make such commercialization or marketing economically unfeasible.

We and our subsidiaries, collaborators and affiliates rely on third parties to manufacture and supply high-quality APIs and their starting materials in the quantities and quality we and our subsidiaries, collaborators and affiliates require on a timely basis.

We and our subsidiaries, collaborators and affiliates currently do not manufacture any APIs ourselves. Instead, we and they rely on third-party vendors for the development, manufacture, and supply of APIs that are used to formulate Talicia^® and products we or our subsidiaries, collaborators and affiliates may commercialize or promote in the future and our therapeutic candidates. If these suppliers are incapable or unwilling to meet our or our subsidiaries’, collaborators’ and affiliates’ current or future needs on acceptable terms or at all, we and our subsidiaries, collaborators and affiliates could experience delays in supplying product to market or commercial supply shortages that would adversely affect our sales of products we or our subsidiaries, collaborators and affiliates currently or may commercialize or promote in the future, or delays in obtaining regulatory clearances or approvals for our therapeutic candidates.

While there may be several alternative suppliers of APIs on the market, for most of our products we and our subsidiaries, collaborators and affiliates have yet to conclude extensive investigations into the quality or availability of their APIs. Changing API suppliers or finding and qualifying new API suppliers can be costly and take a significant amount of time. Many APIs require significant lead-time to manufacture. There can also be challenges in maintaining similar quality or technical standards from one manufacturing batch to the next.

If we and our subsidiaries, collaborators and affiliates are not able to find stable, affordable, high quality, or reliable supplies of our APIs, we  and they may not be able to produce enough supplies of Talicia^® or products we may commercialize or promote in the future, or of our therapeutic candidates, which could have a material adverse effect on our reputation, business, financial condition or results of operations.

In addition, while to date there have been no significant disruptions to our or our subsidiaries’, collaborators’ and affiliates’ supply chain, including to the manufacture of our APIs or their starting materials, there may be unfavorable changes in the availability or cost of raw materials, intermediates, and other materials necessary for production, which may result in disruptions in our or their supply chain.

Talicia Holdings anticipates continued reliance on third party manufacturers for Talicia^®, and we  and our subsidiaries, collaborators and affiliates expect to rely on third-party manufacturers if we are successful in obtaining marketing approval from the FDA and other regulatory agencies for any of our therapeutic candidates.

Talicia Holdings relies on, and it expects to continue to rely on, third-party manufacturers to produce commercial quantities of Talicia^®. In addition, we and our subsidiaries, collaborators and affiliates expect to rely on third-party manufacturers to produce products that we may commercialize or promote in the future. To date, other than Talicia^®, which the FDA has approved for marketing in the U.S., our therapeutic candidates have been manufactured in relatively small quantities for preclinical testing and clinical trials, as well as for other regulatory purposes by third-party manufacturers. If the FDA or other regulatory agencies approve any of our current or future therapeutic candidates for commercial sale, we expect that we and our subsidiaries, collaborators and affiliates would rely, at least initially, on third-party manufacturers to produce commercial quantities of our approved therapeutic candidates. These manufacturers may not be able to successfully increase or maintain the manufacturing capacity for Talicia^® or any product we may commercialize or promote in the future or any of our therapeutic candidates that may be approved in the future, in a timely or economic manner, or at all. The significant scale-up of manufacturing may require additional validation studies, which the FDA must review and

approve. Foreign regulatory agencies may also require the approval of additional validation studies for scaling up the manufacturing process of any of our therapeutic candidates or current or future commercial products. If the third-party manufacturers are unable to successfully increase or maintain the manufacturing capacity for a therapeutic candidate, Talicia^® or for products that we or our subsidiaries, collaborators and affiliates may commercialize or promote in the future, or if we or our subsidiaries, collaborators and affiliates are unable to secure replacement third-party manufacturers or unable to establish our or their own manufacturing capabilities, the commercial launch of any approved products may be delayed or there may be a shortage in supply. A supply disruption from any of our third-party manufacturers could have a material adverse effect on our reputation, business, financial condition or results of operations.

Reliance on third-party manufacturers entails risks, including, but not limited to:

If we are unable to establish collaborations for our therapeutic candidates or products we may commercialize or promote, or otherwise not be able to raise significant additional capital, we will likely need to alter or abandon our development and commercialization plans.

Our drug development programs and the potential commercialization of our approved products or our therapeutic candidates and products that we may commercialize or promote in the future will require additional cash to fund expenses. As such, our strategy includes either selective partnering or collaborating with multiple pharmaceutical and biotechnology companies to assist us in furthering the development or potential commercialization of our approved products and therapeutic candidates, if approved, promoting or commercializing products, in whole or in part, in some or all jurisdictions or through our own commercialization capabilities, such as our partnerships with Cumberland, Gaelan Medical and Hyloris. With respect to potential new third-party partners for the development or commercialization of our approved products and therapeutic candidates, if approved, and development or commercialization of products that we may commercialize or promote in the future, we may not be successful in entering into collaborations with third parties on acceptable terms, or at all. In addition, if we fail to negotiate and maintain suitable development, commercialization or promotion agreements or otherwise raise significant additional capital to secure our own commercialization capabilities, we may have to limit the size or scope of our activities or we may have to delay or terminate one or more of our development or commercialization programs. Any failure to enter into (or in the case of Cumberland, Gaelan Medical and Hyloris, any failure to maintain) development or commercialization agreements with respect to the development, marketing and commercialization of any therapeutic candidates or products we may commercialize or promote or failure to develop, market and commercialize such commercial products or therapeutic candidates or products we may commercialize or promote independently may have an adverse effect on our reputation, business, financial condition or results of operations.

We may depend on our ability to identify, consummate and integrate in-licenses or acquire additional therapeutic candidates to achieve commercial success, including products approved or cleared for marketing in the U.S. or elsewhere.

Talicia^® and our five clinical-stage development therapeutic candidates were all acquired or licensed by us from third parties and we may in the future pursue in-licenses or acquisitions of additional therapeutic candidates or products and seek to integrate them into our operations as well. We evaluate internally and with external consultants each therapeutic candidate we in-license or acquire. However, there can be no assurance as to our ability to accurately or consistently identify therapeutic candidates or products that have been approved or cleared for marketing in the U.S. or elsewhere that are likely to achieve commercial success. In addition, even if we identify additional therapeutic candidates or products that have been approved or cleared for marketing in the U.S. or elsewhere that are likely to achieve commercial success, there can be no assurance as to our ability to in-license or acquire such therapeutic candidates or products under favorable terms or at all. In-licenses and acquisitions of therapeutic candidates and products involve risks that could adversely affect our future results of operations.

We compete with other entities for some in-license or acquisition opportunities.

As part of our overall strategy, we pursue opportunities to in-license or acquire therapeutic candidates and products that have been approved or cleared for marketing in the U.S. We may compete for in-license and acquisition opportunities with other companies, including established and well-capitalized companies. As a result, we may be unable to in-license or acquire additional therapeutic candidates or products that have been approved or cleared for marketing in the U.S. at all or on favorable terms. Our failure to further in-license or acquire therapeutic candidates or products that have been approved or cleared for marketing in the U.S. in the future may materially hinder our ability to grow and could materially harm our reputation, business, financial condition or results of operations.

If we or a licensor or a partner of ours cannot meet our or their respective obligations under our acquisition, in-license or other development or commercialization agreements or renegotiate the obligations under such agreements, or if other events occur that are not within our control, such as bankruptcy of a licensor or a partner, we could lose the rights to our therapeutic candidates or products we may commercialize or promote, experience delays in developing or commercializing our therapeutic candidates or products we may commercialize or promote or incur additional costs, which could have a material adverse effect on our reputation, business, financial condition or results of operations.

We acquired our rights to Talicia^® and RHB-104 from a third party pursuant to an asset purchase agreement. In addition, we in-licensed our rights to three other therapeutic candidates, RHB-102 (Bekinda^®), opaganib, and RHB-107 (upamostat), pursuant to license agreements in which we received exclusive perpetual licenses to certain patent rights and know-how related to these therapeutic candidates. These agreements require us to make payments and satisfy various performance obligations in order to maintain our rights and licenses with respect to these marketed products and therapeutic candidates. If we or our collaborators do not meet our or their respective obligations under these or future agreements, or if other events occur that are not within our control, such as the bankruptcy of a licensor, we could lose the rights to commercialize Talicia^® and any future commercial products or to our therapeutic candidates, experience delays in developing our therapeutic candidates or incur additional costs.

In addition, we are responsible for the cost of filing and prosecuting certain patent applications and maintaining certain issued patents licensed to us. If we do not meet our obligations under these agreements in a timely manner or if other events occur that are not within our control, such as the bankruptcy of a licensor, which impact our ability to prosecute certain patent applications and maintain certain issued patents licensed to us, we could lose the rights to Talicia^® and any future commercial products or our therapeutic candidates which could have a material adverse effect on our reputation, business, financial condition or results of operations. We manage a large portfolio of patents and may decide to discontinue maintaining certain patents in certain territories for various reasons, including costs, such as a current belief that the commercial market for the therapeutic candidate will not be large or that there is a near-term patent expiration that may reduce the value of the therapeutic candidate. In the event we discontinue maintaining such patents, we may not be able to enforce rights for our therapeutic candidates or protect our therapeutic candidates from competition in those territories.

Disputes may arise between us and third parties from whom we have acquired assets or commercialization rights, with which we have license agreements or with which we have commercialization agreement. Any conflict, dispute or disagreement with such third parties may result in disruptions to our business relationships, require us to pay damages and incur costs, adversely affect our results of operations and may lead to loss of rights that are important to our business or costly litigation.

Our existing agreements impose, and we expect that future acquisition, commercialization or license agreements will impose, various diligence, milestone payments, royalty or other obligations on us. Such agreements require, or may in the future require, us to remit upfront and royalty payments or performance milestone payments for commercial products that we in-license and to supply and delivery of know-how for products that we out-license. Any failure on our part to perform our obligations could lead to us losing rights under our licenses or commercialization agreements, including rights to certain of the actual products under certain circumstances, and could thereby adversely affect our business. If there is any conflict, dispute, disagreement or issue of non-performance between us and our third-party partners regarding our rights or obligations under the acquisition, commercialization or license agreements, including any such conflict, dispute or disagreement arising from our failure to satisfy payment obligations under any such agreement or to perform certain activities or to adhere to any contractual obligation, we may be liable to pay damages and incur costs, and it could lead to delays in the research, development, collaboration, and commercialization of Talicia^®, products we may promote or commercialize in the future or our therapeutic candidates. The resolution of such disputes could require or result in litigation or arbitration, which could be time-consuming and expensive. Such third-party partner may have a right to terminate the affected license or commercialization agreement subject to a dispute. If our existing agreements are terminated, it would have a material adverse effect on our reputation, business, financial condition or results of operations.

Our business could suffer if we are unable to attract and retain key personnel and additional highly qualified personnel.

The loss of the services of members of senior management or other key personnel could delay or otherwise adversely impact the successful completion of our planned clinical trials or the commercialization of Talicia^® and therapeutic candidates, if approved, and any product we may commercialize or promote in the future, or otherwise affect our ability to manage our company effectively and to carry out our business plan. These key personnel are Dror Ben-Asher, our Chief Executive Officer, Reza Fathi, Ph.D., our Senior Vice President for Research and Development, Gilead Raday, our Chief Operating Officer, Adi Frish, our Chief Corporate and Business Development Officer, Guy Goldberg, our Chief Business Officer, Razi Ingber, our Chief Financial Officer, Rick D. Scruggs, President, RedHill U.S. and our Chief Commercial Officer, and Dr. Mark Levitt, our Chief Scientific Officer. We do not maintain key-man life insurance. Although we have entered into employment or consultancy agreements with all of the members of our senior management team, members of our senior management team may resign at any time. High demand exists for senior management and other key personnel in the pharmaceutical industry. There can be no assurance that we will be able to continue to retain and attract such personnel.

Our growth and success also depend on our ability to attract and retain additional highly qualified scientific, technical, business development, marketing, sales, managerial and finance personnel. We experience intense competition for qualified personnel, and the existence of non-competition agreements between prospective employees and their former employers may prevent us from hiring those individuals or subject us to liability from their former employers. A sustained labor shortage or increased turnover rates within our employee base as a result of general macroeconomic or other factors, could lead to increased costs, such as increased overtime to meet demand and increased wage rates to attract and retain employees, and could negatively affect our ability to efficiently operate our manufacturing and distribution facilities and overall business. If we are unable to hire and retain employees capable of performing at a high-level, or if mitigation measures we may take to respond to a decrease in labor availability, such as overtime and third-party outsourcing, have unintended negative effects, our business could be adversely affected. An overall labor shortage, lack of skilled labor, increased turnover or labor inflation could have a material adverse impact on our operations, results of operations, liquidity or cash flows.

We face several risks associated with international business.

We operate our business in multiple international jurisdictions. Such operations could be materially affected by changes in foreign exchange rates, capital and exchange controls, expropriation and other restrictive government actions, changes in intellectual property legal protections and remedies, changes in data privacy laws, trade regulations and procedures and actions affecting approval, production, pricing, and marketing of, reimbursement for and access to, Talicia^® and products we may commercialize or promote, or our therapeutic candidates, as well as by political unrest, unstable governments and legal systems, and inter-governmental disputes. For example, although we entered into an exclusive worldwide development and commercialization licensing agreement, excluding North America, with Hyloris for RHB-102 (Bekinda^®), an exclusive license agreement  for Talicia^® in the UAE and additional territories in the middle east , our licensing partners may not be able to obtain regulatory approval  for RHB-102 (excluding North America), may experience a termination of the agreements, or may be unable to sell the products or sell the products in sufficient quantities to generate meaningful revenues. In addition, we are subject to global events beyond our control, including war, public health crises, such as pandemics and epidemics (as described above), tariffs and trade disputes and other international events. In the UAE, for example, threats to the stability of the Abraham Accords between the UAE, the U.S. and Israel may disrupt our ability to supply Talicia^®. Also, given that some of our operations are conducted in Israel, our business and operations are directly affected by economic, political, geopolitical and military conditions in Israel, and any existing conflicts may potentially escalate in the future to more violent events. Any of these changes could have a material adverse effect on our reputation, business, financial condition or results of operations. In addition, the current armed conflict in Ukraine and the subsequent economic sanctions imposed by some countries on Russia and certain territories in Ukraine may negatively impact the supply chain for our commercial product, our R&D activities and our business development activities.  See “ - We conduct some of our operations in Israel. Conditions in Israel, including the recent attack by Hamas and other terrorist organizations from the Gaza Strip and Israel’s war against them, may affect our operations.”

We face risks associated with the lawsuit we initiated against Kukbo. While we prevailed in the lawsuit against Kukbo, Kukbo has not promptly paid the judgment, and we are now pursuing enforcement in South Korea.

On September 2, 2022, we filed a lawsuit against Kukbo in the Supreme Court of the State of New York, County of New York, Commercial Division, as a result of Kukbo’s default in delivering to us $5.0 million under the Subscription Agreement (as defined herein), in exchange for the ADSs we were to issue to Kukbo, and in delivering to us the further payment of $1.5 million due under the Exclusive License Agreement. Kukbo thereafter filed counterclaims alleging breach of contract, misrepresentation, and the breach of the duty of good faith and fair dealing, among other claims. On December 2, 2024, we were awarded a judgment of approximately $6.5 million in principal and approximately $1.5 million in accrued interest as of the date of the judgment, in a summary judgment by the Supreme Court of the State of New York. The court dismissed the entirety of Kukbo’s counterclaims in the case. On August 11, 2025, the New York Supreme Court awarded us approximately $1.82 million in legal costs and expenses (including interest) in our action against Kukbo.

On September 23, 2025, the New York Appellate Division, First Department, on appeal, upheld the Supreme Court’s  original summary judgment ruling and award in our favor, unequivocally dismissing, once again, the entirety of Kukbo’s defense.  As of October 27, 2025, the New York Supreme Court’s summary judgment in our favor against Kukbo became final and eligible for enforcement and foreign recognition, with no further appeal permissible following expiry of the appeal period. The Court awarded more than $10.5 million in total to us, comprised of the main judgment of approximately $8.6 million, and the award for legal fees and expenses of approximately $1.9 million, both now final and eligible for enforcement (both include the principal amounts and accrued interest, to date).  9% annual statutory interest continues to accrue on both awards.

In addition, RedHill recently won an attachment grant against Kukbo, from Korea’s Incheon District Court, providing a court-ordered seizure (attachment) of Kukbo’s assets, preventing their disposal prior to judgment enforcement.

We are party to a contingency fee agreement with our legal counsel, Haynes and Boone, LLP, entered into on November 20, 2023, as amended on December 29, 2024. Under this agreement, such firm is entitled to a double-digit percentage of any gross recovery, if and only if the case ends in a final favorable outcome not subject to further appeal. If no collection is made within six months of such an outcome, we are required to pay such firm its standard hourly fees incurred since

entering the agreement approximately $1.4 million as of December 31, 2025 and must pay the full contingency amount if collection occurs later.

We intend to vigorously pursue the recovery of attorneys’ fees and the collection of the judgment. We can give no assurance that we will succeed in collecting any or all of the amounts awarded to us. If we are unable to collect in a timely manner, we still will be required to pay the legal fees described above even if we do not receive any recovery. The collection efforts against Kukbo may additionally divert management’s attention and resources in preparing for any continued litigation and defending our claim, result in disruptions to our business, and require us to pay legal fees, damages, or associated expenses, all of which could adversely affect our ability to conduct our business.

Risks Related to Regulatory Matters

If we or our  current or future development or commercialization partners are unable to obtain or maintain the FDA or other foreign regulatory clearance and approval for Talicia^® and any future commercial products or therapeutic candidates, we or our commercialization partners will be unable to commercialize Talicia^® or future products or therapeutic candidates, upon approval, if any.

Talicia^® must maintain, and any future products must obtain and maintain, FDA and other foreign regulatory clearance and approval before commercialization.

Talicia^® was approved for marketing in the U.S. for the treatment of H. pylori infection in adults in November 2019. Pursuant to our license agreement with Gaelan Medical, Gaelan Medical received marketing approval for Talicia^® in the UAE and Gaelan Medical subsequently placed the first commercial order for Talicia^®, which was dispatched from the contract manufacturing organization (“CMO”) in December 2023. In August 2024, we announced the launch of Talicia in the UAE.  However, future regulatory developments may lead to a loss of the right to commercialize Talicia^® or any product we may commercialize or promote in the future.

We currently have five therapeutic candidates in development, most of which are in mid - to - late - stage clinical development, with the goal of eventually seeking FDA or other foreign regulatory approvals. Our commercial product and therapeutic candidates are subject to extensive governmental laws, regulations, and guidelines relating to the development, clinical trials, manufacturing, marketing, promotion, and commercialization of pre- and post-approval prescription drugs. We may not be able to submit for or obtain marketing approval for any of our therapeutic candidates in a timely manner or at all.

Any material delay in obtaining or maintaining, or the failure to obtain or maintain, required regulatory clearances and approvals will increase our costs and may materially adversely affect our ability to continue to generate meaningful revenues and could adversely impact our reputation, business, financial condition, results of operations or ability to attain or sustain revenues from other markets. We also are, and will be, subject to numerous regulatory requirements from both the FDA and other foreign regulatory authorities that govern the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement. Moreover, clearance or approval by one regulatory authority does not ensure clearance or approval by other regulatory authorities in separate jurisdictions. Each jurisdiction may have different approval processes and requirements and may impose additional testing, development and manufacturing requirements for Talicia^® and products that we or our subsidiaries, collaborators and affiliates may commercialize or promote in the future and for our therapeutic candidates.

Additionally, the FDA or other foreign regulatory authorities may require, or companies may pursue, additional clinical trials after a product is approved for marketing. Such postmarketing studies may be mandated by the FDA or other foreign regulatory authorities as conditions for initial or continued approval for marketing. The FDA or other foreign regulatory authorities have expressed statutory authority to require holders of NDAs to conduct postmarketing trials to specifically address safety and other issues identified by the regulatory authority. Failure to comply with postmarketing requirements may result in enforcement actions from the FDA, including, but not limited to, warning letters and/or civil monetary penalties.

Certain changes related to an approved drug, including changes to the product labeling, manufacturing process, indications and other certain specifications set forth within the product’s NDA, may not be made until a new NDA or NDA supplement reflecting the applicable changes is submitted to and approved by the FDA. An NDA supplement for a new indication typically requires clinical data similar to that in the original application, including relevant pediatric data, and the FDA typically uses the same procedures and standards in reviewing NDA supplements as it does in reviewing NDAs.

Even if a therapeutic candidate receives regulatory marketing approval, such approval will be limited to a specific disease state(s) and might contain significant limitations on use in the form of warnings, precautions or contraindications, or in the form of onerous risk management plans, restrictions on distribution, among other possible restrictions. Further, even after regulatory approval is obtained, later discovery of previously unknown information, such as safety risks, problems with a product or such information, the extent or severity of which were previously unknown, may result in restrictions on the product’s ability to be marketed as initially approved or even complete withdrawal of the product’s NDA approval and, in effect, its removal from the market.

Additionally, the FDA or other foreign regulatory authorities may change their clearance or approval policies or adopt new laws, regulations or guidelines that materially delay or impair our ability to commercialize Talicia^® and products that we may commercialize or promote in the future, or our ability to obtain the necessary regulatory clearances or approvals for any of our current or future therapeutic candidates.

Further, if there are significant reductions in the FDA’s workforce, specifically at the Center for Drug Evaluation and Research, there may be unforeseen delays in the review of a future product’s NDA or a current or future product’s NDA supplement application. A delay in the review of such applications could delay our ability to commercialize and promote any of our future products in the United States.

Talicia^® or products which we may commercialize or promote in the future may be subject to recalls or market withdrawal that could have an adverse effect on our reputation, business, financial condition or results of operations.

The FDA and similar foreign governmental authorities have the authority to require the recall of regulated products in the event of material deficiencies or defects in design or manufacture. In the case of the FDA, the authority to require a recall must be based on an FDA finding that there is a reasonable probability that the product would cause serious injury or death. In addition, foreign governmental bodies have the authority to require the recall of our products in the event of material deficiencies or defects in design or manufacture.

Product manufacturers or owners, as applicable, may, on their own initiative, recall a product if any material deficiency in a product is found. A government-mandated or voluntary recall by us or one of our collaborators, as applicable, could occur as a result of manufacturing errors, design or labeling defects or other deficiencies and issues. Recalls of any of our products would divert managerial and financial resources and will have an adverse effect on our reputation, business, financial condition or results of operations. The FDA requires that certain classifications of recalls be reported to the FDA within 10 working days after the recall is initiated. Companies are required to maintain certain records of recalls even if they are not reportable to the FDA. We may initiate voluntary recalls involving our products in the future that we determine do not require notification of the FDA. If the FDA disagrees with our determinations, they could require us to report those actions as recalls. A future recall announcement could harm our reputation with customers and negatively affect our sales. In addition, the FDA could take enforcement action for failing to report the recalls when they were conducted.

Regulatory authorities in other jurisdictions may have similar procedures that may subject any product we may commercialize or promote to limitations or withdrawal requests. In addition, the FDA or other foreign regulatory authorities may determine that the chemistry, manufacturing and controls (“CMC”) of marketed products that we develop, acquire or to which we acquire commercialization rights, such as Talicia^® , is unsatisfactory due to the manufacturing standards of the products. If either of these or any regulatory action is taken, Talicia^® or any product we  or our subsidiaries, collaborators and affiliates commercialize or promote in the future could be withdrawn from the market at any time. In addition, we may suffer from delays in further commercialization of any product we or our subsidiaries, collaborators and affiliates commercialize or promote.

We and our third-party manufacturers or our partners’ manufacturers are, and will be, subject to regulations of the FDA and other foreign regulatory authorities, such as applicable current good manufacturing practices and other quality-based regulations.

We and our third-party manufacturers or our partners’ manufacturers are, and will be, required to adhere to laws, regulations, and guidelines of the FDA and other foreign regulatory authorities setting forth current good manufacturing practices (“cGMP”). These laws, regulations, and guidelines cover all aspects of the manufacturing, testing, quality control and recordkeeping relating to Talicia^® and any products we may commercialize or promote, and our therapeutic candidates with varying cGMP rigors depending on what phase each of our respective therapeutic candidates is in with respect to its drug development process. We and our third-party manufacturers and our partners’ manufacturers may not be able to comply with applicable laws, regulations, and guidelines. We and our third-party manufacturers and our partners’ manufacturers are, and will be, subject to unannounced inspections by the FDA, state regulators and similar foreign regulatory authorities outside the U.S. Our failure, or the failure of our third-party manufacturers or our partners’ manufacturers, to comply with applicable laws, regulations and guidelines could result in the imposition of sanctions on us, including fines, injunctions, civil penalties, delays or suspension of clinical trials, failure of regulatory authorities to grant marketing approval of our therapeutic candidates, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of Talicia^® and any future commercial products and therapeutic candidates, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect regulatory approval and supplies of Talicia^® and any future commercial products and therapeutic candidates, and materially and adversely affect our reputation, business, financial condition or results of operations.

Furthermore, changes in the manufacturing process or procedure, including a change in the location where the product is manufactured or a change of a third-party manufacturer, will require prior FDA or other regulatory review or approval of the manufacturing process and procedures in accordance with the FDA’s regulations or comparable foreign requirements. This review may be costly and time-consuming and could delay or prevent the launch or commercial production of a product. The new facility will also be subject to pre-approval inspection. In addition, we will have to demonstrate that the product made at the new facility is equivalent to the product made at the former facility by physical and chemical methods, which are costly and time-consuming. It is also possible that the FDA may require clinical testing as a way to prove equivalency, which would result in additional costs and delay, and may also result in delays in approval or commercialization of a product or render it unfeasible.

Talicia^® , and any product we may commercialize or promote in the future, even if all regulatory clearances and approvals are obtained, will be subject to ongoing regulatory review. If we, or our current or future development or commercialization partners, fail to comply with continuing U.S. and applicable foreign laws, regulations, and guidelines, we could lose those clearances and approvals, and our reputation, business, financial condition or results of operations may be materially and adversely affected.

We or our development or commercialization partners, as applicable, are and will be subject to ongoing reporting obligations with respect to Talicia^®, RHB-102 and any cleared or approved product that we may develop, commercialize or promote in the future, including pharmacovigilance, and with respect to our therapeutic candidates, even if they receive regulatory clearance or approval. In addition, the manufacturing of Talicia^®, the development of RHB-102 and any other product we may develop, commercialize or promote, whether currently or in the future, and our therapeutic candidates, will be subject to continuing regulatory review and approval, including inspections by the FDA and other foreign regulatory authorities. The results of any ongoing review may result in withdrawal from the market of Talicia^® , RHB-102 or products we may develop, commercialize or promote in the future, interruption of manufacturing or development operations or imposition of labeling or marketing limitations for such commercial or development products or therapeutic candidate, or other potentially significant enforcement actions. Since many more patients are exposed to drugs following their marketing clearance or approval, serious adverse reactions that were not observed in clinical trials may occur during the commercial marketing of Talicia^® , the development of RHB-102 or any product we may develop, commercialize or promote in the future, including therapeutic candidates.

If a product receives regulatory approval, the approval is limited to the specific indications for use identified in the approved marketing application and by any additional requirements, restrictions, and limitations identified at the time of the product’s approval or thereafter, which could restrict the commercial value of the product. As a condition of approval or after approval (if the FDA becomes aware of new safety information), the FDA may require us to implement a Risk Evaluation and Mitigation Strategy (REMS), which may include distribution or use restrictions to manage a known or potential serious risk associated with the product. REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use (ETASU). ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The requirement for a REMS can materially affect the potential market and profitability of a given drug. Once adopted, REMS are subject to periodic assessment and modification. Additionally, the FDA may require post-approval, “Phase 4” clinical trials to generate additional information on safety or efficacy. The results of such postmarketing studies may be negative and could cause the FDA to, among other things, further limit marketing efforts or a product’s approved uses or even withdraw approval.

If we or our current or future development or commercialization partners, as applicable, are required to conduct additional clinical trials or other testing of Talicia^®, RHB-102 or any other product we may develop, commercialize or promote, or of our therapeutic candidates, we may face substantial additional expenses, be delayed in obtaining marketing clearance or approval, if required by the FDA, or may never obtain marketing clearance or approval for such product we may develop, commercialize or promote or therapeutic candidate.

Third-party manufacturers and the manufacturing facilities that we and our development or commercialization partners use to manufacture Talicia^® , develop RHB-102 and any other products that we may develop, commercialize or promote, and therapeutic candidate, will be subject to periodic review and inspection by the FDA and may be subject to similar review by other regulatory authorities. Later discovery of previously unknown problems with Talicia^® , RHB-102 and products we may develop, commercialize or promote, or any therapeutic candidate, manufacturer or manufacturing process, or failure to comply with rules and regulatory requirements, may result in actions, including but not limited to the following:

If we or our current or future development or commercialization partners, suppliers, third-party contractors or clinical investigators are slow to adapt, or are unable to adapt, to changes in existing regulatory requirements or the adoption of new regulatory requirements or policies, we and our development or commercialization partners may lose marketing clearance or approval for any products already cleared or approved for marketing in any jurisdiction, resulting in decreased or lost revenue from such products and could also result in other civil or criminal sanctions, including fines and penalties, and we may lose marketing clearance or approval of any of our therapeutic candidates, if any of our therapeutic candidates are approved for marketing.

We may encounter delays in receipt of FDA approval, if any, for our therapeutic candidates due to CMC, clinical studies, efficacy, safety, or regulatory or other issues.

We may encounter significant delays in receipt of FDA approval, if any, for our therapeutic candidates. For example, the FDA may determine that the CMC of one of our therapeutic candidates is not satisfactory due to the manufacturing standards of the products or that additional CMC work, information or quality assurances are needed. The FDA may also consider the clinical studies conducted with a therapeutic candidate and the additional information provided to be inadequate, or insufficient, or require us to provide additional information, which may require us to conduct additional studies or otherwise significantly delay potential FDA approval of the potential NDA for a therapeutic candidate, if at all. In addition, we cannot guarantee that potential future manufacturers or other vendors related to manufacturing will be able to perform as required, will not terminate their agreements with us, or otherwise will not perform satisfactorily. The potential delay in identifying, engaging, qualifying and training an alternative manufacturer may be extended, leading to a significant delay. Furthermore, the FDA may also change its clearance or approval policies or adopt new laws, regulations or guidelines in a manner that materially delays or impairs our ability to obtain approval of the potential NDA for a therapeutic candidate, if any.

In addition, the ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory, and policy changes and other events that may otherwise affect the FDA’s ability to perform routine functions. Average review times at the agency have fluctuated in recent years as a result. In addition, government funding of other government agencies that fund research and development activities is subject to the political process, which is inherently fluid and unpredictable. In addition, the U.S. government has shut down multiple times in the past (including the shutdown that started on October 1, 2025 and became the longest government shutdown in history based on data going back to fiscal 1977) and certain regulatory agencies, such as the FDA, had to furlough employees and stop some of their activities. The effects of any prolonged government shutdown (including effects related to the shutdown that began October 2025) or a widespread freeze on federal funding could significantly impact the ability of the FDA to timely review and process our regulatory submissions, or cause other agencies that support the FDA to slow their work. Any such factors could have a material adverse effect on our business.

Further, presidential and congressional seat turnover may result in increased regulatory and economic uncertainty, including the spending priorities of the new U.S. presidential administration and Congress and what challenges budget reductions will present for us and our industry generally. For example, on January 20, 2025, President Trump announced an executive order establishing the “Department of Government Efficiency” to reform federal government processes and reduce expenditures. Changes in federal policy by the executive branch and regulatory agencies may occur over time through the new presidential administration’s and/or Congress’s policy and personnel changes, which could lead to changes involving our industry.

If any of these or other issues occur, we may face substantial additional expenses and otherwise experience delays in obtaining FDA approval of the NDAs we may file in the future for our therapeutic candidates, including RHB-104/RHB-204 for Crohn’s disease, or may never obtain the FDA approval for such NDAs.

Clinical trials and related non-clinical studies may involve a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results. We or our development or commercialization partners may not be able to obtain regulatory approvals for our therapeutic candidates or commercialize products we may commercialize or promote without completing such trials in accordance with the applicable regulatory standards, even products that may have already been cleared or approved for marketing.

We have limited resources and experience in conducting and managing the clinical trials that are required to obtain or maintain regulatory approvals and commence or continue commercial sales. Clinical trials and related non-clinical studies are expensive, complex, can take many years and have uncertain outcomes. We cannot predict whether we, independently or through third parties, will encounter problems with any of the completed, ongoing or planned clinical trials that will cause delays, including suspension of a clinical trial, delay of data analysis or release of the final report. The clinical trials of our therapeutic candidates may take significantly longer to complete than estimated. Failure can occur at any stage of the testing, and we may experience numerous unforeseen events during, or as a result of, the clinical trial process that

could materially delay or prevent the obtainment of a regulatory approval of current or future therapeutic candidates and delay or prevent their commercialization. In addition, clinical trial results are subject to varying interpretations. Even if we consider a clinical trial successful, the FDA may find our data insufficient to support approval of an NDA, which may prevent our products from obtaining regulatory approval or may necessitate additional clinical trials.

In connection with the clinical trials for our therapeutic candidates and other therapeutic candidates that we may seek to develop in the future, either on our own or through licensing or partnering agreements, we face various risks and uncertainties, including but not limited to:

A number of companies in the pharmaceutical and biotechnology industries, including those with greater resources and experience than us, have suffered significant setbacks in advanced clinical trials, even after seeing promising results in earlier clinical trials. As such, despite the results reported in earlier clinical trials or related non-clinical studies of our therapeutic candidates, we do not know if we will be able to complete the clinical trials or related non-clinical studies we conduct or if such clinical trials will demonstrate adequate safety and efficacy sufficient to request and obtain regulatory approval to market our therapeutic candidates. If any of the clinical trials or related non-clinical studies of any of our current or future therapeutic candidates do not produce favorable results sufficient to support an application for marketing approval or are found to have been conducted in violation of the FDA’s or other regulatory body’s standards governing such studies, our ability to request and obtain regulatory approval for the therapeutic candidate may be adversely impacted, which could have a material adverse effect on our reputation, business, financial condition or results of operations.

If a validated lab test for MAP will not become available, our ability to develop or obtain approval for RHB-104/RHB-204 in Crohn’s disease may be adversely impacted.

A validated lab test for the detection of MAP bacteria in Crohn’s disease patients is likely to be required in order to advance this development program. We do not know if and when such a test for MAP will become available and we depend on third parties’ resources and expertise in this area. If such a test for MAP will not become available, our ability to develop or obtain regulatory approval to market RHB-104/RHB-204 may be adversely impacted.

We rely on third parties to conduct our clinical trials and related non-clinical studies and those third parties may not perform satisfactorily, including but not limited to failing to meet established deadlines and compliance with applicable laws and regulations for the completion of such clinical trials.

We currently do not have the ability to independently conduct clinical trials and related non-clinical studies for our therapeutic candidates, and we rely on third parties, such as contract research organizations, medical institutions, contract laboratories, development and commercialization partners, clinical investigators and independent study monitors to perform these functions. Our reliance on these third parties for research and development activities reduces our control over these activities. Furthermore, these third parties may also have relationships with other entities, some of which may be our competitors. Although we have, in the ordinary course of business, entered into agreements with such third parties, we continue to be responsible for confirming that each of our clinical trials and related non-clinical studies is conducted in accordance with its general investigational plan and protocol, as well as all applicable laws and regulations. For example, the FDA requires us to comply with regulations and standards, commonly referred to as good clinical practices (“GCP”), for conducting, recording and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the trial participants are adequately protected, and regulatory authorities in other jurisdictions may have similar responsibilities and requirements. Our reliance on third parties does not relieve us of these responsibilities and requirements. If these third parties do not successfully carry out their contractual duties or meet expected deadlines, we may be required to replace them or perform such functions independently. Although we believe that there are a number of other third-party contractors we could engage to continue these activities, it may result in a delay of the affected trial and additional costs. Accordingly, we may be materially delayed in obtaining regulatory approvals, if any, for our therapeutic candidates and may be materially delayed in our commercialization efforts for the targeted indications.

In addition, our ability to bring our therapeutic candidates to market depends on the quality and integrity of data that we present to regulatory authorities in order to obtain marketing authorizations. Although we attempt to audit and control the quality of third-party data, we cannot guarantee the authenticity or accuracy of such data, nor can we be certain that such data has not been fraudulently generated. Furthermore, the FDA may consider clinical studies inadequate where steps have not been taken in the design, conduct, reporting, and analysis of the studies to minimize bias. For example, one potential source of bias in clinical studies is a clinical investigator with a financial stake in the outcome of the study. Accordingly, we (or the applicant of the IND or Biologics License Application, as applicable) must submit for all applicable clinical investigators either: (i) a completed Form FDA 3454 attesting to the absence of financial interests and arrangements described in the regulations, dated and signed by the chief financial officer or another responsible corporate official; or (ii) for any investigators for whom a Form FDA 3454 is not submitted, a Form FDA 3455 disclosing completely and accurately the following:

The FDA may refuse to accept a filing of an NDA that does not contain the required certifications and disclosures or attestations by the applicant that the applicant has acted with due diligence to obtain the information but was unable to do so and stating the reason. Additionally, FDA refusal of an NDA on potential bias grounds may have a material adverse effect on our reputation, business, financial condition or results of operations and the credibility of our other commercial products or therapeutic candidates.

We rely on contract research organizations for the management of clinical data generated from our studies, and such contract research organizations may not perform satisfactorily.

We rely on contract research organizations to provide monitors for and to manage data for our studies. Our reliance on these contract research organizations for data management reduces our control over clinical data management. While we have agreements governing their activities, we have limited influence over their actual performance. If these contract research organizations do not successfully carry out their contractual duties or obligations or meet expected deadlines, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or for other reasons, we may be required to replace them, or our clinical studies may be extended, delayed or terminated. In addition, such failure of our contract research organizations would pose risks to the accuracy and usability of clinical data from our clinical studies. Replacing a contract research organization may result in a delay in our clinical studies and generation of data from such studies. In addition, we face the risk of potential unauthorized disclosure or misappropriation of our intellectual property by contract research organizations, which may reduce our trade secret protection and allow our potential competitors to access and exploit our proprietary technology.

We may fail to receive or maintain the benefits from the orphan drug and QIDP designations granted by the FDA for our applicable products or therapeutic candidates, as applicable.

In the U.S., under the Orphan Drug Act, the FDA may grant orphan drug designation to a drug or biologic intended to treat a rare disease or condition, which is defined as one occurring in a patient population of fewer than 200,000 in the U.S., or a patient population greater than 200,000 in the U.S. where there is no reasonable expectation that the cost of developing the drug or biologic will be recovered from sales in the U.S. In 2011, the FDA granted to RHB-104 orphan drug designation for the treatment of Crohn’s disease in the pediatric population; in 2017, the FDA granted to opaganib orphan drug designation for the treatment of cholangiocarcinoma and granted to RHB-107 (upamostat, formerly Mesupron) orphan drug designation for the treatment of pancreatic cancer; in 2020, the FDA granted orphan drug designation to RHB-204 for the treatment of nontuberculous mycobacteria (“NTM”) infections; and in 2024, the FDA granted opaganib orphan drug designation for the treatment of neuroblastoma, a type of childhood cancer.

In the U.S., the orphan drug designation entitles a party to financial incentives, such as opportunities for grant funding toward clinical trial costs, tax advantages and user-fee waivers. In addition, if a product that has the orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications, including an NDA, to market the same drug or biologic for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or where the original manufacturer is unable to assure sufficient product quantity.

Exclusive marketing rights from a given orphan drug designation may be limited if we seek approval for an indication broader than the orphan-designated indication or may be lost if the FDA later determines that the request for designation was materially defective, or if we are unable to assure sufficient quantities of the product to meet the needs of patients with the orphan-designated disease or condition. Further, even if we obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because different drugs with different active moieties may receive and be approved for the same condition, and only the first applicant to receive approval will receive the benefits of marketing exclusivity. Even after an orphan-designated product is approved, the FDA can subsequently approve a later drug with the same active moiety for the same condition if the FDA concludes that the later drug is clinically superior if it is shown to be safer, more effective or makes a major contribution to patient care. Orphan drug designation neither shortens the development time or regulatory review time of a drug nor gives the drug any advantage in the regulatory review or approval process.

In addition, in 2017, we announced that RHB-204 had been granted QIDP designation by the FDA for the treatment of pulmonary NTM infections. Like orphan drugs, QIDPs may take advantage of market exclusivity, which in the case of QIDPs is five years (total period of twelve years together with the orphan drug designation). However, the five-year exclusivity extension does not apply to a supplement to an application under Section 505(b) of the FDCA for any QIDP for which an extension is in effect or has expired; a subsequent application submitted with respect to a product approved by the FDA for a change that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength; or a product that does not meet the definition of a QIDP under Section 505(g) based upon its approved uses.

Modifications to Talicia^® or to any product that we or our subsidiaries, collaborators and affiliates  may commercialize or promote in the future, or our therapeutic candidates, may require new regulatory clearances or approvals or may require us or our development or commercialization partners, as applicable, to recall or cease marketing any of our approved products, or delay further studies of our therapeutic candidates in human subjects until clearances or approvals are obtained.

Modifications to Talicia^® and any products we or our subsidiaries, collaborators and affiliates may commercialize or promote, or to our therapeutic candidates, after they have been cleared or approved for marketing, if at all, may require new regulatory clearance or approvals, in particular, if we or our subsidiaries, collaborators and affiliates seek or are required to expand our operations to jurisdictions outside of the U.S., and, if necessitated by a problem with a marketed product, may result in the recall or suspension of marketing of the previously approved and marketed product until clearances or approvals of the modified product are obtained. The FDA and other regulatory authorities require pharmaceutical product and device manufacturers to initially make and document a determination of whether or not a modification requires a new approval, supplement or clearance. A manufacturer may determine in conformity with applicable laws, regulations, and guidelines that a modification may be implemented without pre-clearance by the FDA or other regulatory authorities. However, the FDA or other regulatory authorities can review a manufacturer’s decision and may disagree. The FDA or other regulatory authorities may also, on their own initiative, determine that a new clearance or approval is required. If the FDA or other regulatory authorities require new clearances or approvals of any pharmaceutical product for which we or our partners, including development or commercialization partners, previously received marketing approval, we or our partners, including development or commercialization partners, may be required to recall and stop marketing such marketed product, which could require us or our partners, including development or commercialization partners, to redesign the marketed product and may cause a material adverse effect on our reputation, business, financial condition or results of operations.

Risks Related to Our Industry

The development of opaganib and RHB-107 have been supported by government-funded programs and thus may be subject to federal regulations such as “march-in” rights and certain reporting requirements, and compliance with such regulations may limit our exclusive rights and our ability to contract with manufacturers. In addition, the government is under no obligation to continue to support research and development of our products and can cease such support at any time which could be irreplaceable to the research and development process of our products.

Our intellectual property rights to opaganib, which we in-licensed from Apogee Biotechnology Corporation, have been generated through the use of U.S. federal and state government funding and are therefore subject to certain federal regulations. As a result, the U.S. government may have certain rights to intellectual property embodied in opaganib pursuant to the Bayh-Dole Act of 1980, or the Bayh-Dole Act. These U.S. government rights include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. In addition, the U.S. government has the right, under certain limited circumstances, to require the licensor to grant exclusive, partially exclusive or non-exclusive licenses to any of these inventions to a third party if it determines that (i) adequate steps have not been taken to commercialize the invention, (ii) government action is necessary to meet public health or safety needs or (iii) government action is necessary to meet requirements for public use under federal regulations (also collectively referred to as “march-in rights”). The U.S. government also has the right to take title to these inventions if the licensor fails to disclose the invention to the government or fails to file an application to register the intellectual property within specified time limits. These rights of the government may affect us even though the U.S. government has not previously contacted us with respect to these intellectual property rights. Any exercise by the government of such rights could harm our competitive position, business, financial condition, results of operations and prospects. Intellectual property generated under a government-funded program is also subject to certain reporting requirements, compliance with which may require us to expend substantial resources.

In addition, the U.S. government requires that any products embodying any of these inventions or produced through the use of any of these inventions be manufactured substantially in the U.S. The manufacturing preference requirement can be waived if the owner of the intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be likely to manufacture substantially in the U.S. or that under the circumstances domestic manufacture is not commercially feasible. This preference for having products covered by such intellectual property be substantially manufactured in the U.S. may limit our ability to contract with non-U.S. product manufacturers or even U.S. product manufacturers whose manufacturing capacity is offshore.

The research and development of opaganib and RHB-107 has relied on support by the National Institutes of Health and the U.S. Department of Defense and other government bodies. These government bodies can withdraw, reduce or end their support of our products at any time, and this would significantly impair our ability to research and develop them further. In addition, the government is under no obligation to continue to support research and development of our products and can cease such support at any time which could be irreplaceable to the research and development process of our products as well as any current or future preclinical or clinical studies. For example, on January 30, 2025, we were notified that funding from the U.S. Government Department of Defense's Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) for the ongoing 300-patient Phase 2 RHB-107 arm of the ACESO PROTECT platform trial for early COVID-19 outpatient treatment is subject to termination, prior to completion. The study was terminated on April 24, 2025, due to challenges to enrollment and U.S. Government funding limitations and enrolled 92 out of the planned 300 participants. While a benefit in time to resolution of symptoms and time to viral clearance were observed regarding the efficacy of RHB-107 in this study it did not reach statistical significance.

Moreover, with the change in presidential administration that recently occurred in the United States, government spending programs have become even more difficult to predict and may be subject to greater risk. Considerable uncertainty exists regarding how future budget and program decisions will unfold, including the spending priorities of the new U.S. presidential administration and Congress and what challenges budget reductions may present for our industry generally or for our Company. In particular, U.S. President Trump recently attempted to place a widespread freeze on most federal grants and loans. Any freeze on government support for our products, programs or studies could significantly impair our research and development activities, business and operations.

The market for Talicia^®, for any product we may commercialize or promote in the future and for our therapeutic candidates is rapidly changing and competitive, and new drug delivery mechanisms, drug delivery technologies, new drugs, generic products, treatments and products which may be developed by others could impair our ability to maintain and grow our business and remain competitive.

The pharmaceutical and biotechnology industry is highly competitive, and we face significant competition from many pharmaceutical, biopharmaceutical and biotechnology companies that are researching, developing and marketing products designed to address the indications for which we are currently developing therapeutic candidates or may develop therapeutic candidates in the future or for which we may commercialize or promote products. There are various other companies that currently market, are in the process of developing or may develop in the future products that address all of the indications or diseases treated by Talicia^®, products that we may commercialize or promote in the future, and our therapeutic candidates.

New drug delivery mechanisms, drug delivery technologies, new drugs and new treatments that have been developed or that are in the process of being developed or will be developed by others may render Talicia^®, products we may commercialize or promote in the future and our therapeutic candidates noncompetitive or obsolete, or we may be unable to keep pace with technological developments or other market factors. Some of these technologies may have an entirely different approach or means of accomplishing similar therapeutic effects compared to Talicia^®, products we may commercialize or promote in the future and our therapeutic candidates. In addition, Talicia^® and products we may commercialize or promote in the future may compete with products of third parties for market share, and generic drugs or products that treat the same indications as Talicia^® or products we may commercialize or promote in the future, which can have an adverse effect on our revenues by reducing our market share or requiring us to reduce the price of the products we market.

Talicia^® primarily competes with several branded and generic therapies already approved and used extensively to treat H. pylori.

Technological competition from, and commercial capabilities of, pharmaceutical and biotechnology companies, universities, governmental entities, and others is intense and is expected to increase. Many of these entities have significantly greater research and development capabilities, human resources, and budgets than we do, as well as substantially more marketing, manufacturing, financial and managerial resources than us or our subsidiaries, collaborators and affiliates. These entities represent significant competition for us. Acquisitions of, or investments in, competing pharmaceutical or biotechnology companies by large corporations could increase such competitors’ financial, marketing, manufacturing, and other resources.

The potential widespread acceptance of therapies that are alternatives to ours may limit market acceptance of our formulations, Talicia^® or products we may commercialize or promote in the future, even if commercialized and therapeutic candidates. Many of our targeted diseases and conditions can also be treated by other medications or drug delivery technologies. These treatments may be widely accepted in medical communities and have a longer history of use, among other possible advantages. The established use of these competitive drugs may limit the potential for widespread acceptance of Talicia^®, products we may commercialize or promote in the future and our therapeutic candidates.

Talicia^® or any product for which we may obtain regulatory approval or acquire commercialization rights may not become or continue to be commercially viable products.

Other than Talicia^®, none of our therapeutic candidates have been cleared or approved for marketing, and none of our therapeutic candidates are currently being marketed or commercialized in any jurisdiction. Even if any of our therapeutic candidates or any product we may commercialize or promote receives regulatory clearance or approval, such as Talicia^®, or do not require regulatory clearance or approval, it may not become a commercially viable product. For example, even if we or our development or commercialization partners receive regulatory clearance or approval to market a therapeutic candidate or receive regulatory clearance or approval to commercialize or promote any product, the clearance or approval may be subject to limitations on the indicated uses or subject to labeling or marketing restrictions, which could materially and adversely affect their marketability and profitability. In addition, a new therapeutic candidate may appear promising at an early stage of development or after clinical trials but never reach the market, or it may reach the market but not result in sufficient product sales, if any. A therapeutic candidate or any product that we may commercialize or promote, may not result in commercial success for various reasons, including but not limited to:

Physicians, various other healthcare providers, patients, payors or the medical community, in general, may be unwilling to accept, utilize or recommend Talicia^® and any product we may commercialize or promote. If we are unable, either on our own or through third parties, to manufacture, commercialize or market Talicia^®, our proposed formulations, therapeutic candidates or any product we may commercialize or promote when planned, or to develop them commercially, we may not achieve any market acceptance or generate meaningful revenue.

The increasing use of AI and machine learning in drug discovery and development introduces new and evolving risks that could harm our business and competitive position.

AI is increasingly playing a role in our industry, being used for target identification, drug discovery, preclinical modeling, clinical operations, and data analysis, among other things. As with many new and emerging technologies, AI presents numerous risks and challenges that could adversely affect our business.

AI technologies are inherently complex and evolving. They may not function as intended, produce accurate results, or provide actionable insights. The quality of AI outputs depends heavily on the quality and quantity of input data, which in the life sciences context may be limited, biased, incomplete, or subject to regulatory and privacy constraints. If we utilize AI in the future and our AI systems fail to achieve their intended purposes, such as identifying viable therapeutic candidates or targets, predicting biological outcomes, producing reproducible results, optimizing clinical trial designs or operations, and other similar or related purposes, our product development efforts may be delayed or unsuccessful. If we are unable to successfully integrate and manage AI within our business, or if AI fails to deliver the expected benefits, our ability to develop our products or any new therapies could be materially adversely affected.

The industry in which we compete is characterized by rapid technological advancements, frequent introductions of new products and heavy competition. Even with the successful implementation of AI, we may fail to correctly identify indications and allocate resources efficiently, which could adversely impact our pipeline and ability to compete effectively. Developing, testing and deploying resource-intensive AI systems may also require additional investment and increase our costs, and there is no guarantee that our investment in such systems would lead to more effective or efficient development of our products or other investigational products, or lead to eventual regulatory approval or commercialization of any new products.

We also face increased competition from other companies that are using AI and related methods for drug discovery and development, some of which have more resources than we do and may have developed more effective methods than we and any third-party collaborators have, which may reduce our and any third-party collaborators’ effectiveness in identifying potential targets and attracting additional collaborators to work with us. If our competitors are able to utilize new technologies more effectively (including but not limited to those that may involve AI or be created using AI) to discover, develop and commercialize products that compete with any of our product candidates or potential commercial products, such technologies could adversely impact our ability to compete.

Further, AI presents additional risks and challenges, especially as the use of these technologies becomes more important to our operations over time. Generative AI may be used improperly or inappropriately which could lead to the tainting of our proprietary information and render us unable to qualify for certain patent or trade secret protection. Its use by people, including our vendors, employees, suppliers and contractors, with access to our proprietary and confidential information, including trade secrets, may continue to increase and may lead to the release of such information, which may impact our ability to realize the benefit of our intellectual property. The increasing use of AI and machine learning in drug discovery and development introduces new and evolving risks related to ownership, inventorship, and protection of intellectual property generated by or with the assistance of AI technologies. Regulatory and legal frameworks governing AI-generated inventions are still developing and may create uncertainty regarding our ability to secure and enforce rights in such inventions. Our use of generative AI platforms may lead to cybersecurity and privacy risks, which may adversely affect our operations and reputation, as well as the operations of any third-party collaborators. Emerging ethical issues surround the use of AI, and we may be subject to reputational and legal risk if our deployment or use of AI becomes controversial. Regulators could limit our, or any third-party collaborator’s ability to develop or implement AI-based technologies as part of measures taken against us or any third-party collaborators in particular or as a consequence of broader legislation, which could have an adverse effect on our or any third-party collaborator’s business, results of operations and financial condition.

Unexpected product safety or efficacy concerns may arise and cause any product we may commercialize or promote to fail to gain or lose market acceptance.

Unexpected safety or efficacy concerns can arise with respect to any product we may commercialize or promote, whether or not scientifically justified, potentially resulting in product recalls, withdrawals or declining sales, as well as product liability, consumer fraud or other claims. The market perception and reputation of any product we or our subsidiaries, collaborators and affiliates commercialize or may commercialize or promote in the future, and their safety and efficacy are important to our business and the continued acceptance of any such product. Any negative publicity about any of our current or future commercial products, such as the pricing of any product, discovery of safety issues, adverse events, or even public rumors about such events, could have a material adverse effect on our reputation, business, financial condition or results of operations. In addition, the discovery of one or more significant problems with a product similar to Talicia^® or products we may commercialize or promote in the future that implicate (or are perceived to implicate) an entire class of products or the withdrawal or recall of such similar products could have an adverse effect on the current or future commercialization of any product we may commercialize or promote. New data about Talicia^® or products that we may commercialize or promote in the future, or products similar to Talicia^® or those we may commercialize or promote in the future, could cause us reputational harm and could negatively impact demand for such products due to real or perceived side effects or uncertainty regarding safety or efficacy and, in some cases, could result in product withdrawal. Any of the foregoing could have a material adverse effect on our reputation, business, financial condition or results of operations.

We could be adversely affected if healthcare reform measures substantially change the market for medical care or healthcare coverage in the U.S.

On March 23, 2010, President Obama signed the “Patient Protection and Affordable Care Act” (P.L. 111-148) (the “ACA”) and on March 30, 2010, he signed the “Health Care and Education Reconciliation Act” (P.L. 111-152), collectively commonly referred to as the “Healthcare Reform Law.” The Healthcare Reform Law included a number of new rules regarding health insurance, the provision of healthcare, conditions to reimbursement for healthcare services provided to Medicare and Medicaid patients, and other healthcare policy reforms. Through the law-making process, substantial changes have been and continue to be made to the current system for paying for healthcare in the U.S., including changes made to extend medical benefits to certain Americans who lacked insurance coverage and to contain or reduce healthcare costs (such as by reducing or conditioning reimbursement amounts for healthcare services and drugs, and imposing additional taxes, fees, and rebate obligations on pharmaceutical and medical device companies). This legislation was one of the most comprehensive and significant reforms ever experienced by the U.S. in the healthcare industry and has significantly changed the way healthcare is financed by both governmental and private insurers. This legislation has impacted the scope of healthcare insurance and incentives for consumers and insurance companies, among others. Additionally, the Healthcare Reform Law’s provisions were designed to encourage providers to find cost savings in their clinical operations. Pharmaceuticals represent a significant portion of the cost of providing care. This environment has caused changes in the purchasing habits of consumers and providers and resulted in specific attention to the pricing negotiation, product selection and utilization review surrounding pharmaceuticals. This attention may result in Talicia^®, products we may commercialize or promote in the future, and our therapeutic candidates, being chosen less frequently or the pricing being substantially lowered. At this stage, it is difficult to estimate the full extent of the direct or indirect impact of the Healthcare Reform Law on us.

These structural changes could entail further modifications to the existing system of private payors and government programs (such as Medicare, Medicaid, and the Children’s Health Insurance Program), creation of government-sponsored healthcare insurance sources, or some combination of both, as well as other changes. Restructuring the coverage of medical care in the U.S. could impact the reimbursement for prescribed drugs and pharmaceuticals, including Talicia^®, those we and our development or commercialization partners are currently developing or those that we may commercialize or promote in the future. If reimbursement for the products we currently commercialize or promote, any product we may commercialize or promote, or approved therapeutic candidates is substantially reduced or otherwise adversely affected in the future, or rebate obligations associated with them are substantially increased, it could have a material adverse effect on our reputation, business, financial condition or results of operations.

Extending medical benefits to those who currently lack coverage will likely result in substantial costs to the U.S. federal government, which may force significant additional changes to the healthcare system in the U.S. Much of the funding for expanded healthcare coverage may be sought through cost savings. While some of these savings may come from realizing greater efficiencies in delivering care, improving the effectiveness of preventive care and enhancing the overall quality of care, much of the cost savings may come from reducing the cost of care and increased enforcement activities. Cost of care could be reduced further by decreasing the level of reimbursement for medical services or products (including Talicia^®, our development or commercialization partners or any product we may commercialize or promote, or those therapeutic candidates currently being developed by us), or by restricting coverage (and, thereby, utilization) of medical services or products. In either case, a reduction in the utilization of, or reimbursement for Talicia^®, any product we may commercialize or promote, or any therapeutic candidate, or for which we receive marketing approval in the future, could have a material adverse effect on our reputation, business, financial condition or results of operations.

Several states and private entities initially mounted legal challenges to the Healthcare Reform Law, in particular, the ACA, and they continue to litigate various aspects of the legislation. On June 28, 2012, the U.S. Supreme Court generally upheld the provisions of the ACA at issue as constitutional. However, the U.S. Supreme Court held that the legislation improperly required the states to expand their Medicaid programs to cover more individuals. As a result, states have a choice as to whether they will expand the number of individuals covered by their respective state Medicaid programs. Some states have not expanded their Medicaid programs and have chosen to develop other cost-saving and coverage measures to provide care to currently uninsured individuals. Many of these efforts to date have included the institution of Medicaid-managed care programs. The manner in which these cost-saving and coverage measures are implemented could have a material adverse effect on our reputation, business, financial condition or results of operations.

Further, the healthcare regulatory environment has seen significant changes in recent years and is still in flux. Legislative initiatives to modify, limit, replace, or repeal the ACA and judicial challenges have continued. We cannot predict the impact on our business of future legislative and legal challenges to the ACA or other aspects of the Healthcare Reform Law or other changes to the current laws and regulations. The financial impact of U.S. healthcare reform legislation over the next few years will depend on a number of factors, including the policies reflected in implementing regulations and guidance and changes in sales volumes for therapeutics affected by the legislation. From time to time, legislation is drafted, introduced and passed in the U.S. Congress that could significantly change the statutory provisions governing coverage, reimbursement, and marketing of pharmaceutical products. In addition, third-party payor coverage and reimbursement policies are often revised or interpreted in ways that may significantly affect our business and our products.

During his first term in office, President Trump supported the repeal of all or portions of the ACA. President Trump also issued an executive order in which he stated that it is his administration’s policy to seek the prompt repeal of the ACA and in which he directed executive departments and federal agencies to waive, defer, grant exemptions from, or delay the implementation of the provisions of the ACA to the maximum extent permitted by law. Congress has enacted legislation that repeals certain portions of the ACA, including but not limited to the Tax Cuts and Jobs Act, passed in December 2017, which included a provision that eliminates the penalty under the ACA’s individual mandate, effective January 1, 2019, as well as the Bipartisan Budget Act of 2018, passed in February 2018, which, among other things, repealed the Independent Payment Advisory Board (which was established by the ACA and was intended to reduce the rate of growth in Medicare spending).

Additionally, in December 2018, a district court in Texas held that the individual mandate is unconstitutional and that the rest of the ACA is, therefore, invalid. On appeal, the Fifth Circuit Court of Appeals affirmed the holding on the individual mandate but remanded the case back to the lower court to reassess whether and how such holding affects the validity of the rest of the ACA. The Fifth Circuit’s decision on the individual mandate was appealed to the U.S. Supreme Court. On June 17, 2021, the Supreme Court held that the plaintiffs (comprised of the state of Texas, as well as numerous other states and certain individuals) did not have standing to challenge the constitutionality of the ACA’s individual mandate and, accordingly, vacated the Fifth Circuit’s decision and instructed the district court to dismiss the case. As a result, the ACA will remain in-effect in its current form for the foreseeable future; however, we cannot predict what additional challenges may arise in the future, the outcome thereof, or the impact any such actions may have on our business.

The Biden administration also introduced various measures in 2021 focusing on healthcare and drug pricing, in particular. For example, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace, which began on February 15, 2021, and remained open through August 15, 2021. The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. On the legislative front, the American Rescue Plan Act of 2021 was signed into law on March 11, 2021, which, in relevant part, eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source drugs and innovator multiple source drugs, which began on January 1, 2024. And, in July 2021, the Biden administration released an executive order entitled, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In response, on September 9, 2021, HHS released a “Comprehensive Plan for Addressing High Drug Prices” that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.  On August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”) was signed into law. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (which was first due in 2023), and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025). The IRA also authorizes HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. Further, on July 4, 2025, President Trump signed the One Big Beautiful Bill Act into law which, among other things, is expected to reduce funding to federal healthcare programs, imposes additional requirements to be eligible for healthcare, and clarifies exclusions for orphan drugs under IRA’s Drug Price Negotiation Program. We cannot yet assess the impact that the IRA will have on us or the pharmaceutical industry as a whole, but it will likely be significant.

More recently, the current Trump Administration is also pursuing policies intended to, among other things, reduce regulations and expenditures across government, lower prescription drug prices, and enhance drug price transparency. These actions, including those directed by executive orders, may propose policy changes that create additional uncertainty for our business. For example, on April 15, 2025, the Trump Administration released an executive order entitled, “Lower Drug Prices by Once Again Putting Americans First,” which among other things, included multiple directives to various agencies aimed at lowering prescription drug prices. In May 2025, the Trump Administration released two executive orders aimed to promote domestic production of critical medicines and to establish a most-favored-nation (“MFN”) drug pricing policy that would tie U.S. drug prices to the prices paid for drugs in other countries. On September 9, 2025, the Make America Healthy Again (MAHA) Commission issued a Strategy Report that included proposed policy reforms across multiple government agencies, including measures to increase enforcement related to direct‑to‑consumer pharmaceutical advertising. On November 6, 2025, CMS announced a new voluntary payment initiative called the GENEROUS Model (GENErating cost Reductions for U.S. Medicaid Model) where drug manufacturers may voluntarily offer supplemental rebates to participating state Medicaid programs that are intended to provide such Medicaid programs with an MFN price for participating manufacturers’ products. On December 23, 2025, CMS published two proposed rules that would incorporate MFN pricing principles into federal reimbursement for prescription drugs. The first proposal, the GLOBE Model (Global Benchmark for Efficient Drug Pricing Model) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility criteria. The second proposal, the GUARD Model (Guarding U.S. Medicare Against Rising Drug Costs) for Medicare Part D, would similarly mandate manufacturer rebates for qualifying sole source drugs where the Medicare net price exceeds an MFN benchmark derived from international reference pricing methodologies. On January 15, 2026, the Trump Administration called on Congress to enact the “The Great Healthcare Plan” to, among other things, codify and expand MFN pricing, lower government subsidies to private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase, and enact restrictions on pharmacy benefit managers. On February 5, 2026, the Trump Administration launched the TrumpRx platform designed to allow consumers to purchase certain drugs at reduced prices as negotiated between the drug manufacturers and the Trump Administration. These actions and policies may significantly reduce drug prices, potentially impacting manufacturers’ drug pricing strategies and profitability, while increasing operational costs and compliance risks, and the scope, timing, and ultimate impact of these initiatives and any related future regulatory or legislative actions remain uncertain.

There is uncertainty as to what healthcare programs and regulations may be implemented or changed at the federal and/or state level in the U.S. or the effect of any future legislation or regulation may have on us, which uncertainty is even greater given the new Trump Administration’s recent initiatives. Furthermore, we cannot predict what actions the Trump administration will implement in connection with the Health Reform Law during President Trump’s second term. However, it is possible that any such initiatives could have an adverse effect on our ability to obtain approval and/or successfully commercialize products in the U.S. in the future. For example, any changes that reduce, or impede the ability to obtain, reimbursement for the type of products we currently, or intend to, commercialize in the U.S. or that reduce medical procedure volumes could adversely affect our operations and/or future business plans.

Third-party payors may not adequately reimburse customers for any of our products that we may commercialize or promote, including Talicia^®, and may impose coverage restrictions or limitations such as prior authorizations and step edits that affect their use.

Our revenues and profits depend heavily upon the availability of adequate reimbursement for the use of Talicia^®, and any products that we may commercialize or promote, from governmental or other third-party payors, both in the U.S. and in foreign markets. Reimbursement by a third-party payor may depend upon a number of factors, including, but not limited to, the third-party payor’s determination that the use of an approved or cleared therapeutic candidate or product is:

Obtaining reimbursement approval for a product that we may commercialize or promote, including Talicia^®, from any government, commercial or other third-party payor is a time-consuming and costly process that could require us or our development or commercialization partners to provide supporting scientific, clinical and cost-effectiveness data for the use of our products that we currently, or may, commercialize or promote to each payor. Even when a payor determines that a product that we currently or may commercialize or promote is eligible for reimbursement under its criteria, the payor may impose coverage limitations that preclude payment for some uses that are approved by the FDA or other foreign regulatory authorities, or may impose restrictions, such as prior authorization requirements, or may simply deny coverage altogether. Reimbursement rates may vary according to the use of the product that we subsidiaries, collaborators and affiliates commercialize or may commercialize or promote in the future and the clinical setting in which it is used, may be based on payments allowed for lower-cost products that are already reimbursed, may be incorporated into existing payments for products or services, and may reflect budgetary constraints or imperfections in Medicare, Medicaid or other data used to calculate these rates. In particular, reimbursement for our products may not be available from Medicare or Medicaid, and reimbursement from other third-party payors may be limited, reduced or revoked. Overall, our ability to get reimbursement coverage for our commercial products has historically been limited. Successful commercialization of Talicia^® and any future commercial products requires a conducive reimbursement environment. If our products do not receive adequate reimbursement coverage, or if reimbursement coverage is reduced or otherwise adversely affected, then their respective commercial prospects could be severely limited. Although certain payors may currently provide some form of coverage for Talicia^®, payors may suspend or discontinue reimbursement at any time, may require or increase co-payments from patients, may impose restrictions or limitations on coverage, or may reduce reimbursement rates for our products. If we fail to establish broad adoption of and reimbursement for Talicia^® and any future commercial products, or if we are unable to maintain any existing reimbursement from payors, our ability to generate revenue could be harmed and this could have a material adverse effect on our reputation, business, financial condition or results of operations. In addition to our existing commercial products, any new product we may commercialize or promote in the future may require that we expend substantial time and resources in order to obtain and retain reimbursement, and any of these efforts may not be successful.

In the U.S., there have been, and we expect that there will continue to be, federal and state proposals to constrain expenditures for medical products and services, which may affect payments for any product that we currently or may commercialize or promote in the U.S. In addition, there is a growing emphasis on comparative effectiveness research, both by private payors and by government agencies. To the extent other drugs or therapies are found to be more effective than

our products, payors may elect to cover such therapies in lieu of our products or reimburse our products at a lower rate. Legislation that reduces reimbursement for our current or future commercial products could adversely impact how much or under what circumstances healthcare providers will prescribe or administer those products. This could materially and adversely impact our reputation, business, financial condition or results of operations by reducing our ability to continue to generate meaningful revenue, raise capital, obtain additional collaborators and market share. At this stage, we are unable to estimate the extent of the direct or indirect impact of any such federal and state proposals.

Furthermore, the Centers for Medicare and Medicaid Services frequently change product descriptors, coverage policies, product and service codes, payment methodologies and reimbursement values. Third-party payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates, and both the Centers for Medicare and Medicaid Services and other third-party payors may have sufficient market power to demand significant price reductions. Price reductions or other significant coverage policies or payment limitations could materially and adversely affect our reputation, business, financial condition or results of operations.

We are subject to U.S. federal and state healthcare laws and regulations relating to our business, and our failure to comply with such laws could have a material adverse effect on our reputation, business, financial condition or results of operations.

We are subject to additional healthcare regulation and enforcement by the U.S. federal government and the states in which we conduct or will conduct our business. Healthcare providers, physicians, and third-party payors play a primary role in the recommendation and prescription of Talicia^® or any products we may commercialize or promote in the future. Our arrangements with our subsidiaries, collaborators, or affiliates, third-party payors, customers, employees, or others may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell, and distribute our products. The laws that may affect our ability to operate include, but are not limited to, the following:

Compliance efforts may involve substantial costs, and if our, or our subsidiaries', collaborators', or affiliates', operations or business arrangements with third parties are found to be in violation of any such requirements, we may be subject to penalties, including civil or criminal penalties, monetary damages, the curtailment or restructuring of our operations, or exclusion from participation in government contracting, healthcare reimbursement or other government programs, including Medicare and Medicaid, any of which could adversely affect our financial results. Although effective compliance programs can help mitigate the risk of investigation and prosecution for violations of these laws, these risks cannot be entirely eliminated. Any violation of these laws, or any action against us for violation of these laws, even if we successfully defend against it, could result in a material adverse effect on our reputation, business, financial condition or results of operations.

The Healthcare Reform Law also imposes reporting requirements on certain medical device and pharmaceutical manufacturers, among others, to make annual public disclosures of certain payments and other transfers of value to physicians (and certain other healthcare providers) and teaching hospitals and ownership or investment interests held by physicians or their immediate family members. Failure to submit required information may result in civil monetary penalties for all payments, transfers of value or ownership or investment interests that are not reported. In addition, there has been a recent trend of increased federal and state regulation of payments made to physicians for marketing, medical directorships, and other purposes. Some states impose a legal obligation on companies to adhere to voluntary industry codes of behavior (e.g., the PhRMA Code and the AdvaMed Code of Ethics), which apply to pharmaceutical and medical device companies’ interactions with healthcare providers; some mandate implementation of corporate compliance programs, along with the tracking and reporting of gifts, compensation and other remuneration to physicians, and some states limit or prohibit such gifts.

Most recently, there has been heightened governmental scrutiny over the manner in which drug manufacturers set and disclose prices for their marketed products, which has resulted in the enactment (or proposal) of federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products. For example, the Trump Administration has proposed and is pursuing policies intended to, among other things, reduce regulations and expenditures across government, lower prescription drug prices, and enhance drug price transparency. Additionally, several states have passed or introduced bills designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

The scope and enforcement of these laws are uncertain and subject to change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and guidance. We cannot predict the impact that new legislation or any changes in existing legislation will have on our reputation, business, financial condition, or results of operations. Federal or state regulatory authorities may challenge our, or our subsidiaries’, collaborators’, or affiliates’, current or future activities under these laws. Any such challenge could have a material adverse effect on our reputation, business, financial condition or results of operations. Any state or federal regulatory review of us, regardless of the outcome, would be costly and time-consuming and could negatively and adversely affect our business or results of operations.

Our marketing, promotional and business practices  and those of our subsidiaries, collaborators and affiliates, including with respect to pricing, as well as the manner in which sales forces interact with purchasers, prescribers and patients, are subject to extensive regulation, including but not limited to, state and federal anti-kickback laws and any material failure to comply could result in significant sanctions against us.

The marketing, promotional, and business practices, including with respect to pricing, of pharmaceutical companies, as well as the manner in which companies’ in-house or third-party sales forces interact with purchasers, prescribers, and patients, are subject to extensive regulation, the enforcement of which may result in the imposition of civil or criminal penalties, injunctions, or limitations on marketing practices for some of our products or pricing restrictions or mandated price reductions for some of our products. Many companies have been the subject of claims related to these practices asserted by state or federal authorities. These claims have resulted in fines and other consequences, such as entering into corporate integrity agreements with the U.S. government. Companies may not promote drugs for “off-label” use, that is, uses that are not described in the product’s labeling and that differ from those approved by the FDA or other applicable regulatory agencies. A company that is found to have improperly promoted drug products for off-label use may be subject to significant liability, including civil and administrative remedies, as well as criminal sanctions. In addition, enforcement action against us or any of our current or future commercialization partners could cause management’s attention to be diverted from our business operations and damage our reputation.

We and our subsidiaries, collaborators and affiliates could be exposed to significant drug product liability claims which could be time-consuming and costly to defend, divert management attention and adversely impact our ability to obtain and maintain insurance coverage.

The clinical trials that we conduct and the testing, manufacturing, marketing and commercial sale and use or misuse of our therapeutic candidates and any products we or our subsidiaries, collaborators and affiliates may commercialize or promote, involve and will involve an inherent risk that significant liability claims may be asserted against us or our development or commercial partners. Product liability claims, or other claims related to our therapeutic candidates and any products we or our subsidiaries, collaborators and affiliates  may commercialize or promote, regardless of merit or their outcome, could require us to spend significant time and money in litigation or to pay significant settlement amounts or judgments. A product liability claim could also significantly harm our reputation and the market price of our shares and decrease demand for Talicia^®, products that we or our subsidiaries, collaborators and affiliates commercialize or promote or that are commercialized or promoted by our commercial partners, and delay market acceptance of our therapeutic candidates or products we may commercialize or promote. In addition, regardless of merit or eventual outcome, product liability claims may result in:

We and our research and development or commercialization partners currently have product-liability policies that include coverage for our clinical trials and our commercial operations. However, our insurance may prove inadequate to cover claims or litigation costs, especially in the case of wrongful death claims. Any successful product liability or other claim may prevent us from obtaining adequate liability insurance in the future on commercially desirable or reasonable terms. An inability to obtain sufficient insurance coverage at an acceptable cost or otherwise to protect against potential product liability claims could prevent or inhibit the commercialization of Talicia^® or products we may commercialize or promote in the future, or the development of our therapeutic candidates.

Our clinical trials may indicate unexpected serious adverse events or other adverse events or undesirable side effects that may harm our reputation, business, financial condition or results of operations. Serious adverse events identified during one of our Expanded Access Programs (EAPs) may present additional risks that may adversely affect our development of the therapeutic candidates involved in the applicable EAP.

As is the case with pharmaceuticals generally, certain side effects and adverse events may emerge as safety risks associated with the use of our therapeutic candidates. Similarly, serious adverse events have occurred and may occur in the future in connection with our clinical trials. Results of our clinical trials could reveal a high and unacceptable severity and prevalence of side effects or unexpected characteristics. Undesirable side effects caused by our therapeutic candidates could cause us or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or comparable foreign regulatory authorities. The drug-related side effects could affect patient recruitment or the ability of enrolled patients to complete the trial or result in potential product liability claims. Any of these occurrences may have a material adverse effect on our reputation, business, financial condition or results of operations.

Patients who receive access to investigational new drugs that have not yet received regulatory marketing approval through expanded access programs may be suffering from life-threatening illnesses and poor prognosis and may have exhausted all other available therapies. The risk for serious adverse events in this patient population is high, which could have a negative impact on the prospects of our therapeutic candidates that are provided under the EAP.

Serious adverse events or other undesirable side effects in connection with the use of our therapeutic candidates provided under the EAP could cause significant delays or an inability to successfully develop or commercialize such therapeutic candidates, which could materially harm our business. In particular, any such serious adverse events or other undesirable side effects could cause us or regulatory authorities to interrupt, delay or halt non-clinical studies and clinical trials, or could make it more difficult for us to enroll patients in our clinical trials. If serious adverse events or other undesirable side effects, or unexpected characteristics of our investigational new drugs that have not yet received regulatory marketing approval are observed in patients who were granted expanded access to our investigational new drugs under the EAP, further clinical development of such therapeutic candidate may be delayed or we may not be able to continue development of such therapeutic candidates at all, and the occurrence of these events could have a material adverse effect on our business. Undesirable side effects caused by our therapeutic candidates could also result in the delay or denial of regulatory approval by the FDA or other regulatory authorities or in a more restrictive label than we expect and could cause us to incur additional costs.

Global economic conditions may make it more difficult for us to commercialize Talicia^® and any products that we may commercialize or promote in the future and develop our therapeutic candidates.

The pharmaceutical industry, like other industries and businesses, continues to face the effects of the challenging economic environment. Patients experiencing the effects of the challenging economic environment, including increases in co-pays, may switch to generic products, delay treatments, skip doses or use other less effective treatments to reduce their costs. Challenging economic conditions in the U.S. include the demands by payors for substantial rebates and formulary restrictions limiting access to brand-name drugs. In addition, in Europe and in a number of emerging markets there are government-mandated reductions in prices for certain pharmaceutical products, as well as government-imposed access restrictions in certain countries. All of the aforesaid may make it more difficult for us to commercialize Talicia^®, any products that we may commercialize or promote, and our therapeutic candidates, upon approval, if any.

Tariff policies and potential countermeasures could increase our costs and disrupt our supply chain, which could negatively impact the results of our operations.

U.S. President Trump has increased, and has indicated his willingness to continue to increase, the use of tariffs by the U.S. to accomplish certain U.S. policy goals. Such tariffs and any countermeasures, including any refunds granted following the Supreme Court of the United States’ decision invalidating certain tariffs, could increase the cost of raw materials and components necessary for our operations, disrupt our supply chain and create additional operational challenges. Further, it is possible that government policy changes and related uncertainty about policy changes could increase market volatility. Because of these dynamics, we cannot predict the impact of any future changes to the U.S.’s or other countries’ trading

relationships or the impact of new laws or regulations adopted by the U.S. or other countries on our business. Such changes in tariffs and trade regulations could have a material adverse effect on our financial condition, results of operations and cash flows.

Our business involves risks related to handling regulated substances, which could severely affect our ability to commercialize Talicia^® and any products that we may commercialize or promote in the future and to conduct research and development of our therapeutic candidates.

In connection with our or our development or commercialization partners’ research and development activities, as well as the manufacture of commercial products, materials, and therapeutic candidates and any products that we may commercialize or promote in the future, we and our development or commercialization partners are subject to federal, state and local laws, rules, regulations and policies governing the use, generation, manufacture, storage, air emission, effluent discharge, handling and disposal of certain materials, biological specimens and waste. We and our research and development or commercialization partners may be required to incur significant costs to comply with environmental and health and safety regulations in the future. Our research and development, as well as the activities of our commercial and clinical manufacturing and commercialization partners, both now and in the future, may involve the controlled use of hazardous materials, including, but not limited to, certain hazardous chemicals. We cannot completely eliminate the risk of accidental contamination or injury from these materials. In the event of such an occurrence, we could be held liable for any damages that could result and any such liability could exceed our resources.

Security breaches, loss of data, and other disruptions could compromise sensitive information and expose us to liability, which would cause our business and reputation to suffer.

In the ordinary course of our business, we may collect and store sensitive data, including intellectual property, compliance-related data, research data, our proprietary business information and that of our suppliers and business partners, technical information about our products, clinical trial plans as well as personally identifiable information of patients, clinical trial participants and employees. We also have outsourced elements of our information technology structure, and as a result, we are managing independent vendor relationships with third parties who may or could have access to our confidential information. Similarly, our business partners and other third-party providers possess certain of our sensitive data and confidential information. The secure maintenance of this information is critical to our operations and business strategy. Despite the implementation of security measures, our internal computer systems, and those of third parties on which we rely, are vulnerable to damage from computer viruses, malware, ransomware, cyber-fraud, natural disasters, terrorism, war, telecommunication and electrical failures, cyber-attacks or cyber-intrusions over the Internet, attachments to emails, persons inside our organization, or persons with access to systems inside our organization. The risk of a security breach or disruption, particularly through cyber-attacks or cyber-intrusion, including by computer hackers, foreign governments, and cyber-terrorists, has generally increased as the number, intensity and sophistication of attempted attacks and intrusions from around the world have increased.

We, our partners, vendors, and other third-party providers could be susceptible to attacks on our and their information security systems, which attacks are of ever-increasing levels of sophistication and are made by groups and individuals with a wide range of motives and expertise, including criminal groups. Any such breach could compromise our and their networks and the information stored there could be accessed, publicly disclosed, lost or stolen. Any such access, inappropriate disclosure of confidential or proprietary information or other loss of information, including our data being breached at third-party providers, could result in legal claims or proceedings, liability or financial loss under laws that protect the privacy of personal information, disrupt our operations, or our product development programs and damage our reputation, any of which could adversely affect our business. For example, the loss of clinical trial data from completed or ongoing or planned clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.

We are highly dependent on information technology networks and systems, including the Internet, to securely process, transmit and store this critical information. Security breaches of this infrastructure, including physical or electronic break-ins, computer viruses, attacks by hackers and similar breaches, can create system disruptions, shutdowns or unauthorized disclosure or modification of confidential information. The secure processing, storage, maintenance and transmission of this critical information is vital to our operations and business strategy, and we devote significant resources to protecting

such information. Although we take measures to protect sensitive information from unauthorized access or disclosure, our information technology and infrastructure may be vulnerable to attacks by hackers or viruses or breached due to employee error, malfeasance or other disruptions.

A security breach or privacy violation that leads to disclosure or modification of or prevents access to consumer information (including personally identifiable information or protected health information) could harm our reputation, compel us to comply with disparate state breach notification laws, require us to verify the correctness of database contents and otherwise subject us to liability under laws that protect personal data, resulting in increased costs or loss of revenue. If we are unable to prevent such security breaches or privacy violations or implement satisfactory remedial measures, our operations could be disrupted, and we may suffer a loss of reputation, financial loss, and other regulatory penalties because of lost or misappropriated information, including sensitive consumer data. In addition, these breaches and other inappropriate access can be difficult to detect, and any delay in identifying them may lead to increased harm of the type described above.

Any such breach or interruption could compromise our networks, and the information stored there could be inaccessible or could be accessed by unauthorized parties, publicly disclosed, lost or stolen. Any such interruption in access, improper access, disclosure or other loss of information could result in legal claims or proceedings, liability under laws that protect the privacy of personal information, such as HIPAA and the General Data Protection Regulation (GDPR), and regulatory penalties. Unauthorized access, loss or dissemination could also disrupt our operations, including our ability to perform tests, provide test results, bill facilities or patients, process claims and appeals, provide customer assistance services, conduct research and development activities, collect, process and prepare Company financial information, provide information about our current and future solutions and other patient and clinician education and outreach efforts through our websites, and manage the administrative aspects of our business and damage our reputation, any of which could adversely affect our reputation, business, financial condition or results of operations. Any such breach could also result in the compromise of our trade secrets and other proprietary information, which could adversely affect our competitive position.

In addition, the interpretation and application of consumer, health-related, privacy and data protection laws in the U.S. and elsewhere are often uncertain, contradictory, and in flux. It is possible that these laws may be interpreted and applied in a manner that is inconsistent with our practices. If so, this could result in government-imposed fines or orders requiring that we change our practices, which could adversely affect our reputation, business, financial condition or results of operations. Complying with these various laws could cause us to incur substantial costs or require us to change our business practices and compliance procedures in a manner adverse to our business.

Risks Related to Intellectual Property

We may be unable to adequately protect or enforce our rights to intellectual property, causing us to lose valuable rights. Loss of patent rights may lead us to lose market share and anticipated profits.

Our success depends, in part, on our ability, and the ability of our commercialization or development partners to obtain patent protection for our therapeutic candidates and any products that we may commercialize or promote, maintain the confidentiality of our trade secrets and know-how, operate without infringing or violating on the proprietary rights of others and prevent others from infringing or violating on our proprietary rights.

We try to protect our proprietary position by, among other things, filing U.S., European, and other patent applications related to our therapeutic candidates, inventions and improvements that may be important to the continuing development of Talicia^® and any future commercial products and therapeutic candidates, and we plan to try to do the same with products we may acquire, commercialize or promote in the future, where this is possible.

Because the patent position of pharmaceutical companies involves complex legal and factual questions, we cannot predict the scope, validity or enforceability of patents with certainty. Our issued patents and the issued patents of our commercialization or development partners may not provide us with any competitive advantages, may be held invalid or unenforceable as a result of legal challenges by third parties or could be circumvented. Ownership of the patent rights we in-license from our commercialization or development partners or the patent rights to the products already approved for

marketing that we develop, acquire or for which we acquire commercialization rights may be challenged, and as a result, the rights we in-license and the rights to products we acquire may turn out not to be exclusive or we may not actually have rights under the patents despite receiving representations from a commercialization or development partner. Our competitors may also independently develop drug delivery technologies or products similar to ours or design around or otherwise circumvent patents issued to, or licensed by, us. Thus, any patents that we own or license from others may not provide any protection against competitors. Our pending patent applications, those we may file in the future or those we may license from third parties may not result in patents being issued. If these patents are issued, they may not provide us with proprietary protection or competitive advantages. The degree of future protection to be afforded by our proprietary rights is uncertain because legal means afford only limited protection and may not adequately protect our rights or permit us to gain or keep our competitive advantage.

In the U.S., Europe, and other jurisdictions, patent applications are typically not published until 18 months after filing. In addition, many companies and universities do not publish their discoveries until after patent filings are made. This makes it difficult to be certain that we were the first to file for protection of the inventions or the first to invent the inventions. As a result, we may not be able to obtain or maintain protection for certain inventions. Therefore, the enforceability and scope of our patents and patent applications in the U.S., Europe, and other jurisdictions are uncertain and unpredictable. Any patents that we own may not provide sufficient protection against competitors and may be of insufficient scope to achieve our business objectives. Additionally, the patent filings of others might act as an impediment to our ability to commercialize our current or future commercial products.

Patent rights are territorial; thus, the patent protection we do have will only extend to those countries in which we have issued patents. Even so, the laws of certain countries do not protect our intellectual property rights to the same extent as do the laws of the U.S. and the European Union. Competitors may successfully challenge our patents, produce similar drugs or products that do not infringe our patents or produce drugs in countries where we have not applied for patent protection or that do not respect our patents. Furthermore, it is not possible to know the scope of claims that will be allowed in published applications, and it is also not possible to know which claims of granted patents, if any, will be deemed enforceable in a court of law.

In some cases, litigation may be necessary to enforce our patent rights. If we choose to take an infringing third party to court, the third party may challenge the validity or enforceability of our patent rights or may assert that their activities do not infringe our patents. Litigation is expensive and unpredictable, and we may not have the proper resources to pursue such litigation or to protect our patent rights. Moreover, there is the risk that the court will find that our patents are not valid or enforceable, or that the third party does not infringe our rights in these patents. Adverse results in any such litigation could materially impair our patent rights and our ability to prevent generic and other competition for our products. Such results might also materially affect our economics and our ability to require third parties to enter a license with us or to pay us a reasonable royalty for using our technology.

Changes in patent law and regulations in other countries or jurisdictions or changes in governmental bodies that enforce them or changes in how the relevant governmental authority enforces patent laws or regulations may weaken our ability to obtain new patents or to enforce patents that we have licensed or that we may obtain in the future. For example, since June 1, 2023, European applications and patents may be subjected to the jurisdiction of the Unified Patent Court (UPC) for a single pan-European infringement action or revocation proceeding. European applications will for now have the option in certain circumstances, upon grant of a patent, of becoming a Unitary Patent that will be subject to the jurisdiction of the UPC. This is a significant change in European patent practice. As the UPC is a relatively new court system with few decisions rendered, there is little precedent for parties to rely on at the court, increasing the uncertainty. The UPC may provide our competitors with a new forum to seek to centrally revoke our European patents if we do not opt our patents out of the UPC where permitted, and allows for the possibility of a competitor to obtain pan-European injunctions with their own UPC-designated European patents. As a single court system can invalidate a European patent, we, where applicable, may opt out of the UPC and as such, each European patent would then need to be challenged in each individual country and each infringement action pursued in each country. We cannot predict how future decisions by any courts, or the United States Congress, or the USPTO, may impact the value of our patents. Any similar adverse change in the patent laws of other jurisdictions could also adversely affect our business, financial condition, results of operations, and prospects.

After the completion of the development and registration of our patents, third parties may still manufacture or market products in infringement of our patent-protected rights. Such manufacture or market of products in infringement of our patent-protected rights is likely to cause us damage and lead to a reduction in the prices of Talicia^®, any product we may commercialize or promote, or any of our therapeutic candidates, thereby reducing our potential profits.

While patent term extensions under the Hatch-Waxman Act in the United States and under supplementary protection certificates in Europe may be available to extend the patent exclusivity term for our drug product candidates, we cannot provide any assurances that any such patent term extension will be obtained and, if so, for how long. In addition, upon issuance in the United States any patent term can be adjusted based on certain delays caused by the applicant(s) or the U.S. Patent and Trademark Office, or USPTO. For example, a patent term can be reduced based on certain delays caused by the patent applicant during patent prosecution.

In addition, due to the extensive time needed to develop, test and obtain regulatory approval for our therapeutic candidates or any product we may commercialize or promote, any patents that protect our therapeutic candidate or any product we may commercialize or promote may expire early during commercialization. This may reduce or eliminate any market advantages that such patents may give us. Following patent expiration, we may face increased competition through the entry of generic products into the market and a subsequent decline in market share and profits.

In addition, in some cases, we may rely on our licensors to conduct patent and trademark prosecution, patent and trademark maintenance or patent and trademark enforcement or defense on our behalf. Therefore, our ability to ensure that these patents and trademarks are properly prosecuted, maintained, enforced, or defended may be limited, which may adversely affect our rights in the commercialization of Talicia^® and any future commercial products, development of our therapeutic candidates, and potential approval for marketing of our therapeutic products. Any failure by our licensors or commercialization or development partners to properly conduct patent and trademark prosecution, patent and trademark maintenance, patent and trademark enforcement, or patent defense could materially harm our ability to obtain suitable patent protection covering Talicia^® and any future commercial products or therapeutic candidates or ensure freedom to commercialize the products in view of third-party patent rights, thereby materially reducing our potential profits.

If we are unable to protect the confidentiality of our inventions, trade secrets or know-how, such proprietary information may be used by others to compete against us.

In addition to filing patents, we generally try to protect our inventions, trade secrets, know-how, and technology by entering into confidentiality or non-disclosure agreements with parties that have access to them, such as our development or commercialization partners, employees, contractors, and consultants. We also enter into agreements that purport to require the disclosure and assignment to us of the rights to the ideas, developments, discoveries and inventions of our employees, advisors, research collaborators, contractors and consultants while we employ or engage them. However, these agreements can be difficult and costly to enforce or may not provide adequate remedies. Any of these parties may breach the confidentiality agreements and willfully or unintentionally disclose our confidential information, or our competitors might learn of the information in some other way. The disclosure to, or independent development by, a competitor of any trade secret, know-how or other technology not protected by a patent could materially adversely affect any competitive advantage we may have over any such competitor.

To the extent that any of our employees, advisors, research collaborators, contractors or consultants independently develop, or use independently developed, intellectual property in connection with any of our projects, disputes may arise as to the proprietary rights to this type of information. If a dispute arises with respect to any proprietary right, enforcement of our rights can be costly and unpredictable, and a court may determine that the right belongs to a third party.

Legal proceedings or third-party claims of intellectual property infringement and other challenges may require us to spend substantial time and money and could prevent us from developing or commercializing Talicia^® and any future commercial products and our therapeutic candidates.

The development, manufacture, use, offer for sale, sale or importation of Talicia^® and any future commercial products or any of our therapeutic candidates may infringe on the claims of third-party patents or other intellectual property rights. Patentability, invalidity, freedom-to-operate or other opinions may be required to determine the scope and validity of third-

party proprietary rights. The nature of claims contained in unpublished patent filings around the world is unknown to us and it is not possible to know which countries patent holders may choose for an extension of their filings under the Patent Cooperation Treaty or other mechanisms. We may also be subject to claims based on the actions of employees and consultants with respect to the usage or disclosure of intellectual property learned at other employers. The cost to us of any intellectual property litigation or other infringement proceeding, even if resolved in our favor, could be substantial. Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively because of their substantially greater financial resources. Uncertainties resulting from the initiation and continuation or defense of intellectual property litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace. Intellectual property litigation and other proceedings may also absorb significant management time. Consequently, we are unable to guarantee that we will be able to manufacture, use, offer for sale, sell or import Talicia^® and any future commercial products or of our therapeutic candidates in the event of an infringement action.

In the event of patent infringement claims, or to avoid potential claims, we may choose or be required to seek a license from a third party and would most likely be required to pay license fees or royalties or both. These licenses may not be available on acceptable terms, or at all. Even if we were able to obtain a license, the rights may be non-exclusive, which could potentially limit our competitive advantage. Ultimately, we could be prevented from commercializing a therapeutic candidate and any products that we may commercialize or promote or be forced to cease some aspect of our business operations if, as a result of actual or threatened patent infringement or other claims, we are unable to enter into licenses on acceptable terms. This inability to enter into licenses or the ability to exclude others using proprietary rights could have a material adverse effect on our reputation, business, financial condition or results of operations.

We may be subject to other patent-related litigation or proceedings that could be costly to defend and uncertain in their outcome.

In addition to infringement claims against us, we may become a party to other patent litigation or proceedings before regulatory agencies, including post-grant review, inter parties review, interference or re-examination proceedings filed with the U.S. Patent and Trademark Office or opposition proceedings in other foreign patent offices regarding intellectual property rights with respect to our therapeutic candidates or any products that we may commercialize or promote, as well as other disputes regarding intellectual property rights with development or commercialization partners, or others with whom we have contractual or other business relationships. Post-issuance proceedings challenging patent claims validity are not uncommon, and we or our development or commercialization partners will be required to defend these procedures as a matter of course. Such procedures may be costly, and there is a risk that we may not prevail, which could harm our business significantly.

Risks Related to the ADSs

Our failure to regain and maintain compliance with Nasdaq’s continued listing requirements could result in the delisting of the ADSs.

The ADSs are currently listed for trading on Nasdaq. We must satisfy Nasdaq’s continued listing requirements, including, among other things, a minimum bid price requirement of $1.00 per ADS and a minimum shareholders’ equity of $2.5 million, or risk delisting, which would have a material adverse effect on our business.

On April 8, 2026, we received a letter from the Listings Qualifications Department of Nasdaq notifying us that, for a period of thirty consecutive business days prior to April 2, 2026, the bid price for the ADSs had closed below the minimum $1.00 per ADS requirement for continued listing on The Nasdaq Capital Market under Nasdaq Listing Rule 5550(a)(2) (“Minimum Price Rule”). In accordance with Nasdaq Listing Rule 5810(c)(2)(B), we have been provided an initial period of 180 calendar days, or until October 5, 2026, to regain compliance. The letter states that the Nasdaq staff will provide written notification that we have achieved compliance with Rule 5550(a)(2), if at any time during the 180-day period, the bid price of the ADSs closes at least as $1.00 per share or more for a minimum of ten consecutive business days.

If we are not compliant with the minimum bid price requirement at the end of the 180-day cure period, we may be eligible for an additional 180-calendar day extension. To be eligible for the second 180-day period, we would be required to meet the continued listing requirement for market value of publicly held shares and all other initial listing standards for Nasdaq,

with the exception of the bid price requirement, and will need to provide written notice of our intention to cure the deficiency during the second compliance period, by effecting a reverse stock split, if necessary. Under Nasdaq rules, after the second 180-day compliance period expires, if we do not regain compliance with the price criteria for 10 consecutive business days prior to the end of the second period, a request for a hearing no longer stays the suspension and delisting of the ADSs pending the Nasdaq Hearing Panel’s decision. After the second 180-day period expires, trading of the ADSs is automatically suspended, and the ADSs will move to the over-the-counter market while the appeal is pending. In addition, under the amended rule, we will not be eligible for any cure period to address a deficiency in the minimum bid price requirement if we effected a reverse stock split in the prior year.

We have previously implemented two ratio changes of the ADSs to the Company’s non-traded Ordinary Shares in connection with previous non-compliance with the Minimum Price Rule. The most recent ratio change was implemented on August 20, 2024 and changed the previous ratio of one (1) ADS representing four hundred (400) ordinary shares to a new ratio of one (1) ADS representing ten thousand (10,000) ordinary shares, which change had the same effect as a one-for-twenty-five reverse ADS split.

Under the Nasdaq rules, companies that fall out of compliance with the minimum bid price requirement are issued a delisting decision without being granted any cure period if they have effectuated one or more reverse stock splits within a two-year period with a cumulative ratio of 250 shares or more to one.  In addition, if we fall out of compliance with the minimum bid price requirement within one year of having conducted the most recent ratio change, we will be issued a delisting decision rather than being granted any cure period. Accordingly, we may fail to maintain long-term compliance with such minimum bid price requirement.

On April 15, 2025, we received the Notification Letter from the Listing Qualifications Department of Nasdaq, notifying us that we were no longer in compliance with Nasdaq Listing Rule 5550(b)(1) (the “Minimum Stockholders’ Equity Rule”). The Minimum Stockholders’ Equity Rule requires companies listed on The Nasdaq Capital Market to maintain a minimum of $2,500,000 in stockholders' equity for continued listing. However, based on our Annual Report on Form 20-F for the fiscal year ended December 31, 2024, filed on April 10, 2025, we reported a stockholders’ deficit of $4,683,000 and did not meet the alternatives of market value of listed securities or net income from continuing operations, and we were thus non-compliant with the Minimum Stockholders’ Equity Rule. On December 1, 2025, we announced that we had received confirmation from Nasdaq that we had regained compliance with the Minimum Stockholders’ Equity Rule. There is no guarantee that we will maintain long-term compliance with the Minimum Stockholders’ Equity Rule.

Additionally, Nasdaq has recently proposed a new rule change to (i) adopt Listing Rules 5450(a)(3) and 5550(a)(6) to require issuers listed on the Nasdaq Global and Capital Markets, respectively, to maintain a minimum Market Value of Listed Securities (as defined in Nasdaq Listing Rule 5005(a)(23)) of at least $5 million for a period of 30 consecutive business days, and (ii) amend Rule5810 to suspend trading and immediately delist, without a cure period, from Nasdaq securities of issuers that do not satisfy the proposed new requirements, and Rule 5815 to set forth the procedures for requesting a hearing before a Hearings Panel and the scope of the Panel’s discretion (collectively, the “Proposed $5 Million MVLS Rule”). As of the date of the filing of this Annual Report the market value of our listed securities is less than $5 million. The market value of our common stock may fluctuate significantly due to a number of factors, many of which are outside of our control, including market conditions, investor sentiment toward small-cap companies, our operating performance, and general economic conditions. If the SEC approves the Proposed $5 Million MVSL Rule and the market value of our listed securities does not meet the $5.0 million requirement as of the date it goes into effect, our securities will be subject to delisting.

Additionally, in the recent past, we did not meet the continued listing requirement for market value of publicly held shares (“MVPHS”), and only regained compliance with such requirement by transferring the listing of the ADSs to the Nasdaq Capital Market from the Nasdaq Global Market in November 2023. No assurance can be given that the price of the ADSs will not again be in violation of Nasdaq’s minimum bid price requirement or the MVPHS requirement in the future.

Our failure to meet any these requirements or any future requirement may result in our securities being delisted from Nasdaq. A delisting could substantially decrease trading in the ADSs, adversely affect the market liquidity of the ADSs as a result of the loss of market efficiencies associated with Nasdaq and the loss of federal preemption of state securities laws, adversely affect our ability to obtain financing on acceptable terms, if at all, and may result in the potential loss of

confidence by investors, suppliers, customers and employees and fewer business development opportunities. Additionally, the market price of the ADSs may decline further and shareholders may lose some or all of their investment.

U.S. holders of ADSs may suffer adverse tax consequences if we were characterized as a passive foreign investment company.

Based on the current composition of our gross income and assets and on reasonable assumptions and projections no assurance can be given that we will not be treated as a passive foreign investment company (a “PFIC”), for U.S. federal income tax purposes for 2026. If we were characterized as a PFIC, U.S. holders of the ADSs  may suffer adverse tax consequences such as (i) having gains realized on the sale of the ADSs treated as ordinary income rather than capital gain, not qualifying for the preferential rate otherwise applicable to dividends received in respect of the ADSs by individuals who are U.S. holders, and (ii) having interest charges apply to certain distributions by us and upon certain sales of the ADSs.

There has been a limited market for the ADSs. We cannot ensure investors that an active market will continue or be sustained for the ADSs on Nasdaq and this may limit the ability of our investors to sell the ADSs.

In the past, there was limited trading in the ADSs, and there is no assurance that an active trading market of the ADSs will continue or will be sustained. Limited or minimal trading in the ADSs has in the past, and may in the future, lead to dramatic fluctuations in market price and investors may not be able to liquidate their investment at all or at a price that reflects the value of the business.

While the ADSs began trading on Nasdaq in December 2012, on the Nasdaq Global Market in July 2018, and on Nasdaq again in December 2023, we cannot assure you that we will maintain compliance with all of the requirements for the ADSs to remain listed. Additionally, there can be no assurance that trading of the ADSs will be sustained or desirable.

As a foreign private issuer, we are permitted to follow certain home country corporate governance practices instead of applicable SEC and Nasdaq Stock Market requirements, which may result in less protection than is accorded to investors under rules applicable to domestic issuers.

As a foreign private issuer, we are permitted to follow certain home country corporate governance practices instead of those otherwise required under the Nasdaq Listing Rules for domestic issuers. For instance, we follow the home country practice in Israel with regard to, among other things, director nomination procedures and quorum at shareholders’ meetings. In addition, we follow our home country law, instead of the Nasdaq Listing Rules, which require that we obtain shareholder approval for certain dilutive events, such as for the establishment or amendment of certain equity-based compensation plans, an issuance that will result in a change in control, certain transactions other than a public offering involving issuances of a 20% or more interest in us and certain acquisitions of the stock or assets of another company. Following our home country governance practices as opposed to the requirements that would otherwise apply to a U.S. domestic issuer listed on the Nasdaq Stock Market may provide less protection than is accorded to investors under the Nasdaq Listing Rules applicable to domestic issuers.

In addition, as a foreign private issuer, we are exempt from the rules and regulations under the Securities Exchange Act of 1934, as amended (the “Exchange Act”), related to the furnishing and content of proxy statements, and our officers, directors and principal shareholders are exempt from the short-swing profit recovery provisions contained in Section 16 of the Exchange Act. Our principal shareholders are also exempt from the reporting requirements in Section 16(a) of the Exchange Act. In addition, we are not required under the Exchange Act to file annual, quarterly and current reports and financial statements with the SEC as frequently or as promptly as domestic companies whose securities are registered under the Exchange Act.

We are a non-accelerated filer, and we cannot be certain if the reduced disclosure requirements applicable to us will make the ADSs less attractive to investors.

We are currently a “non-accelerated filer”, as that term is defined in the Securities Act. Accordingly, we take advantage of certain exemptions from various reporting requirements that are applicable to other public companies that are not a “non-accelerated filers,” in particular, reduced disclosure obligations regarding exemptions from the provisions of Section 404(b) of the Sarbanes-Oxley Act of 2002 (the “Sarbanes-Oxley Act”) requiring that independent registered public accounting firms provide an attestation report on the effectiveness of internal control over financial reporting. Decreased disclosures in our SEC filings due to our status as a “non-accelerated filer” may make it harder for investors to analyze our results of operations and financial prospects.

We cannot predict if investors will find the ADSs less attractive if we rely on exemptions applicable to non-accelerated filers. If some investors find the ADSs less attractive as a result, there may be a less active trading market for the ADSs and our ordinary share price may be more volatile.

We currently do not anticipate paying cash dividends, and accordingly, investors must rely on the appreciation in the ADSs for any return on their investment.

We currently anticipate that we will retain future earnings, if any, for the development, operation and expansion of our business and do not anticipate declaring or paying any cash dividends for the foreseeable future. In addition, the terms of our term loan facility prohibit us from paying dividends. Therefore, the success of an investment in the ADSs will depend upon any future appreciation in their value. There is no guarantee that the ADSs will appreciate in value or even maintain the price at which our investors have purchased their securities.

Investors in the ADSs may not receive the same distributions or dividends as those we make to the holders of our ordinary shares, par value NIS 0.01 per share (“Ordinary Shares”), and, in some limited circumstances, investors in the ADSs may not receive dividends or other distributions on our Ordinary Shares and may not receive any value for them, if it is illegal or impractical to make them available to investors in the ADSs.

The depositary for the ADSs has agreed to pay to investors in the ADSs the cash dividends or other distributions it or the custodian receives on Ordinary Shares or other deposited securities underlying the ADSs, after deducting its fees and expenses. Investors in the ADSs will receive these distributions in proportion to the number of Ordinary Shares such ADSs represent. However, the depositary is not responsible if it decides that it is unlawful or impractical to make a distribution available to any holders of ADSs. For example, it would be unlawful to make a distribution to a holder of ADSs if it consists of securities that require registration under the Securities Act of 1933, as amended, but that is not properly registered or distributed under an applicable exemption from registration. In these cases, the depositary may determine not to distribute such property and hold it as “deposited securities” or may seek to effect a substitute dividend or distribution, including net cash proceeds from the sale of the dividends that the depositary deems an equitable and practicable substitute. We have no obligation to register under U.S. securities laws any ADSs, Ordinary Shares, rights or other securities received through such distributions. We also have no obligation to take any other action to permit the distribution of ADSs, Ordinary Shares, rights or anything else to holders of ADSs. In addition, the depositary may deduct from such dividends or distributions its fees and may withhold amounts on account of taxes or other governmental charges to the extent the depositary believes it is required to make such withholding. This means that investors in the ADSs may not receive the same distributions or dividends as those we make to the holders of our Ordinary Shares, and, in some limited circumstances, investors in the ADSs may not receive any value for such distributions or dividends if it is illegal or impractical for us to make them available to investors in the ADSs. These restrictions may cause a material decline in the value of the ADSs.

Holders of ADSs must act through the depositary to exercise their rights.

Holders of the ADSs may only exercise the voting rights with respect to the underlying Ordinary Shares in accordance with the provisions of the deposit agreement for the ADSs. Under Israeli law, the minimum notice period required to convene a shareholders’ meeting is no less than 35 or 21 calendar days, depending on the proposals on the agenda for the shareholders’ meeting. When a shareholders’ meeting is convened, holders of the ADSs may not receive sufficient advance notice of a shareholders’ meeting to permit them to cancel the ADSs and withdraw their Ordinary Shares to allow them to cast their vote with respect to any specific matter. In addition, the depositary and its agents may not be able to send voting instructions to holders of the ADSs or carry out their voting instructions in a timely manner. We will make all reasonable efforts to cause the depositary to extend voting rights to holders of the ADSs in a timely manner, but we cannot assure holders that they will receive the voting materials in time to ensure that they can instruct the depositary to vote their ADSs. Furthermore, the depositary and its agents are not responsible for any failure to carry out any instructions to vote, for the manner in which any vote is cast or for the effect of any such vote. As a result, holders of the ADSs may not be able to exercise their right to vote and they may lack recourse if their ADSs are not voted as they requested. In addition, in the capacity as an ADS holder, they are not able to call a shareholders’ meeting.

The depositary for the ADSs gives us a discretionary proxy to vote our Ordinary Shares underlying ADSs if a holder of the ADSs does not give voting instructions, except in limited circumstances.

Under the deposit agreement for the ADSs, the depositary gives us a discretionary proxy to vote our Ordinary Shares underlying ADSs at shareholders’ meetings if a holder of the ADSs does not give voting instructions, unless:

The effect of this discretionary proxy is that a holder of the ADSs cannot prevent our Ordinary Shares underlying such ADSs from being voted by us at our discretion, absent the situations described above. Holders of our Ordinary Shares are not subject to this discretionary proxy.

Risks Related to our Operations in Israel

We conduct some of our operations in Israel. Conditions in Israel, including the recent attack by Hamas and other terrorist organizations from the Gaza Strip and Israel’s war against them, may affect our operations.

Because we are incorporated under the laws of the State of Israel and some of our operations are conducted in Israel, our business and operations are directly affected by economic, political, geopolitical and military conditions in Israel. Since the establishment of the State of Israel in 1948, a number of armed conflicts have occurred between Israel and its neighboring countries and terrorist organizations active in the region. These conflicts have involved missile strikes, hostile infiltrations and terrorism against civilian targets in various parts of Israel, which have negatively affected business conditions in Israel.

In addition, Israel faces many threats from more distant neighbors, in particular, Iran. Parties with whom we do business have sometimes declined to travel to Israel during periods of heightened unrest or tension, forcing us to make alternative arrangements when necessary. In addition, the political and security situation in Israel may result in parties with whom we have agreements involving performance in Israel claiming that they are not obligated to perform their commitments under those agreements pursuant to force majeure provisions in such agreements. Any hostilities involving Israel or the interruption or curtailment of trade within Israel or between Israel and its trading partners could adversely affect our operations or results of operations and could make it more difficult for us to raise capital.

​

In October 2023, Hamas terrorists infiltrated Israel’s southern border from the Gaza Strip and conducted a series of attacks on civilian and military targets. Hamas also launched extensive rocket attacks on Israeli population and industrial centers located along Israel’s border with the Gaza Strip and in other areas within the State of Israel. These attacks resulted in extensive deaths, injuries and kidnapping of civilians and soldiers. Following the attack, Israel’s security cabinet declared war against Hamas and a military campaign against these terrorist organizations commenced in parallel to their continued rocket and terror attacks. In addition, since the commencement of these events, there have been continued hostilities along Israel’s northern border with Lebanon (with the Hezbollah terror organization) and on other fronts from various extremist groups in the region, such as the Houthis in Yemen and various rebel militia groups in Syria and Iraq. In October 2024, Israel began limited ground operations against Hezbollah in Lebanon, and in November 2024, a ceasefire was brokered between Israel and Hezbollah. In addition, in April 2024 and October 2024, Iran (in concert with other regional actors) launched direct attacks on Israel involving hundreds of drones and missiles and has threatened to continue to attack Israel and is widely believed to be developing nuclear weapons. Additionally, Yemeni rebel group, the Houthis, launched a series of attacks on global shipping routes in the Red Sea, causing disruptions of supply chain. On June 12, 2025, Israel conducted a series of air strikes in Iran targeting Iran’s nuclear program and leadership, and on June 21, 2025, the United States conducted air strikes against three nuclear sites within Iran.

In late February 2026, the United States and Israel launched significant military operations against Iran, and Iran responded with retaliatory missile and drone attacks on Israel, U.S. military assets and Gulf states, including the United Arab Emirates, Saudi Arabia, Qatar, Kuwait and Bahrain. This conflict has caused significant casualties in the region, disrupted commercial air travel, damaged critical infrastructure, and effectively suspended shipping through the Strait of Hormuz. The duration and ultimate scope of this conflict remain highly uncertain. A prolonged or expanding conflict could result in sustained disruptions to regional and global economic conditions, continued volatility in energy markets and further deterioration of commercial and financial activity across the Middle East and globally. Any or all of these situations may potentially escalate in the future to more violent events which may affect Israel and us.

Although we currently do not expect the ongoing conflict to affect our customers, manufacturing, research and development, supply chain, commercialization activities and current clinical studies, which are all located in and/or take place outside of Israel, there can be no assurances that further unforeseen events will not have a material adverse effect on us or our operations in the future.

The Israel Defense Force (the “IDF”), the national military of Israel, is a conscripted military service, subject to certain exceptions. Following the October 7, 2023 attacks, the IDF called up more than 350,000 of its reserve forces to serve. One member of management is currently subject to military service in the IDF and has been called to serve. It is possible that there will be further military reserve duty call-ups in the future, which may affect our business due to a shortage of skilled labor and loss of institutional knowledge, and necessary mitigation measures we may take to respond to a decrease in labor availability, such as overtime and third-party outsourcing, for example, may have unintended negative effects and adversely impact our results of operations, liquidity or cash flows.

Additionally, five members of our management team and 8 of our non-management employees reside in Israel. Shelter-in-place and work-from-home measures, government-imposed restrictions on movement and travel and other precautions taken to address the ongoing conflict may temporarily disrupt our management and employees’ ability to effectively perform their daily tasks.

It is currently not possible to predict the duration or severity of the ongoing conflict or its effects on our business, operations and financial conditions. The ongoing conflict is rapidly evolving and developing, and could disrupt our business and operations, interrupt our sources and availability of supply and hamper our ability to raise additional funds or sell our securities, among others.

Our commercial insurance does not cover losses that may occur as a result of events associated with the security situation in the Middle East. The Israeli government is currently committed to cover the reinstatement value of direct damages that are caused by terrorist attacks or acts of war. However, there is no assurance that this government coverage will be maintained, or if maintained, will be sufficient to compensate us fully for damages incurred. Any losses or damages incurred by us could have a material adverse effect on our business.

Several countries, principally in the Middle East, restrict doing business with Israel and Israeli companies, and additional countries may impose restrictions on doing business with Israel and Israeli companies. In addition, there have been increased efforts by activists to cause companies and consumers to boycott Israeli goods based on Israeli government policies. Such business restrictions and boycotts, particularly if they become more widespread, may materially and adversely impact our business.

Furthermore, prior to the attacks by Hamas, the Israeli government was pursuing extensive changes to Israel’s judicial system. This led to protests at various levels domestically, and investment banks and other investors have voiced concerns that the proposed changes may negatively impact the business environment in Israel. This may, in turn, could slow the flow of international investment and negatively affect our business, financial condition and prospects.

Because a certain portion of our expenses is incurred in currencies other than the U.S. dollar, our results of operations may be harmed by currency fluctuations and inflation.

Our reporting and functional currency is the U.S. dollar. Most of our revenues and royalty payments from our agreements with our development or commercialization partners are in U.S. dollars, and we expect our revenues from future licensing and co-promotion agreements to be denominated mainly in U.S. dollars or in Euros. We pay a substantial portion of our expenses in U.S. dollars; however, a portion of our expenses, including salaries of our employees in Israel and payment to part of our service providers in Israel and other territories, are paid in NIS and in other currencies. In addition, a portion of our financial assets is held in NIS and in other currencies. As a result, we are exposed to currency fluctuation risks. For example, if the NIS strengthens against the U.S. dollar, our reported expenses in U.S. dollars may be higher. In addition, if the NIS weakens against the U.S. dollar, the U.S. dollar value of our financial assets held in NIS will decline.

Provisions of the RedHill Biopharma Ltd. Award Plan, Israeli law, our articles of association and our change in control retention plan may delay, prevent or otherwise impede a merger with, or an acquisition of, our Company, or an acquisition of a significant portion of our shares, which could prevent a change in control, even when the terms of such a transaction are favorable to us and our shareholders.

Our Amended and Restated Award Plan (2010) (the “Award Plan”) provides that all options granted by us will be fully accelerated upon a “hostile takeover” of us. A “hostile takeover” is defined in our Award Plan as an event in which any person, entity or group that was not an “interested party”, as defined in the Israeli Securities Law – 1968, on the date of the initial public offering of our Ordinary Shares on the TASE, will become a “controlling shareholder” as defined in the Israel Securities Law, 1968, or a “holder,” as defined in the Israeli Securities Law – 1968, of 25% or more of our voting rights or any merger or consolidation involving us, in each case without a resolution by our board of directors supporting the transaction. In addition, if a “Significant Event” occurs and following which the employment of a grantee with us or a related company is terminated by us or a related company other than for “Cause”, and unless the applicable agreement provides otherwise, all the outstanding options held by or for the benefit of any such grantee will be accelerated and immediately vested and exercisable. A “Significant Event” is defined in our Award Plan as a consolidation or merger with or into another corporation approved by our board of directors in which we are the continuing or surviving corporation or in which the continuing or surviving corporation assumes the option or substitutes it with an appropriate option in the surviving corporation.

The Israeli Companies Law, 1999 (the “Israeli Companies Law”), regulates mergers, requires tender offers for acquisitions of shares or voting rights above specified thresholds, requires special approvals for transactions involving directors, officers or significant shareholders and regulates other matters that may be relevant to these types of transactions. For example, a merger may not be consummated unless at least 50 days have passed from the date that a merger proposal was filed by each merging company with the Israel Registrar of Companies and at least 30 days from the date that the shareholders of both merging companies approved the merger. In addition, a majority of each class of securities of the target company must approve a merger. Moreover, the Israeli Companies Law provides that certain purchases of securities of a public company are subject to tender offer rules. As a general rule, the Israeli Companies Law prohibits any acquisition of shares or voting power in a public company that would result in the purchaser holding 25% or more, or more than 45% of the voting power in the company, if there is no other person holding 25% or more, or more than 45% of the voting power in a company, respectively, without conducting a special tender offer. The Israeli Companies Law further provides that a purchase of shares or voting power of a public company or a class of shares of a public company which will result in the purchaser’s holding 90% or more of the company’s shares, class of shares or voting rights, is prohibited unless the purchaser conducts a full tender offer for all of the company’s shares or class of shares. The purchaser will be allowed to purchase all of the company’s shares or class of shares (including those shares held by shareholders who did not respond to the offer), if either (i) the shareholders who do not accept the offer hold less than 5% of the issued and outstanding share capital of the company or of the applicable class, and more than half of the shareholders who do not have a personal interest in the offer accept the offer, or (ii) the shareholders who do not accept the offer hold less than 2% of the issued and outstanding share capital of the company or of the applicable class. The shareholders, including those who indicated their acceptance of the tender offer (except if otherwise detailed in the tender offer document), may, at any time within six months following the completion of the tender offer, petition the court to alter the consideration for the acquisition. At the request of an offeree of a full tender offer which was accepted, the court may determine that the consideration for the shares purchased under the tender offer was lower than their fair value and compel the offeror to pay to the offerees the fair value of the shares. Such an application to the court may be filed as a class action.

In addition, the Israeli Companies Law provides for certain limitations on a shareholder that holds more than 90% of the company’s shares, or class of shares.

Pursuant to our articles of association, the size of our board of directors may be no less than five persons and no more than eleven, including any external directors whose appointment is required under the law. The directors who are not external directors are divided into three classes, as nearly equal in number as possible. At each annual general meeting, the term of one class of directors expires, and the directors of such class are re-nominated to serve an additional three-year term that expires at the annual general meeting held in the third year following such election. This process continues indefinitely. Such provisions of our articles of association make it more difficult for a third party to effect a change in control or takeover attempt that our management and board of directors oppose.

In addition, we have adopted a change in control employee retention plan and entered into employment agreements providing for compensation to Company officers and employees in the event of a change in control (as defined by the plan and employment agreements), subject to the satisfaction of various conditions. See “Item 6 B. – Compensation – Change in Control Retention Plan.”

Furthermore, Israeli tax considerations may, in certain circumstances, make potential transactions unappealing to us or to some of our shareholders. For example, Israeli tax law does not recognize tax-free share exchanges to the same extent as U.S. tax law. With respect to mergers, Israeli tax law allows for tax deferral in certain circumstances but makes the deferral contingent on the fulfillment of numerous conditions, including a holding period of two years from the date of the transaction during which sales and dispositions of shares of the participating companies are restricted. Moreover, with respect to certain share swap transactions, the tax deferral is limited in time, and when such time expires, the tax becomes payable even if no actual disposition of the shares has occurred.

These and other similar provisions could delay, prevent or impede an acquisition of us or our merger with another company, or an acquisition of a significant portion of our shares, even if such an acquisition or merger would be beneficial to us or to our shareholders.

It may be difficult to enforce a U.S. judgment against us and our directors and officers in Israel or the U.S. or to serve process on our directors and officers.

We are incorporated in Israel. Most of our directors and executive officers reside outside of the U.S., and most of the assets of our directors and executive officers may be located outside of the U.S. Therefore, a judgment obtained against us or most of our executive officers and our directors in the U.S., including one based on the civil liability provisions of the U.S. federal securities laws, may not be collectible in the U.S. and may not be enforced by a U.S. or Israeli court. It may also be difficult to effect service of process on these persons in the U.S. or to assert U.S. securities law claims in original actions instituted in Israel.

The obligations and responsibilities of our shareholders are governed by Israeli law, which may differ in some respects from the obligations and responsibilities of shareholders of U.S. companies. Israeli law may impose obligations and responsibilities on a shareholder of an Israeli company that are not imposed upon shareholders of corporations in the U.S.

We are incorporated under Israeli law. The obligations and responsibilities of the shareholders are governed by our articles of association and Israeli law. These obligations and responsibilities differ in some respects from the obligations and responsibilities of shareholders in typical U.S.-based corporations. In particular, a shareholder of an Israeli company has a duty to act in good faith toward the company and other shareholders and to refrain from abusing its power in the company, including, among other things, in voting at the general meeting of shareholders on matters such as amendments to a company’s articles of association, increases in a company’s authorized share capital, mergers and acquisitions and interested party transactions requiring shareholder approval. In addition, a shareholder who knows that it possesses the power to determine the outcome of a shareholder vote or to appoint or prevent the appointment of a director or executive officer in the company has a duty of fairness toward the company. There is limited case law available to assist us in understanding the implications of these provisions that govern shareholders’ actions. These provisions may be interpreted to impose additional obligations and responsibilities on our shareholders that are not typically imposed on shareholders of U.S. corporations.

Claims for indemnification by our directors and officers may reduce our available funds to satisfy successful shareholder claims against us and may reduce the amount of money available to us.

The Israeli Companies Law and our articles of association permit us to indemnify our directors and officers for acts performed by them in their capacity as directors and officers. The Israeli Companies Law provides that a company may not exempt or indemnify a director or an officer nor enter into an insurance contract, which would provide coverage for any monetary liability incurred as a result of: (a) a breach by the director or officer of his duty of loyalty, except for insurance and indemnification where the director or officer acted in good faith and had a reasonable basis to believe that the act would not prejudice the company; (b) a breach by the director or officer of his duty of care if the breach was done intentionally or recklessly, except if the breach was solely as a result of negligence; (c) any act or omission done with the intent to derive an illegal personal benefit; or (d) any fine, civil fine, monetary sanctions, or forfeit imposed on the officer or director. Our articles of association provide that we may exempt or indemnify a director or an officer to the maximum extent permissible under law.

We have issued letters of indemnification to our directors and officers, pursuant to which we have agreed to indemnify them in advance for any liability or expense imposed on or incurred by them in connection with acts they perform in their capacity as a director or officer, subject to applicable law. The amount of the advance indemnity is limited to the higher of 25% of our then shareholders’ equity, per our most recent annual financial statements, or $10 million.

Our indemnification obligations limit the personal liability of our directors and officers for monetary damages for breach of their duties as directors by shifting the burden of such losses and expenses to us. Although we have obtained directors’ and officers’ liability insurance, certain liabilities or expenses covered by our indemnification obligations may not be covered by such insurance or the coverage limitation amounts may be exceeded. As a result, we may need to use a significant amount of our funds to satisfy our indemnification obligations, which could severely harm our business or financial condition and limit the funds available to those who may choose to bring a claim against us. These provisions and resultant costs may also discourage us from bringing a lawsuit against directors and officers for breaches of their duties and may similarly discourage the filing of derivative litigation by our shareholders against the directors and officers even though such actions, if successful, might otherwise benefit our security holders.

Our Amended and Restated Articles of Association designate courts located either within the State of Israel, or the Federal District Courts of the United States, as the exclusive forum for certain litigation that may be initiated by our shareholders, which could limit our shareholders’ ability to bring a favorable or convenient judicial forum for disputes with us.

Our Amended and Restated Articles of Association provide that, unless we consent in writing to the selection of an alternative forum, the Tel Aviv District Court (Economic Division in the State of Israel (or, if the Tel Aviv District Court does not have jurisdiction, and no other Israeli court has jurisdiction, the federal district court for the District of New York) shall be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers or other employees to us or our shareholders, and (3) any action asserting a claim arising pursuant to any provision of the Companies Law or the Israeli Securities Law 5728-1968, in all cases subject to the court’s having personal jurisdiction over the indispensable parties named as defendants. In addition, the federal district courts of the United States for the District of New York shall be the exclusive forum for any complaint asserting a cause of action arising under the Securities Act of 1933, as amended. Any person or entity purchasing or otherwise acquiring any interest in shares of our capital stock shall be deemed to have notice of and consented to these provisions.

This forum selection provision may limit shareholders’ ability to bring a claim in a judicial forum for disputes that it finds favorable or convenient for disputes with us or our directors, officers, or other employees, which may discourage lawsuits with respect to such claims. Alternatively, a court, including an Israeli court, could find these provisions of our Articles of Association to be inapplicable or unenforceable in respect of one or more of the specified types of actions or proceedings, which may require us to incur additional costs associated with resolving such matters in other jurisdictions, which could adversely affect our business and financial condition.

General Risks

We must comply with the U.S. Foreign Corrupt Practices Act.

The U.S. Foreign Corrupt Practices Act (the “FCPA”) applies to companies, such as us, with a class of securities registered under the Exchange Act. The FCPA to which various of our operations may be subject generally prohibits companies and their intermediaries from engaging in bribery or making other improper payments to officials for the purpose of obtaining or retaining business. In various jurisdictions, our operations require that we and third parties acting on our behalf routinely interact with government officials, including medical personnel who may be considered government officials for purposes of these laws because they are employees of state-owned or controlled facilities. Our policies mandate compliance with these anti-bribery laws; however, we operate in many parts of the world that have experienced governmental or private corruption to some degree. As a result, the existence and implementation of a robust anti-corruption program cannot eliminate all risks that unauthorized reckless or criminal acts have been or will be committed by our employees or agents. If our employees or other agents are found to have engaged in such practices, we could suffer severe penalties. Violations of the FCPA, or allegations of such violations, could disrupt our business and result in a material adverse effect on our reputation, business, financial condition or results of operations.

Future issuances or sales of ADSs could reduce the market price of the ADSs and result in dilution to our shareholders.

As of April 24, 2026, we had outstanding options to purchase up to an aggregate of 23,170,000 Ordinary Shares (equivalent to 2,317 ADSs) under our Award Plan and 376,141 outstanding Restricted Share Units (“RSUs”), each with respect to one ADS, which represents 10,000 of our Ordinary Shares. In addition, as of April 24, 2026, there were 22,160,330,200 Ordinary Shares (equivalent to 2,216,033 ADSs) reserved for issuance under our Award Plan (including Ordinary Shares subject to outstanding options and RSUs under such plan).

As of April 24, 2026, we also had outstanding warrants to purchase an aggregate of 808,216 ADSs. All warrants are exercisable at any time before June 20, 2030, subject to certain limitations and exceptions. The weighted average exercise price of the warrants is approximately $19.78 per ADS, which is above the current market price of the ADSs, which was $1.025 per ADS based on the closing price of the ADSs on Nasdaq on April 24, 2026. The likelihood that the holders of our warrants will exercise their warrants, and the amount of any cash proceeds that we would receive upon such exercise, is dependent upon the market price of the ADSs. However, there is no guarantee that our outstanding warrants will be in the money prior to their respective expirations, and as such, they may expire worthless.

Future substantial issuance or sale of the ADSs or of securities exercisable, convertible or exchangeable into ADSs, or the perception that such sales may occur in the future, including sales of ADSs issuable upon vesting of RSUs and the exercise of options, warrants or other equity-based securities, may cause the market price of the ADSs to decline. To the extent that our outstanding options or warrants are exercised, additional shares of the ADSs will be issued, which will result in dilution to the holders of the ADSs and increase the number of shares of the ADSs eligible for resale in the public market. Sales of substantial numbers of such shares in the public market or the fact that such outstanding options and warrants may be exercised may cause the market price of the ADSs to decline.

The market price of the ADSs is subject to fluctuation, which could result in substantial losses by our investors. Volatility in the financial market could have a material adverse impact on the market price of the ADSs. This may affect the ability of our investors to sell their ADSs, and the value of an investment in the ADSs may decline.

The stock market in general and the market price of the ADSs on Nasdaq, in particular, are subject to fluctuation, and changes in the price of our securities may be unrelated to our operating performance. The market price of the ADSs on Nasdaq has fluctuated in the past, and we expect they will continue to do so. The market price of the ADSs is and will be subject to a number of factors, including but not limited to:

These factors and any corresponding price fluctuations may materially and adversely affect the market price of the ADSs and result in substantial losses by our investors.

Additionally, market prices for securities of biotechnology and pharmaceutical companies historically have been very volatile. The market for these securities has from time to time, experienced significant price and volume fluctuations for reasons unrelated to the operating performance of any one company. In the past, the COVID-19 pandemic resulted in significant financial market volatility and uncertainty. A resurgence of the levels of market disruption and volatility seen in the recent past could have an adverse effect on our ability to access capital, on our business, results of operations and financial condition, and on the market price of the ADSs. In the past, following periods of market volatility, shareholders have often instituted securities class action litigation and derivative actions. If we were involved in securities or other litigation, it could have a substantial cost and divert resources and attention of management from our business, even if we are successful.

Our business is subject to cybersecurity risks.

Our operations are increasingly dependent on information technologies and services. Threats to information technology systems associated with cybersecurity risks and cyber incidents or attacks continue to grow, and include, among other things, storms and natural disasters, terrorist attacks, utility outages, theft, viruses, phishing, malware, design defects, human error, and complications encountered as existing systems are maintained, repaired, replaced, or upgraded. Risks associated with these threats include, among other things:

Although we utilize various procedures and controls to mitigate our exposure to such risk, cybersecurity attacks and other cyber events are evolving and unpredictable. Moreover, we have no control over the information technology systems of third parties conducting our clinical trials, our suppliers, and others with which our systems may connect and communicate. As a result, the occurrence of a cyber incident could go unnoticed for a period of time.

We cannot ensure that we have sufficient means to cover any particular losses we may experience as a result of cyberattacks. Any cyber incident could have a material adverse effect on our business, financial condition and results of operations.

We incur significant costs as a result of the listing of the ADSs on Nasdaq, and we may need to devote substantial time and resources to new and current compliance initiatives and reporting requirements.

As a public company in the U.S., we incur significant accounting, legal and other expenses as a result of the listing of our securities on Nasdaq. These include costs associated with the reporting requirements of the SEC and the requirements of the Nasdaq Listing Rules, as well as any applicable requirements under Section 404 and other provisions of the Sarbanes-Oxley Act. These rules and regulations have increased our legal and financial compliance costs, introduced new costs such as investor relations, travel costs, stock exchange listing fees, and shareholder reporting, and made some activities more time-consuming and costly. Any future changes in the laws and regulations affecting public companies in the U.S. and Israel, including any applicable requirements under Section 404 and other provisions of the Sarbanes-Oxley Act, the rules and regulations adopted by the SEC and the Nasdaq Listing Rules, as well as applicable Israeli reporting requirements, may result in an increase to our costs as we respond to such changes. These laws, rules, and regulations could make it more difficult and costly for us to obtain certain types of insurance, including director and officer liability insurance, and we may be forced to accept reduced policy limits and coverage or incur substantially higher costs to obtain the same or similar coverage. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our board of directors, our board committees or as executive officers and may require us to pay more for such positions.

​

ITEM 4.          INFORMATION ON THE COMPANY

A.          History and Development of the Company

Our legal and commercial name is RedHill Biopharma Ltd. Our company was incorporated on August 3, 2009, and was registered as a private company limited by shares under the laws of the State of Israel. Our principal executive offices are located at 21 Ha’arba’a Street, Tel-Aviv, Israel, and our telephone number is +972-3-5413131.

In February 2011, we completed our initial public offering in Israel, pursuant to which we issued 14,302,300 Ordinary Shares, and 7,151,150 tradable Series 1 Warrants to purchase 7,151,150 Ordinary Shares for aggregate gross proceeds of approximately $14 million. On December 27, 2012, we completed the listing of ADSs on Nasdaq, and on July 20, 2018, the ADSs were listed on the Nasdaq Global Market. On February 13, 2020, our Ordinary Shares were voluntarily delisted from trading on the Tel-Aviv Stock Exchange. On November 15, 2023, the ADSs were transferred from the Nasdaq Global Market to Nasdaq. The ADSs are currently traded on Nasdaq under the symbol “RDHL.”

The Securities and Exchange Commission (the “SEC”), maintains an internet site that contains reports, proxy and information statements and other information regarding issuers that file electronically with the SEC at http://www.sec.gov.

Our website address is http://www.redhillbio.com. Information contained on, or that can be accessed through, our website does not constitute a part of this Annual Report.

Our capital expenditures for the years ended December 31, 2025, 2024, and 2023, were approximately $4,500, $8,700 and $9,500, respectively. Our current capital expenditures involve basic equipment and leasehold improvements.

B.           Business Overview

We are a specialty biopharmaceutical company, primarily focused on U.S. development and commercialization of drugs for GI diseases, infectious diseases and oncology. Our primary goal is to become a leading specialty biopharmaceutical company.

We are currently focused primarily on the advancement of our development pipeline of clinical-stage therapeutic candidates. We also commercialize our GI-related product, Talicia^® (omeprazole, amoxicillin, and rifabutin) in the U.S. in partnership with Cumberland, and continue to explore our strategic plans for other potential products and activities.

Among our therapeutic candidates, we are exploring opaganib as a potential treatment for various conditions, including the treatment of several cancers such as prostate cancer, cholangiocarcinoma and chronic lymphocytic leukemia; virus-induced acute respiratory distress syndrome (ARDS), informed by data from a Phase 2/3 clinical study in COVID-19, Ebola and other viral infections; as well as metabolic disorders, including diabetes, obesity and nuclear radiation protection. Furthermore, we are investigating RHB-107 (upamostat) as a potential treatment for COVID-19 and other viruses as part of pandemic preparedness, including influenza.

Our current pipeline consists of five therapeutic candidates, part of which are in mid-to-late stage clinical development. We generate our pipeline of therapeutic candidates by identifying, validating and in-licensing or acquiring products that are consistent with our product and corporate strategy and that have the potential to exhibit a favorable probability of therapeutic and commercial success. We have one product, Talicia^®, that we primarily developed internally which has been approved for marketing and, to date, none of our other therapeutic candidates has generated revenues. We have out-licensed our commercial product, Talicia^®, for specific territories outside the U.S., including certain Middle East markets, and one of our therapeutic candidates, RHB-102, worldwide (except for the U.S., Canada, and Mexico). Furthermore, we plan to commercialize our therapeutic candidates, upon approval, if any, through licensing and other commercialization arrangements with pharmaceutical companies on a global and territorial basis or independently with a dedicated commercial operation or in potential partnership with other commercial-stage companies. We also evaluate, on a case-by-case basis, co-development, co-promotion, licensing, acquisitions and similar arrangements.

Our Strategy

Our goal is to become a leading specialty pharmaceutical company in the commercialization and development of pharmaceuticals for the treatment of GI, infectious diseases and oncology.

Key elements of our strategy are to:

The pharmaceutical and biotechnology industries are intensely competitive. Our therapeutic candidates, if commercialized, and our approved drugs, compete with existing drugs and therapies. In addition, there are many pharmaceutical companies, biotechnology companies, medical device companies, public and private universities, government agencies and research organizations actively engaged in the research and development of products targeting the same markets as our therapeutic candidates. Many of these organizations have substantially greater financial, technical, manufacturing and marketing resources than we or our subsidiaries, collaborators and affiliates do. In certain cases, our competitors may also be able to use alternative technologies that do not infringe upon our patents to formulate the active materials in our therapeutic candidates. They may, therefore, bring to market products that are able to compete with our candidates, or other products that we may develop in the future.

Commercial Operations in the U.S.

We have established the headquarters of our U.S. commercial operations in Raleigh, North Carolina. Following the October 2025 transaction with Cumberland, the commercialization of Talicia^® in the United States is conducted through Talicia Holdings under our Exclusive Joint Commercialization Agreement with Cumberland. Talicia Holdings’ U.S. commercial infrastructure could potentially serve as the platform for a future launch of proprietary late-clinical-stage therapeutic candidates in the United States, if approved by the FDA, as well as for potential in-licensed or acquired commercial-stage products in the United States.

As of December 31, 2025, our U.S. commercial operations had two employees. This does not include employees of Talicia Holdings who, following the closing of the transaction with Cumberland in October 2025 and the establishment of Talicia Holdings, transitioned from employment by RedHill Biopharma Inc. to employment by Talicia Holdings to support the Talicia^® business.

We continue to pursue acquisition of additional commercial products through licensing or promotion transactions, asset purchases, joint ventures, acquisitions, mergers or other business combinations involving companies with rights to commercial GI and other relevant assets. We intend to pursue such opportunities in the U.S. and, if available, in other jurisdictions.

Talicia^® (omeprazole magnesium, amoxicillin, and rifabutin) delayed-release capsules 10.3 mg/250 mg/12.5 mg

Talicia^® is our proprietary drug approved by the FDA for marketing in the U.S. for the treatment of H. pylori infection in adults. Talicia^® is a combination of three approved drug products – omeprazole magnesium, which is a proton pump inhibitor (preventing the secretion of hydrogen ions, increasing the pH of the stomach), plus two antibiotics, amoxicillin and rifabutin. Talicia^® is administered to patients orally in the form of a fixed-dose, all-in-one capsule. Talicia^® is the first product we developed that was approved for marketing in the U.S., which we launched in March 2020 with our dedicated sales force.

Chronic infection with H. pylori irritates the mucosal lining of the stomach and small intestine. The original discovery of H. pylori bacteria and its association with peptic ulcer disease warranted the Nobel Prize in 2005. H. pylori infection has since been associated with a variety of sequalae, including dyspepsia, peptic ulcer disease (duodenal ulcer and gastric ulcer), primary gastric B-cell lymphoma, vitamin B12 deficiency, iron deficiency, anemia, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer (Vakil et al. J Clin Pharmacol. 2025; Malfertheiner et al. Nat Rev Dis Primers. 2024; National Toxicology Program. Report on Carcinogens, 15^th ed. U.S. Dep. of Health and Human Services. 2021. Helicobacter pylori (Chronic Infection)).

Gastric cancer is one of the most prevalent cancers worldwide and one of the most common causes of cancer-related deaths, accounting for approximately 660,000 deaths in 2022, according to the World Health Organization (“WHO”) GLOBOCAN 2022 estimates. Chronic infection with H. pylori is the strongest known risk factor for the development of non-cardia gastric cancer (Moss. Cell Mol Gastroenterol Hepatol. 2017) and is responsible for nearly 90% of all cases (Morgan et al. eClinicalMedicine. 2022). Notably, confirmed eradication of H. pylori infection following treatment has been shown to reduce the risk of gastric cancer by approximately 75% (Kumar et al. Gastroenterology. 2020).

We acquired the rights to Talicia^® pursuant to an agreement with Giaconda Limited. See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – Acquisition of Talicia^®, RHB-104, and RHB-106.”

On December 5, 2021, we entered into an exclusive license agreement with Gaelan Medical for Talicia^®, in the UAE. See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – License Agreement with Gaelan Medical”. On August 1, 2023, we announced that Gaelan Medical had received marketing approval for Talicia in the UAE and subsequently placed the first commercial order for Talicia^®, which was dispatched from the CMO in December 2023. In August 2024, we announced the launch of Talicia^® in the UAE, and in August 2025, we announced the receipt of the first Talicia ex-U.S. sales milestone, royalties and other payments totaling $1.1 million.

In September 2025, we entered into an amendment to the license agreement with Gaelan Medical, pursuant to which the licensed territory was expanded to include additional countries in the Gulf Cooperation Council (“GCC”), subject to our approval and other contractual conditions. The amendment provides for additional non-refundable upfront and milestone payments, including aggregate fixed payments of $0.5 million payable regardless of regulatory approvals or commercialization outcomes, as well as additional contingent milestone payments and continued minimum tiered royalties on net sales across the expanded territory. See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – License Agreement for Talicia^® in New Middle East Markets.”

On October 25, 2025, we announced the signing of a strategic partnership with Cumberland, whereby Cumberland  invested $4 million payable in two equal tranches, $2 million of which was paid at closing and $2 million to be paid within 12 months of execution of the definitive agreements to acquire a 30% ownership stake in RedHill's global Talicia business. RedHill and Cumberland have also entered into an Exclusive Joint Commercialization Agreement for Talicia^® in the United States with an equal sharing of the product's net revenues between Cumberland and Talicia Holdings.   See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – Transaction with Cumberland.”

In November 2022, we announced post hoc analyses of the Phase 3 clinical trials of Talicia^® supporting the efficacy and safety of Talicia^® as empiric first-line treatment for H. pylori infection in patients regardless of obesity, body mass index (BMI), or type-2 diabetic status.

Regulatory Status

On November 1, 2019, Talicia^® was approved by the FDA and was granted a total of eight years of U.S. market exclusivity.

In November 2014, Talicia^® was granted Qualified Infectious Disease Product (QIDP) designation by the FDA. The QIDP designation was granted under the FDA’s Generating Antibiotic Incentives Now (GAIN) Act, which is intended to encourage the development of new antibiotic drugs for the treatment of serious or life-threatening infections that have the potential to pose a serious threat to public health.

​

In September 2023, we announced that the FDA had approved our supplemental new drug application (sNDA) for Talicia^®, allowing a change in dosing to a more flexible schedule, enabling patients to take Talicia^® three times daily, at least 4 hours apart with food. This differs from the previously approved dosing regimen, which required patients to take Talicia^® every eight hours with food. This FDA-approved label change enables patients to follow a convenient “breakfast, lunch and dinner” dosing routine, which may support increased patient adherence and further optimize the potential for successful H. pylori eradication.  

In November 2023, we announced that the FDA had officially granted Talicia^® five years of additional market exclusivity via QIDP designation as provided by the GAIN Act. This grant is on top of the three years’ exclusivity granted for the approval of Talicia^® under section 505(b)(2), providing market exclusivity until November 1, 2027. Talicia is protected by a patent portfolio with the latest patent to expire in 2042^®.

In January 2024, we announced that U.S. Patent and Trademark Office (USPTO) issued a new patent covering Talicia^® as a method for eradicating H. pylori regardless of BMI. The new patent is expected to provide protection for Talicia^® until May 2042.

In March 2024, we announced that Talicia^® had received a new U.S. patent covering its use as an all-in-one treatment for H. pylori infection, extending its patent protection until February 2034.

In August 2023, we announced that Gaelan Medical had received marketing approval for Talicia in the UAE and in August 2024, we announced the launch of Talicia in the UAE.

In March 2025, we announced plans to submit a UK Marketing Authorisation Application (MAA) for Talicia^® for treatment of H. pylori infection under the Medicines and Healthcare products Regulatory Agency's (MHRA) International Recognition Procedure (IRP), a fast-track regulatory process for UK drug approvals based on a recognized reference approval.

Market and Competition

H. pylori infection is the most common chronic bacterial infection among humans, with a global prevalence estimated at over 40% and ranging from 30% to 40% in North America alone (Chey et al. Am J Gastroenterol. 2024). In the U.S., we estimate that approximately 1.6 million patients per annum are treated for H. pylori eradication, based on a 2021 RedHill-funded market assessment performed by IQVIA.

Resistance to key antibiotics used to treat H. pylori infection – such as clarithromycin, levofloxacin, and metronidazole – has been increasing globally, including in the U.S., leading to increasing treatment failure rates. In the U.S., it is estimated that resistance rates to clarithromycin, levofloxacin, and metronidazole have reached 31.5%, 37.6%, and 42.1%, respectively, with dual clarithromycin and metronidazole resistance rates reaching 11.7% (Ho J et al. Am J Gastroenterol. 2022). Research indicates that approximately 20% to 30% of patients treated for H. pylori fail first-line treatment in the U.S., with eradication rates falling to as low as 50% to 75% in some countries due to the development of antibiotic resistance (Cortes et al. J Prim Care Community Health. 2021). The 2024 American College of Gastroenterology (ACG) Clinical Guideline for the treatment of H. pylori infection also reports that in the presence of known clarithromycin resistance, the predicted eradication success rate of standard PPI-clarithromycin triple therapy drops below one-third of patients. Since Talicia^® does not contain clarithromycin, it eliminates concerns regarding potential clarithromycin resistance and the need for prior antimicrobial susceptibility testing. Furthermore, the Guideline lists Talicia^® as an empirical first-line treatment option in treatment-naïve and treatment-experienced patients with H. pylori infection.

​

Talicia^® is designed to address the high resistance of H. pylori bacteria to the antibiotics commonly used in current standard-of-care therapies. Its antibiotics - amoxicillin and rifabutin - have little to no known resistance in the U.S. (Graham, Ann Intern Med, 2020). Talicia’s^® approval was supported, in part, by the results of two positive Phase 3 studies in the U.S. for the treatment of H. pylori-positive adult patients with epigastric pain and/or discomfort. The confirmatory Phase 3 study of Talicia^® demonstrated 84% eradication of H. pylori infection with Talicia^® vs. 58% in the active comparator (amoxicillin and omeprazole, equivalent to Talicia^®, but without rifabutin) arm (ITT; p<0.0001). Further, in a prespecified subpopulation analysis of data from this study, it was observed that subjects with measurable blood levels of drug at Day 13 had response rates of 90.3% in the Talicia^® arm vs. 64.7% in the active comparator arm (confirmed adherent population).

Talicia^® faces competition in the U.S. from certain branded prescription therapies indicated for the treatment of H. pylori infection, including Pylera^® (currently marketed by Juvisé Pharmaceuticals) and Voquezna^®, DualPak and TriplePak (marketed by Phathom Pharmaceuticals) as well as from the generic version of Pylera^® (first launched  by Endo International and Novast Labs) and Prevpac, and individual components of certain therapies which include but are not limited to Pylera and PrevPac. Additionally, the individual components of Talicia^® are available in generic form; however, generic rifabutin is only available in 150 mg capsules, which is not therapeutically equivalent to the low-dose formulation of rifabutin found in Talicia (Howden et al. Aliment Pharmacol Ther. 2023).

Various regimens of individual antibiotics and acid blockers are prescribed by health care professionals in the U.S., requiring multiple prescriptions, copays, and dosing regimens. None of these regimens are approved by the FDA for treatment of H. pylori infection. However, health care professionals continue to prescribe these regimens due to familiarity and lower cost implications for their patients. We may also be exposed to potentially competitive products that may be under development to treat H. pylori infection. We believe that Talicia^® offers a significant benefit over other marketed drugs in part because of the efficacy, safety and tolerability, and resistance profile demonstrated in our Phase 3 program, which showed minimal to zero resistance to amoxicillin and rifabutin and high resistance to clarithromycin and metronidazole. Currently, Talicia^® is the only rifabutin-based triple regimen approved by the FDA for the treatment of H. pylori infection in adults. Additionally, Talicia^® offers an all-in-one capsule, whereas, to our knowledge, no U.S. competitors currently offer all constituents formulated into one capsule.

Our Therapeutic Candidates

Summary

The ongoing development programs of our five therapeutic candidates include “opaganib”, “RHB-204”, “RHB-104”, “RHB-102 (Bekinda^®)”, “RHB-107” (upamostat), and related research and development programs, the most advanced of which are described below.

​

​

Opaganib

Opaganib, a new chemical entity, is a proprietary, first-in-class, orally administered, small molecule sphingosine kinase-2 (SK2) selective inhibitor in development for multiple oncology, viral, inflammatory, metabolic and additional indications. The compound originally designated as ABC294640 received an international non-proprietary name, opaganib, in the Recommended INN: List 79, 2018.

Opaganib inhibits SK2, a lipid kinase that catalyzes the formation of the lipid signaling molecule sphingosine 1-phosphate (“S1P”). S1P promotes cancer growth and proliferation and pathological inflammation, including TNFα signaling and other inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and is also involved in immune-modulation and suppression of innate immune responses from T cells.

Opaganib’s proposed antiviral mechanism, based on pre-clinical studies conducted with the molecule, inhibits the replication of positive-strand single-stranded ribonucleic acid (“RNA”) viruses, of which coronavirus, and specifically SARS-CoV-2, is a member. By binding to SK2, opaganib inhibits SK2 recruited to the viral replication-transcription complex and thus blocks the intracellular viral replication process. Because SK2 is a human host factor, opaganib’s proposed action is expected to maintain effect against known and emerging SARS-CoV-2 variants of concern irrespective of mutations in the viral spike-protein. Additionally, preclinical in vivo studies have demonstrated opaganib's potential to decrease renal fibrosis, have shown decreased fatality rates from influenza virus infection, and amelioration of bacteria-induced pneumonia lung injury by reducing the levels of IL-6 and TNF-alpha in bronchoalveolar lavage fluids.

On March 30, 2015, we entered into an exclusive worldwide license agreement with Apogee Biotechnology Corporation (“Apogee”), pursuant to which Apogee granted us the exclusive worldwide development and commercialization rights to ABC294640 (which we then renamed to opaganib and, as noted above, received an international non-proprietary name, opaganib, in 2018) and additional intellectual property for all indications. See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – License Agreement for opaganib.”

The development of opaganib was supported by grants and contracts from U.S. federal and state government agencies awarded to Apogee, including from the NCI, the U.S. government’s Biomedical Advanced Research and Development Authority (“BARDA”), a center of the Department of Health and Human Services’ (HHS) Administration for Strategic Preparedness and Response (ASPR), the U.S. Department of Defense and the FDA’s Office of Orphan Products Development. Evaluation of opaganib was also supported by the Radiation and Nuclear Countermeasures Program (RNCP), led by the National Institute of Allergy and Infectious Diseases (NIAID). Initial testing under RNCP confirmed activity of opaganib in amelioration of GI-ARS and expanded the observed effects from male mice to include also female mice. However, results from subsequent studies (SRI studies) were inconsistent with the initial positive findings which showed that opaganib significantly reduced mortality in mice in a dose dependent manner. Given the inconclusive overall results of the various studies, a decision was made by the NIAID RNCP not to continue further testing of opaganib in GI-ARS in 2026.

Market and Competition

Opaganib is in development for multiple potential indications, including for the treatment of several cancers such as prostate cancer, cholangiocarcinoma and chronic lymphocytic leukemia; virus-induced acute respiratory distress syndrome (ARDS), informed by data from a Phase 2/3 clinical study in COVID-19, Ebola and other viral diseases; as well as metabolic disorders, including diabetes, obesity and nuclear radiation protection.

Cholangiocarcinoma (bile duct cancer) is a highly lethal malignancy. According to the 2024 American Cancer Society report on bile duct cancer, approximately 8,000 people are diagnosed with intrahepatic and extrahepatic bile duct cancers annually in the U.S., though the report suggests that the actual number of cases may be higher given that these cancers can be difficult to diagnose. Surgery with complete resection is currently known to be the only curative therapy for cholangiocarcinoma; however, only a minority of patients are classified as having a resectable tumor at the time of diagnosis. Additional treatment options include radiation therapy and chemotherapy, but the efficacy of these treatments

in cholangiocarcinoma patients is also limited and the prognosis for relapse patients who have failed initial chemotherapy is very poor, with an overall median survival of approximately one year (Valle J, et al. New Eng J, Med 2010).

The FDA has approved several drug therapies for cholangiocarcinoma which largely include kinase inhibitors and checkpoint inhibitors. In April 2020, the FDA approved Pemazyre^® (pemigatinib, Incyte Corporation), the first drug approved specifically for cholangiocarcinoma, and indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma whose tumor harbors a mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. Lytgobi (futibatinib, Taiho Oncology, Inc.) is another orally administered kinase inhibitor approved by the FDA that targets FGFR2 gene mutations in adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma. FGFR2 gene fusions are found in patients with intrahepatic cholangiocarcinoma and have a reported incidence rate of 14% to 23% (Prete MG, Explor Target Antitumor Ther., 2021). In August 2021, the FDA approved Tibsovo^® (ivosidenib, Servier Pharmaceuticals LLC) for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation. IDH1 mutations are also found in patients with intrahepatic cholangiocarcinoma and have a reported incidence rate of 7% to 20% (Prete, 2021). In September 2022, the FDA approved the first immunotherapy option, Imfinzi^® (durvalumab, AstraZeneca PLC) and later, in October 2023, also approved Keytruda^® (pembrolizumab, Merck & Co., Inc.), which are a programmed death-ligand 1 (PD-L1) blocking antibody and a programmed death receptor-1 (PD-1)-blocking antibody, respectively, and are indicated for the treatment of patients with locally advanced or metastatic biliary tract cancer in combination with gemcitabine and cisplatin.

Additional marketed drugs are available for the treatment of cholangiocarcinoma in the U.S., with others in development, including lirafugratinib (Elevar Therapeutics, Inc.), a late-stage oral small molecule inhibitor of FGFR2 for second line treatment, which may subject us to additional competition. The 5-year relative survival rates of intrahepatic and extrahepatic cholangiocarcinoma patients range between 2% to 23%, depending on the tumor type and stage at diagnosis, according to the American Cancer Society. We believe there remains a high unmet medical need for new therapies for the majority of cholangiocarcinoma patients.

According to the American Cancer Society, prostate cancer was the most frequently diagnosed cancer (excluding skin cancer) and the second leading cause of cancer-related death in American men in 2025. The organization estimates that approximately 313,800 new cases of prostate cancer will be diagnosed in the U.S. in 2025. Prostate cancer is more likely to develop in older men, African American men and Caribbean men of African ancestry. Treatment options depend on each case and can include surgery, radiotherapy, cryotherapy, chemotherapy, hormone therapy, targeted therapy and immunotherapy. There are several approved drugs indicated for the treatment of prostate cancer, as well as several drugs in development for U.S. approval.

CLL is a slow-growing blood and bone marrow cancer that affects a type of white blood cell called lymphocytes. It is the most common type of leukemia in adults and has a highly variable clinical course. In the U.S., CLL is the most common type of leukemia in adults, with approximately 23,690 new cases and 4,460 related deaths estimated in 2025 (NCI PDQ^®, CLL Treatment, PMID: 26389470). Although CLL is considered incurable, many patients can experience long-term remission with existing therapies. The 5-year relative survival rate is approximately 89.3% based on SEER data from 2015 through 2021.

Most patients are asymptomatic at the time of diagnosis, and treatment is often deferred under a “watch-and-wait” approach until the leukemia progresses or symptoms occur. Once treatment is indicated, various factors are considered in selecting treatment plans for CLL patients, such as patient age, overall health and chromosomal abnormalities (e.g., a deletion in chromosome 17, a TP53 gene mutation, as well as an unmutated version of the IGHV gene).

A cornerstone of the CLL treatment landscape is venetoclax (Venclexta^®, marketed by AbbVie Inc. and Genentech in the U.S.), a highly selective B-cell lymphoma-2 (BCL-2) inhibitor. Venetoclax was initially approved by the FDA in 2016 as a continuous monotherapy for high-risk CLL patients harboring a 17p deletion who have received at least one prior therapy. Its use has since evolved toward combination therapies, enabling fixed-duration treatments for first-line use in patients without a del (17p)/TP53 mutation and second-line and subsequent therapy regardless of mutational status. Despite high response rates and prolonged progression-free survival achieved with venetoclax-based regimens, reduced efficacy and subsequent secondary resistance to venetoclax may occur in a subset of patients across continuous and fixed-duration

regimens (Kotmayer et al., Int. J. Mol. Sci. 2023). While some mechanisms underlying venetoclax resistance have been identified, they are not fully characterized, and further elucidation may inform new combination strategies aimed at overcoming venetoclax resistance in CLL patients. Literature reports that various mutations in BCL-2 and/or the upregulation of other anti-apoptotic proteins, such as BCL-XL and MCL-1, contribute to venetoclax resistance (Sarapura Martinez et al., 2023). Furthermore, studies have shown that SPHK2 is overexpressed in venetoclax-resistant cancer cells, and its inhibition may reduce T-cell-induced activation and proliferation of venetoclax-resistant CLL cancer cells and resensitize previously resistant CLL cells (Elías et al., Haematologica 2018; Sarapura Martinez et al., 2023), suggesting the therapeutic potential of SPHK inhibitors in combination with venetoclax as a potentially promising treatment option for CLL patients.  

In addition to the BCL-2 inhibitors such as Venetoclax, other targeted therapy drugs for CLL include Bruton tyrosine kinase (BTK) inhibitors and PI3K inhibitors. Additional treatment options include chemotherapy, immunotherapy, and different combinations of these. In rare cases, radiation, surgery and stem cell transplants are also used. Treatment options for patients with recurrent or refractory CLL are typically the same options used in first-line treatment, guided by prior treatment history.

GI-ARS is a condition caused by exposure to high doses of ionizing radiation to a large portion of the body, which causes damage to rapidly dividing cells in the gastrointestinal tract, leading to a range of symptoms. The severity of the symptoms can vary depending on the radiation dose absorbed. Although GI-ARS is rare, it remains a significant concern in the context of nuclear or radiological incidents that may be intentional (e.g., acts of terrorism) or accidental (e.g., radiation therapy mishaps) as it has the potential to affect large numbers of people. Recognizing this risk, the U.S. Government has prioritized the development of suitable medical countermeasures (MCMs) for GI-ARS and has implemented initiatives to support the research and development of these products.

To the best of our knowledge, no products have been approved for the treatment of GI-ARS as of the filing of this report. A 2024 article summarizing findings from a 2022 workshop organized by the NIAID in partnership with the FDA and BARDA to address the unmet need for MCMs for GI-ARS reported that general classes of candidates under evaluation by the NIAID RNCP include anti-inflammatories, cytokines/cytokine blockers, immunomodulators, cellular therapies, steroids/hormones, anti-apoptotics, anti-microbials, antioxidants, growth factors, and products targeting the microbiome and the vascular endothelium (Winters et al. Radiat Res. 2024). To our knowledge, investigational drugs reported to be in development include, but may not be limited to, MIIST305 (Synedgen Inc.), an orally administered polycationic glycopolymer, and Entolimod™ (Tivic Health Systems, Inc.), an injectable toll-like receptor 5 (TLR5) agonist that is being evaluated in late-stage studies for hematopoietic and gastrointestinal sub-syndromes of acute radiation syndrome.

COVID-19 is a disease caused by a coronavirus virus, SARS-CoV-2. The clinical spectrum has not yet been well defined and ranges from asymptomatic infection to pneumonia and acute respiratory distress syndrome (ARDS) with multiorgan failure, which may lead to death. Patients over 65 years and those with significant comorbidities, such as diabetes, cardiac or pulmonary disease, are more susceptible to developing severe disease and have a relatively higher mortality rate compared to younger, otherwise healthy patients. As of February 8, 2026, there have been over 779 million cumulative confirmed cases of COVID-19 worldwide, including over 7.1 million cumulative reported deaths worldwide according to WHO. FDA-approved or Emergency Use Authorization (EUA)- authorized COVID-19 treatments span multiple therapeutic classes, including antivirals, immunomodulators and monoclonal antibodies targeting SARS-CoV-2. Veklury^® (remdesivir, Gilead Sciences) is the only FDA-approved antiviral for the treatment of hospitalized COVID-19 patients and select high-risk non-hospitalized patients and is administered intravenously. Paxlovid™ (nirmatrelvir co-packaged with ritonavir, Pfizer Inc.) (FDA-approved) and Lagevrio™ (molnupiravir, Merck & Co., Inc.) (authorized under EUA) are oral antivirals but are limited to adults with mild-to-moderate COVID-19 who are at risk of progression to severe disease. The FDA has also approved immunomodulators for severe COVID-19 in hospitalized patients requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). These include Olumiant^® (baricitinib, Eli Lilly and Company), an oral therapy, and Actemra^® (tocilizumab, Genentech, Inc.), which is administered intravenously or subcutaneously and used in patients receiving systemic corticosteroids. In parallel, additional drug therapies are in development, and multiple FDA-licensed SARS-CoV-2 vaccines are available for prevention. To the best of our knowledge, no orally administered antiviral therapy has been approved by the FDA to date for treatment of hospitalized patients with severe COVID-19 pneumonia. Ebola disease is a rare but often deadly illness caused by a group of viruses known as orthoebolaviruses. Of the six identified orthoebolavirus species, four - Zaire, Sudan,

Taï Forest, and Bundibugyo ebolaviruses – are known to cause disease in humans according to the CDC. Zaire ebolavirus is responsible for most outbreaks and causes. According to the World Health Organization, the average case fatality rate for Ebola disease is approximately 50% (Ebola Disease Fact Sheet, 2025). Symptoms generally appear anywhere from 2 to 21 days after infection and include fever, fatigue, muscle pain, headache and sore throat, followed by vomiting, diarrhea, rash, and internal and external bleeding.

There are currently two FDA-approved products indicated for the treatment of Ebola virus disease caused by Zaire ebolavirus in adults and children. These treatments include Ebanga™ (Ansuvimab-zykl, Ridgeback Biotherapeutics) and Inmazeb^® (atoltivimab, maftivimab, and odesivimab-ebgn; Regeneron) and are both intravenously administered monoclonal antibody treatments. The FDA has also approved Ervebo^® (Merck), a vaccine indicated for the prevention of Ebola virus disease caused by Zaire ebolavirus. Additional investigational therapies are in development for the treatment of Ebola virus disease caused by Zaire ebolavirus, including but not limited to, the oral antiviral candidate pyronaridine (Collaborations Pharmaceuticals, Inc.), as well as candidates targeting orthoebolaviruses for which no FDA-approved treatments currently exist.

Clinical Development

COVID-19

Preclinical data have demonstrated both anti-inflammatory and antiviral activities of opaganib, with the potential to reduce inflammatory lung disorders, such as pneumonia, and mitigate pulmonary fibrotic damage. In September 2020, we announced that opaganib demonstrated potent inhibition of SARS-CoV-2, the virus that causes COVID-19, achieving complete blockage of viral replication in an in vitro model of human lung bronchial tissue. Additionally, preclinical in vivo studies have demonstrated that opaganib decreased fatality rates from influenza virus infection and ameliorated Pseudomonas aeruginosa-induced lung injury by reducing the levels of IL-6 and TNF-alpha in bronchoalveolar lavage fluids.

Preliminary results from a preclinical study with opaganib, administered at 250 mg/kg, demonstrated a reduction of thrombosis (blood clotting) in an acute respiratory distress syndrome (ARDS) animal model. The preclinical study was designed to assess the efficacy of opaganib in reducing the incidence of adverse thromboembolic events in situ in the lipopolysaccharide (LPS)-induced model of pulmonary inflammation, a reliable model of ARDS that can mimic COVID-19 inflammation. The preliminary results from our study show opaganib 250 mg/kg reduced blood clot length, weight and total thrombus score in a preclinical model of ARDS. We believe such preliminary results add to the known antiviral and anti-inflammatory activities of opaganib and provide the potential for a unique triple-action effect on the pathophysiological processes associated with COVID-19 disease.

In September 2020, Apogee was awarded a grant from Pennsylvania's COVID-19 Vaccines, Treatments and Therapies Program, which supports the rapid advancement of promising novel COVID-19 therapies.

ABC-201: Global Phase 2/3 Study

In July 2020, we initiated a global Phase 2/3 clinical trial evaluating opaganib in hospitalized patients with severe COVID-19 pneumonia. This global multi-center, randomized, double-blind, parallel-arm, placebo-controlled trial enrolled a total of 475 patients requiring hospitalization and treatment with supplemental oxygen. The study was approved in ten countries.

In September 2021, we reported that preliminary top-line data from the opaganib (ABC294640) global Phase 2/3 study in hospitalized patients with severe COVID-19 pneumonia showed that the study did not meet its primary endpoint. Analysis of the study efficacy endpoints did show trends in favor of the opaganib arm as compared to placebo across multiple endpoints, including the primary endpoint, despite not achieving statistical significance.

In October 2021, we reported new data from a further analysis of this study, showing that treatment with oral opaganib as compared to the placebo-controlled arm resulted in a 62% statistically significant reduction in mortality as well as statistically significant improved outcomes in time to room air and median time to hospital discharge in a group of 251 hospitalized, moderately severe COVID-19 patients, comprising 54% of the study participants.

These results were from a post-hoc analysis of data from the 251 study participants requiring a Fraction of inspired Oxygen (FiO2) up to 60% at baseline. Patients with FiO2 ≤ 60% are still considered to be severely affected and typically require oxygen supplementation via a nasal cannula or face mask.

Analyses of the FiO2 up to 60% patient subset from the opaganib Phase 2/3 study, the median for FiO2 levels in the study, who were treated with either opaganib or placebo in addition to standard-of-care (including dexamethasone and/or remdesivir) demonstrated consistent benefit across endpoints, in this subset of hospitalized moderately severe patients. Given the post-hoc characteristics of this subset, statistical inferences of significance cannot be formally attributed (nominal values presented). We also conducted a sensitivity analysis to account for missing data interpretability:

A detailed analysis of baseline risk factors and their potential impact on the mortality outcome in the sensitivity analysis group has also been undertaken, showing that the benefit is robustly maintained irrespective of the subgroups/risk factors, confirming that the positive outcome observed is due to opaganib.

In January 2022, we reported new data from a prespecified analysis of all Phase 2/3 study patients with positive PCR at screening, demonstrating that opaganib improved the median time to viral RNA clearance by at least 4 days. Treatment with opaganib resulted in viral RNA clearance in a median of 10 days while the median for clearance in the placebo arm was not reached by the end of 14-days treatment for placebo (hazard ratio 1.34; nominal p-value=0.043, N=437/463). To the best of our knowledge, opaganib is the first oral novel drug candidate to show improved viral RNA clearance in patients with severe COVID-19 pneumonia. This data provides clinical evidence supporting opaganib's potential antiviral activity.

In February 2022, we reported additional results from two prespecified analyses from the Phase 2/3 study. The first analysis showed that opaganib significantly reduced mortality when given to patients who received remdesivir and corticosteroids, the best available standard-of-care (SoC) for hospitalized patients. This analysis, undertaken for all patients from the study who were receiving remdesivir and corticosteroids at baseline, demonstrated a significant 70.2% mortality benefit for opaganib-treated patients, with a mortality rate of 6.98% (n=3/43) for the opaganib arm + SoC versus 23.4% (n=11/47) for placebo + SoC by Day 42 (p-value=0.034).

The second analysis further showed that opaganib delivered a significant benefit in time to recovery, defined as achieving a score of 1 or less on the WHO Ordinal Scale by Day 14. The prespecified analysis showed opaganib delivered a significant 34% benefit in time to recovery, with 37.4% of opaganib-treated patients (n=86/230) reaching this event versus 27.9% of patients (n=65/233) treated with placebo + SoC (p-value=0.013, Hazard Ratio 1.49).

Safety data for the Phase 2/3 clinical trial showed good tolerability of opaganib, with balanced adverse events between the study arms.

In September 2024, we reported a publication from the Phase 2/3 study published in the peer-reviewed journal, Microorganisms. Data from the post hoc analysis of oral opaganib in COVID-19 pneumonia showed a 62% reduction in

mortality and a 21% improvement in time to room air. This analysis, conducted on a sub-group of 251 hospitalized, moderately severe patients, also highlighted FiO2 levels above 60% as a potential biomarker for disease severity.

Guidance on the potential path to approval including the requirement of a confirmatory study for future emergency use approvals has been received from the EU's EMA, the U.S. FDA, UK's MHRA and others.

Preclinical evaluation of opaganib has been completed and remains ongoing in collaboration with the U.S. government and non-governmental organizations to support the development of opaganib in areas of public health interest, including pandemic preparedness and medical countermeasures. Discussions are also ongoing with other government agencies and non-governmental organizations, as well as with potential partners who are interested in the rights to opaganib in various territories.

ABC-110: U.S. Phase 2 Study

In December 2020, we announced that our randomized, double-blind, placebo-controlled U.S. Phase 2 trial with opaganib in patients hospitalized with COVID-19 pneumonia demonstrated positive safety and efficacy data. The trial, which was not powered for statistical significance, enrolled 40 patients requiring hospitalization and supplemental oxygen.

The data from the study was published in May 2022 in Open Forum Infectious Diseases.  

ABC-108: Advanced Unresectable Cholangiocarcinoma

A Phase 2a clinical study with opaganib in patients with advanced, unresectable, intrahepatic, perihilar and extrahepatic cholangiocarcinoma is ongoing at Mayo Clinic’s major campuses in Arizona and Minnesota, MD Anderson Cancer Center, the Huntsman Cancer Institute, University of Utah Health and at Emory University. In September 2018, we announced that the study achieved its pre-specified efficacy goal for the first stage of the two-stage study design, and as a result, the study has continued to its second stage. Treatment with opaganib, Part 1 of the study, designed to enroll 39 evaluable patients, completed enrollment in January 2020. The primary objective was to determine the response rate (RR) of cholangiocarcinoma defined as objective responses (OR), i.e. complete and partial responses (CR, PR) plus stable disease (SD) of at least four months to treatment with opaganib. Preliminary data from this cohort indicated that 6 of 39 (of 58 total enrolled) patients evaluable for efficacy achieved the primary endpoint of stable disease or better for at least 4 months, with good safety and tolerability heavily pretreated subjects with advanced cholangiocarcinoma.

In October 2019, an expansion cohort for cotreatment of opaganib and hydroxychloroquine sulfate (HCQ), an anti-autophagy agent, was submitted to the FDA. The primary endpoint of this cohort was to determine Durable Disease Control Rate (“DDCR”), defined as Disease Control Rate ("DCR") of at least four months’ duration to treatment with opaganib and HCQ. Enrollment of this cotreatment cohort, Part 2 of the study, began in July 2020. The cohort consists of two stages: Stage 1, an accelerated dose escalation run-in with enrollment of up to 15 patients evaluable for safety and tolerability, and Stage 2, treatment of 20 patients evaluable in the Stage 1 determined dose to determine safety and tolerability. In May 2022, RedHill closed the enrollment to the second dose tier, 500 mg BID of opaganib and 200 mg of HCQ BID. The main reason for the study’s early closure was a significant slowdown in enrollment since the start of the COVID-19 pandemic. The last patient that was enrolled demonstrated stable disease for 10 cycles and tolerated the treatment very well. Accordingly, RedHill in collaboration with the treating physician in Mayo, AZ, arranged to continue the patient’s treatment under a Single Patient IND.

A total of 65 patients have been enrolled in the study, 7 of those in the Phase I safety run-in of Part 2. Of the 7 patients that were enrolled in Part 2 (4 evaluable for efficacy), one subject has demonstrated durable stable disease for 10 months and has transitioned to a Single Patient IND. RedHill is expected to receive the data analysis and the CSR in H1/2023.

The primary objective of Part 1 is to determine the response rate (RR) of cholangiocarcinoma defined as objective responses (OR), i.e. complete and partial responses (CR, PR) plus stable disease (SD) of at least four months to treatment with opaganib. The primary endpoint of Part 2 is to determine DDCR, defined as DCR of at least four months’ duration to treatment with opaganib and HCQ.

In April 2017, the FDA granted to opaganib orphan drug designation for the treatment of cholangiocarcinoma. The orphan drug designation allows us to benefit from various development incentives to develop opaganib for this indication, including tax credits for qualified clinical testing, the waiver of a prescription drug user fee (PDUFA) upon submission of a potential NDA and, if approved, a seven-year marketing exclusivity period (subject to certain exceptions) for the treatment of cholangiocarcinoma.

Neuroblastoma

In August 2024, the FDA granted orphan-drug designation to opaganib for treatment of neuroblastoma, a type of childhood cancer that develops from immature nerve cells and accounts for 15% of all pediatric cancer-related deaths. The neuroblastoma market is expected to reach almost $1.5 billion before mid-2030s.

EAP for the Treatment of Advanced Unresectable Cholangiocarcinoma

An EAP is for eligible participants who do not qualify for participation in, or who are otherwise unable to access, the ongoing clinical trial ABC-108 for advanced unresectable cholangiocarcinoma. This program is designed to provide access to opaganib for the treatment of cholangiocarcinoma prior to approval by the local regulatory agency. As noted in the section above, one subject from study ABC-108 has transitioned to a Single Patient IND with the termination of study ABC-108. We cannot predict how long this program will continue, and we may decide for various reasons, including but not limited to resources and availability of opaganib, not to continue with the EAP.

ABC-101: Advanced Solid Tumors

A Phase 1 study, first-in-man evaluation of opaganib in advanced solid tumors was completed in the summer of 2015. Final results demonstrated that the study, conducted at the Medical University of South Carolina (MUSC), successfully met its primary and secondary endpoints, demonstrating that the compound is well tolerated and can be safely administered to cancer patients at doses predicted to have therapeutic activity.

Twenty-one patients with advanced solid tumors were treated with opaganib in the study, the majority of who were GI cancer patients, including pancreatic, colorectal and cholangiocarcinoma cancers.

The study included the first-ever longitudinal analysis of plasma S1P levels as a potential pharmacodynamic biomarker for activity of a sphingolipid-targeted drug. Administration of opaganib resulted in a rapid and pronounced decrease in levels of S1P with several patients having prolonged stabilization of disease.

The study was supported by grants from the U.S. National Cancer Institute (NCI) awarded to MUSC Hollings Cancer Center, an NCI-Designated Cancer Center, and from the FDA Office of Orphan Products Development awarded to Apogee.

ABC-107: Prostate Cancer

The investigator-sponsored study “A Phase 2 Study of the Addition of opaganib to Androgen Antagonists in Patients with Prostate Cancer Progression on Enzalutamide or Abiraterone” was initiated in March 2020 at MUSC Hollings Cancer Center and at Emory University. The study is led by Dr. Michael B. Lilly. The study is supported by the National Cancer Institute grant awarded to MUSC.

This is a Phase 2 efficacy study of opaganib in patients with metastatic castration-resistant prostate cancer that is progressing during treatment with androgen signaling blockers, abiraterone or enzalutamide. The study will consist of an initial safety “run in” cohort in which patients will receive opaganib along with continuation of prior abiraterone or enzalutamide to document tolerability in this new patient population and to document the effects of opaganib on blood prostate-specific antigen (PSA) levels. Provided that there is no untoward toxicity in these patients, there will be two additional cohorts with up to 27 patients, with each of patients with worsening disease during abiraterone or enzalutamide treatment. These patients will continue previous androgen blocking agents (abiraterone or enzalutamide, and gonadotropin-releasing hormone GnRH receptor agonist/antagonist). The primary objective of the study is to measure the proportion of patients with disease control during opaganib plus abiraterone or enzalutamide treatment using a composite metric based on PSA, bone scan, and RECIST measurements per Prostate Cancer Working Group 3 (PCWG3) criteria.

The first patient was enrolled in March 2020 and the last patient was enrolled in December 2022, completing enrollment of 66 patients: 3 in cohort 1a (abiraterone + opaganib 250 mg BID), 3 in cohort 1b (enzalutamide + opaganib 250 mg BID), 26 in cohort 2 (abiraterone + opaganib 500 mg BID), 34 in cohort 3 (enzalutamide + opaganib 500 mg BID). All patients are now off study. Disease control, the primary endpoint of the study, was defined as progression-free for at least 16 weeks and was assessed primarily in the 500 mg opaganib bid cohorts, cohorts 2 and 3. A total of 11 patients achieved disease control: 3 in the lead-in cohorts combined; 4 (15%; 95% CI 4-35%) in cohort 2 (abiraterone, and 4 (12%; 95% CI 3-27%) in cohort 3 (enzalutamide). Treatment was generally well tolerated; toxicity was similar to that noted in prior studies of opaganib, mainly neuropsychiatric. A new toxicity, subretinal fluid accumulation which manifest as visual disturbance, was noted in one patient who received opaganib and abiraterone.  This resolved in several days after the patient stopped taking opaganib. While not previously recognized, this toxicity may have been misinterpreted in the past as visual hallucinations.

On July 1, 2025, we announced the initiation of patient recruitment into an ensuing investigator-initiated phase 2 study, to evaluate the efficacy of opaganib in combination with darolutamide in men with metastatic castrate-resistant prostate cancer (mCRPC), sponsored by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd. in Australia and financially supported by Bayer (ETR: BAYN) and the Ramsay Hospital Research Foundation.

ABC-104: Oncology Support, Radioprotectant: Prevention of Radiation-Associated Mucositis in the Treatment of Head and Neck Cancer

A Phase 1b study to evaluate opaganib as a radioprotectant in head and neck cancer patients undergoing therapeutic radiotherapy is currently on hold.

​

Chronic Lymphocytic Leukemia (CLL)

In December 2025 we announced positive in vivo results of a study in mice, indicating that opaganib combined with venetoclax reduces Chronic Lymphocytic Leukemia (CLL) cells by half compared to controls, and further demonstrates opaganib’s potential as an add-on therapy to venetoclax in venetoclax-resistant CLL.

Nuclear Radiation Protection Development Program

In November 2022, we announced acceleration of opaganib’s nuclear radiation protection development program, with newly published data from eight U.S. government-funded in vivo studies, and additional experiments, indicating that opaganib was associated with:

Development of opaganib as a homeland security nuclear medical countermeasure is currently expected to follow the Animal Rule under which human efficacy studies may not be required, and if approved, may be eligible for a Medical Countermeasure Priority Review Voucher.

In February 2023, we announced that the Radiation and Nuclear Countermeasures Program (RNCP), of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, had selected opaganib for the nuclear medical countermeasures product development pipeline as a potential treatment for ARS. As part of this collaboration, contractors directed and supported by the RNCP tested opaganib in established ARS models. Initial testing under RNCP confirmed activity of opaganib in amelioration of GI-ARS and expanded the observed effects from male mice to include also female mice.

In July 2023, we also announced that Apogee had been awarded a further $1.7 million in U.S. government funding, via a Small Business Innovation Research grant, which will support research to further the development of opaganib as an MCM for GI-ARS.

Results from subsequent studies (SRI studies) were inconsistent with the initial positive findings which showed that opaganib significantly reduced mortality in mice in a dose dependent manner. Given the inconclusive overall results of the various studies, a decision was made by the NIAID RNCP not to continue further testing of opaganib in GI-ARS in 2026. Several factors varied across the different experiments, including the type and radiation doses administered, as well as systematic differences in male versus female mice responses to opaganib. Mixed findings from the various studies underscore the need to further evaluate opaganib in additional radiation models.

In February 2024, we announced that the International Journal of Molecular Sciences published data demonstrating that opaganib protects against radiation-induced lung inflammation and fibrosis in an in vivo mouse model of lung damage following exposure to ionizing radiation.

Ebola

In October 2023, we announced that opaganib delivered a statistically significant increase in survival time when given at 150 mg/kg twice a day (BID) in a United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in vivo Ebola virus study, making it the first host-directed molecule to show activity in Ebola virus disease. The U.S. Army study tested three doses of opaganib (50, 100 and 150 mg/kg BID), against an inactive vehicle control arm. The in vivo study results showed a statistically significant survival increase in mean (SE) survival time of 11.2 (2.6) days in the 150 mg/kg opaganib group (p=0.0279) compared to a mean (SE) survival time of 5.5 (0.4) days in the inactive vehicle control group. A 30% mice survival was observed in the 150 mg/kg treated group compared to the vehicle control. A subsequent repeat study showed 20% survival in the vehicle control arm and no statistically significant benefit was observed in the opaganib treated arm.

In December 2023, we announced opaganib and RHB-107 (upamostat) demonstrated robust synergistic effect when combined individually with remdesivir (a leading COVID-19 therapy sold under the brand name Veklury^® by Gilead Sciences, Inc.), significantly improving viral inhibition while maintaining cell viability, in a new U.S. Army-funded and conducted Ebola virus in vitro study.

In October 2024, we announced that BARDA had selected opaganib for development to treat exposure to Ebola.  Under this cost-sharing contract, BARDA provided partial funding for us to further advance the development of opaganib to mitigate infection and contain Ebola virus outbreaks. The overall objective of this contract was to significantly advance the development of opaganib as an oral, host-directed, therapeutic medical countermeasure (MCM) for Ebola infection for prevention of a potential disease outbreak. We proposed three sets of pre-clinical deliverables, that included: Assessment of opaganib in vitro responsiveness in multiple species; Assessment of the mechanism of action of opaganib for suppression of Ebola replication; and Pharmacokinetic/pharmacodynamic (PK/PD) analyses to identify opaganib dose–effect relationships in guinea pigs. These deliverables are aligned with the Animal Rule regulatory pathway and are prerequisites for further development. We successfully finished these three sets of pre-clinical studies.

In early 2026, this project which evaluated opaganib in Ebola via USAMRIID concluded. No additional support is currently expected from BARDA regarding the ongoing development of opaganib in Ebola. Further testing of opaganib in this indication is required and alternative models are being evaluated to further assess the drug.

ABC-105: Moderate to Severe Ulcerative Colitis (“UC”)

A Phase 2 study to evaluate the efficacy of opaganib in patients with moderate to severe UC by the proportion of patients who are in remission at the end of treatment is currently on hold.

ABC-109: Food Effect Study in Healthy Subjects

A Phase 1, randomized, open-label, single-dose, 3-treatment, 3-period, 6-sequence crossover study designed primarily to evaluate the effect of a standardized meal on the absorption and bioavailability of opaganib in healthy subjects, was completed in the U.S. in January 2018. The study also evaluated the effect of the administration of a solution of opaganib via nasogastric (NG) tube on the absorption and bioavailability of opaganib. Twenty-three eligible, healthy, male and female adult subjects were randomized to receive opaganib orally in a state of fast, fed or as a solution by NG tube (after tube feeding). Seventeen subjects received all three treatments. All three treatments, though maximum concentration was lower when the drug was given orally in the fed state as compared to fasted, nasogastric administration after tube feeding led to intermediate results. Subjects experienced fewer gastrointestinal side effects when the drug was given in the fed state than fasted, but the pharmacodynamic effect, as reflected in the decrease in sphingosine-1-phosphate, the product of the target enzyme, was no lower after fed than fasted administration. Thus, the results indicated that opaganib may be administered after eating, with improved tolerance and no loss of pharmacodynamic effect.

​

The following chart summarizes the clinical trial history and status of opaganib:

​

​

We cannot predict with certainty our development costs, and such costs may be subject to changes. See “Item 3. Key Information – D. Risk Factors – Risks Related to Our Financial Condition and Capital Requirements”.

Other Preclinical studies

In September 2021, we announced results of a preclinical study demonstrating opaganib’s efficacy in significantly decreasing renal fibrosis in a unilateral ureteral obstruction-induced renal interstitial fibrosis model. Reported data suggest that over 20% of hospitalized COVID-19 patients experience acute renal failure (Nadim et al., J Am Soc Nephrol, 2020). The aim of the in vivo efficacy study was to verify the effect of opaganib on kidney inflammation and fibrosis in a unilateral

ureteral obstruction (UUO) model – a well characterized model for renal fibrosis. Results from the study showed that opaganib significantly decreased renal fibrosis.

Opaganib demonstrated potent antiviral activity against SARS-CoV-2, the virus that causes COVID-19, completely inhibiting viral replication in an in vitro model of human lung bronchial tissue. In June 2021, we announced that preliminary results from a preclinical study demonstrated potent inhibition of the Beta and Gamma COVID-19 variants of concern by opaganib at non-cytotoxic doses. We further announced in August 2021 that opaganib demonstrated strong inhibition of the Delta variant replication while maintaining cell viability at relevant concentrations in a 3D tissue model of human bronchial epithelial cells. In April 2022, we announced study results in which opaganib was observed to have potent in vitro efficacy against the Omicron SARS-CoV-2 variant, while maintaining host cell viability, and in October 2022, we announced study results showing preliminary evidence of in vitro efficacy against the Omicron COVID-19 sub-variant BA.5 by opaganib and RHB-107. Based on opaganib’s unique host-targeted mechanism and the preliminary results of this study, we believe opaganib is likely to also maintain its activity against emerging variants of COVID-19.

In an in-vitro study sponsored by NIAID, opaganib demonstrated activity against Influenza A H1N1 in a human airway epithelial cell line. Upon successful completion of the above assay, further in-vivo studies of opaganib for treatment of influenza A/CA/04/2009 (H1N1pdm) virus infection in C57BL/6 mice were initiated at Utah State University to determine the efficacy of opaganib.  The experiment was technically flawed, as the positive control was also only minimally effective. One of the groups of mice that were treated with the opaganib dose of 150 mg/kg survived the infection after treatment, which was not statistically significant. Following discussion with NIAID, a repeat of the experiment using Balb-C mice and exploring potential synergy with oseltamivir was not approved.

In August 2024, we announced positive results from multiple in vivo studies of oral opaganib for the treatment of obesity and diabetes. These studies demonstrated the impact of sphingosine kinase-2 (SK2) inhibition in various metabolic disease models, supporting the potential of opaganib therapy for diabetes and obesity-related disorders. In April 2025, we announced the new publication of positive in vivo data in the journal Diabetes, Metabolic Syndrome and Obesity, in an article entitled "Opaganib Promotes Weight Loss and Suppresses High-Fat Diet (HFD)-Induced Obesity and Glucose Intolerance". The data indicates that opaganib effectively suppresses the loss of metabolic control in mice on a high fat diet, suggesting that opaganib, alone and in combination with semaglutide, is associated with improved glucose tolerance, decreased deposition of fat, weight loss and the prevention of weight gain rebound after removal of semaglutide.

RHB-204

RHB-204 is a proprietary, fixed-dose oral capsule containing a combination of clarithromycin, rifabutin and clofazimine in development for the treatment of Mycobacterium avium subspecies paratuberculosis-positive (MAP-positive)-related Crohn's disease. RHB-204 was originally developed for the treatment of pulmonary nontuberculous mycobacterial (NTM) disease caused by Mycobacterium avium complex (MAC).

Crohn’s Disease

RHB-204 is a next-generation, optimized formulation of RHB-104, in development for the treatment of MAP+ moderate to severe Crohn's disease. RHB-204 contains the same antimicrobial agents as RHB-104 with potent intracellular, anti-mycobacterial, and anti-inflammatory properties, but with an optimized dosing profile designed to support enhanced tolerability, safety and adherence. The development of RHB-204 builds on the positive results achieved in the randomized, double-blind, placebo-controlled 331-patient Phase 3 study of RHB-104 in active Crohn’s disease (the “MAP US” study) (see “RHB-104” for additional details).

Crohn’s disease, which is a serious inflammatory disease of the GI system that may cause severe abdominal pain and bloody diarrhea, malnutrition and potentially life-threatening complications.

To date, Crohn’s disease has been considered an autoimmune disease, but the exact pathological mechanism is unclear. Dr. Robert J. Greenstein suggested in The Lancet Infectious Diseases, 2003, that Crohn’s disease is caused by MAP, the same organism responsible for causing a major disease in animal agriculture production, domestic and wild animals. This hypothesis is supported by an expanding number of scientific and clinical studies published in peer-reviewed journals

since a National Institute of Allergy and Infectious Diseases conference that focused on MAP in Crohn’s disease took place in 1998. Specific genetic loci like NOD2/CARD15 have been implicated in the pathogenesis of Crohn’s disease with mutations in NOD2 suspected of leading to defective recognition of MAP and increased compensatory immune activation in patients with Crohn’s disease. Advances in diagnostic technology have led to increasingly higher identification of MAP, with studies, such as Naser S et al. The Lancet, 2004, Bull TJ et al. J Clin Microbiol, 2003 and Shafran I et al. Dig Dis Sci, 2002, demonstrating a high prevalence of MAP in Crohn’s disease patients. However, there is currently no FDA-approved commercial diagnostic test for MAP.

A major hurdle in previous clinical studies for new therapies directed at MAP has been the ability to rapidly and accurately detect MAP. The Company is collaborating with two leading academic centers for the provision of cutting-edge MAP detection diagnostics, supporting the study's novel design and the potential future commercial application of RHB-204.

Market and Competition

According to GlobalData, a provider of market intelligence for the pharmaceutical sector, there were approximately 4.1 million diagnosed prevalent cases of Crohn’s disease in 2025 in the sixteen major pharmaceutical markets (the U.S., France, Germany, Italy, Spain, the UK, Japan, Australia, Brazil, Canada, China, India, Mexico, Russia, South Africa and South Korea).

Therapeutic interventions in Crohn’s disease patients are based on the disease location, severity, and associated complications. Therapeutic approaches for the treatment of Crohn’s disease are individualized according to the patient’s symptomatic response and tolerance to the prescribed treatment. Since the existing treatments are not curative, the current therapeutic approaches are sequential and involve treatment of an acute disease or inducing clinical remission followed by maintenance of the response or remission to improve the patient’s quality of life.

Currently, available drugs on the market for the treatment of Crohn’s disease offer symptomatic relief, the effects of which are largely temporary or partial and are accompanied by numerous adverse effects. Marketed treatments for Crohn’s disease  include 5-Aminosalicylates (5-ASA, such as mesalamine), corticosteroids (such as prednisone), antibiotics, immunomodulators (such as azathioprine and methotrexate) and biologic agents, including TNF-α inhibitors (such as Remicade^®, Humira^®, and Cimzia^®), integrin receptor antagonists (such as Tysabri^® and Entyvio^®) and interleukin biologics targeting IL-12 and/or IL-23 pathways (such as Stelara^®, Skyrizi^® and more recently approved Omvoh^® and Tremfya^®). In 2023, the FDA approved Rinvoq^® (upadacitinib), a Janus kinase (JAK) inhibitor for the treatment of adults with moderately to severely active Crohn’s disease. The initial indication limited the use to patients who had an inadequate response or intolerance to treatment with one or more TNF blockers. In 2025, the FDA approved a supplemental new drug application (sNDA) for Rinvoq, expanding the label to permit use before TNF blockers in patients for whom such therapies are clinically inadvisable, following at least one approved systematic therapy. While Rinvoq is the only FDA-approved once daily-oral pill approved for moderate to severe Crohn’s disease, it carries an FDA black box warning against serious infections, mortality, malignancy, major adverse cardiovascular events and thrombosis. Furthermore, additional products that are approved by the FDA and in development for the treatment of Crohn’s disease may represent additional competition, including novel biologic therapies and biosimilars, small molecules and other types of therapies.

Unlike drugs currently on the market for the treatment of Crohn’s disease, RHB- 204, which is orally administered is intended to address the suspected cause of the disease - MAP bacterial infection. To the best of our knowledge, there are no drugs approved for marketing that target infections caused by MAP bacteria in Crohn’s disease patients.

Nontuberculous Mycobacteria Infections

In November 2020, we initiated a Phase 3 study in RHB-204 for the treatment of pulmonary Mycobacterium avium complex (MAC) disease in adults with nodular bronchiectasis (also referred to hereafter as pulmonary NTM disease caused by MAC).

The study was intended to assess the efficacy and safety of RHB-204 as a potential first-line, stand-alone treatment for pulmonary NTM infections caused by MAC. In May 2023, we announced the termination of the study due to a very low accrual rate, and the shifting of our resources to advance once-daily, oral RHB-107’s late-stage development for outpatient

treatment of COVID-19. We continue to explore potential partnerships for RHB-204 and, following positive FDA feedback in July 2025, are expanding the planned indications to be pursued with RHB-204 to Crohn’s disease.

In January 2017, we announced that RHB-204 had been granted QIDP designation by the FDA for the treatment of pulmonary NTM infections, including eligibility for Accelerated Approval and Priority Review and an extended market exclusivity period, if approved for marketing in the U.S.

In October 2020, we announced that RHB-204 had been granted Orphan Drug designation by the FDA for the treatment of pulmonary NTM infections which would extend market exclusivity period to a total of 12 years, if approved for marketing in the U.S.

In January 2021 we announced that the FDA granted RHB-204 Fast Track designation, allowing RedHill access to early and frequent communications with the FDA, to expedite the RHB-204 development program, and to a rolling review of an NDA.

In August 2022, we announced that the European Commission granted Orphan Drug Designation to RHB-204 for the treatment of NTM disease, following a positive opinion recommendation by the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products, providing eligibility for 10 years post-approval EU market exclusivity.

RHB-204 is a patented fixed-dose combination product of three antibiotics intended to simplify administration and optimize compliance, selected based on modelling to provide optimal balance of the potential safety and efficacy. Each capsule contains the same three antibiotics as RHB-104 (clarithromycin, clofazimine, and rifabutin), but at doses unique from RHB-104. Clarithromycin and rifabutin were selected because mycobacteria live within host cells, and these agents have intracellular activity against MAC. Further, rifabutin enhances the antimicrobial activity of clarithromycin due to increased levels of clarithromycin's active metabolite. Selection of clofazimine was based on its activity against MAC, preferential accumulation in macrophages and bactericidal activity demonstrated in a mouse model of tuberculosis. Moreover, the inclusion of rifabutin and clofazimine has shown to mitigate the emergence of resistance to clarithromycin compared to clarithromycin alone or in combination with only rifabutin or clofazimine in a clarithromycin- susceptible M. avium lung infection mouse model as well as exhibiting significant reductions in bacterial counts in the lung after four and eight weeks of treatment.

Market and Competition

Pulmonary NTM is an orphan disease and is expected to affect approximately 112,000 patients in the U.S. in 2026, according to a 2021 analysis by Foster Rosenblatt. Although rare, the incidence and number of deaths from NTM disease have been steadily increasing globally, according to Ratnatunga CN et al. (Front. Immunol. 2020), with a rise in the number of globally documented NTM infections leading to NTM being recognized as an emerging threat causing significant morbidity and mortality in both immune competent and immune compromised populations. Treatment options remain limited, lengthy and challenging (Ryu YJ et al. Tuberc Respir Dis, 2016; Ratnatunga CN et al. Front. Immunol. 2020).

NTM are naturally occurring organisms found in water and soil, which can cause chronic pulmonary infection. According to Prevots DR (Am J Respir Crit Care Med, 2010) and Winthrop KL (Am J Respir Crit Care Med, 2010), approximately 80% of pulmonary NTM cases in the U.S. are associated with MAC. In some people, infection with NTM may lead to a progressive lung disease characterized by fever, weight loss, chest pain, and blood in sputum. NTM disease is more common in the older adult population and individuals with a compromised immune system or underlying lung disease.

According to the American Lung Association, NTM are relatively resistant to antibiotics and can become more resistant if only one antibiotic is used. Effective treatment of NTM caused by MAC requires three drugs for at least 12 months of treatment. Currently recommended treatment regimens, drug resistance patterns, and treatment outcomes differ according to the NTM species, and management is a lengthy complicated process with limited therapeutic options (Ryu YJ et al. 2016). There is currently no approved first-line therapy for NTM lung disease. Treatment is determined based on guidelines and includes multi- drug regimens with antibiotics not approved for NTM. Adherence to the guidelines for treating NTM lung disease is suboptimal, and potentially harmful antibiotic regimens are commonly prescribed. Management of NTM disease requires prolonged use of costly combinations of multiple drugs with a significant potential for toxicity.

In September 2018, the FDA approved Arikayce^® (amikacin liposome inhalation suspension), a new drug developed by Insmed Incorporated, for the treatment of lung disease caused by MAC in a limited population of refractory patients who do not respond to conventional treatment. To the best of our knowledge, this is the first treatment approved specifically for pulmonary NTM infections caused by MAC. Arikayce^® is indicated as a second-line therapy in refractory patients as part of a combination antibacterial drug regimen. The Arikayce^® prescribing information includes a Boxed Warning regarding the increased risk of respiratory conditions, including hypersensitivity pneumonitis, bronchospasm, exacerbation of underlying lung disease and hemoptysis that have led to hospitalizations in some cases.

A number of investigational drugs are in development for the treatment of NTM infections. This includes Insmed’s Arikayce^®, which is being evaluated in a Phase 3 trial for use in patients with newly diagnosed or recurrent MAC lung disease who have not started antibiotics. Additional drugs under development include Nuzyra^® (Paratek Pharmaceuticals), an oral antibacterial agent in Phase 2 development, and LungFit^® GO (Beyond Air Inc.), an inhaled nitric oxide therapy for NTM designed for at-home use, which has completed a pilot study. Epetraborole (AN2 Therapeutics), an oral antibiotic agent, failed to demonstrate sufficient efficacy in a Phase 2/3 trial in treatment-refractory MAC lung disease and is now being explored in M. abscessus lung disease (another species of non-tuberculous mycobacteria). In parallel, other therapies are being developed for the treatment of NTM infections in the U.S., which, to the best of our knowledge, are largely in early-stage development.

Clinical Development

Although each of the three components of RHB-204 is approved individually and has been tested extensively in humans (e.g., see RHB-104), the formulation and doses represented by RHB-204 are novel and has not previously been tested in humans.

In March 2025, we announced plans to advance the development of RHB-204 in Crohn's disease, with initiation of an innovative Phase 2 study of RHB-204 in Mycobacterium avium subspecies paratuberculosis-positive (MAP+) moderate to severe Crohn’s disease, utilizing novel endpoints and the new gold standard in imaging techniques, pending Type C discussions on path to FDA approval. In July 2025, we announced positive feedback received from the FDA, following the scheduled Type C meeting, in which the FDA provided guidance on the pathway to approval for the Company's RHB-204 Crohn's disease development program.

The planned Phase 2 study in MAP-positive Crohn's disease patients is expected to have primary endpoints of mucosal remission (considered by FDA as a new gold standard in efficacy evaluation in Crohn’s disease), correlated with MAP status and clinical remission, per FDA guidance. These endpoints are supported by the positive RHB-104 Phase 3 study safety and efficacy results. The endpoints and expected use of imaging and cutting-edge MAP detection methods to correlate mucosal healing with MAP infection eradication, enable a potentially smaller sample size allowing for substantially lower study costs and faster time to completion.

Initiation of the trial for pulmonary NTM lung infections was in November 2020, and in May 2023, we announced the termination of the study due to a very low accrual rate, and the shifting of our resources to advance once-daily, oral RHB-107’s late-stage development for outpatient treatment of COVID-19.The following chart summarizes the development history and status of RHB-204:

​

​

RHB-104

Crohn’s Disease

RHB-104 is a patented combination of clarithromycin, clofazimine, and rifabutin, three generic antibiotic ingredients, in a single capsule. The compound was developed to treat Mycobacterium avium subspecies paratuberculosis (MAP) infections in Crohn’s disease and completed a Phase 3 study in this indication, meeting its primary and secondary endpoints. Development efforts for this indication are now centered on RHB-204, a next generation and optimized formulation of RHB-104.

In 2011, we obtained FDA “Orphan Drug” status for RHB-104 for the treatment of Crohn’s disease in the pediatric population. See “Item 4. Information on the Company – B. Business Overview – Government Regulations – Orphan Drug Designation.”

We acquired the rights to RHB-104 pursuant to an asset purchase agreement with Giaconda Limited, an Australian company. See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – Acquisition of Talicia^®, RHB-104, and RHB-106.”

Clinical Development

A Phase 3 clinical trial for RHB-104 was conducted in Australia, sponsored by Pharmacia, a Swedish company (which merged with Pfizer), with the primary endpoint of evaluating the ratio of patients with recurrent symptoms of Crohn’s disease following the initial induction of remission with 16 weeks of treatment with prednisolone initiated at 40 mg/day and weaned over the 16-week period. Subjects were subsequently assessed at 52, 104 and 156 weeks. The main secondary objective was the percentage of patients who achieved clinical remission at 16 weeks. The results of the trial were published by Professor Warwick Selby et al. in 2007 in the medical journal Gastroenterology. Although the study did not meet the main objective of showing a difference in relapse rate with long-term treatment, there was a statistically significant difference between the treatment groups in the percentage of subjects in remission at week 16. Professor Marcel Behr and Professor James Hanley from McGill University published a re-analysis of the study in The Lancet Infectious Diseases in June 2008, based on the intent-to-treat (ITT) principle and found that there was a significant statistical advantage for the active therapy over the placebo throughout the two-year period of administration that disappeared once the active therapy was discontinued.

In June 2011, we entered into an agreement with our Canadian service provider, which entered into a back-to-back agreement with PharmaNet Canada Inc. for the provision of clinical trial services for the RHB-104 adult studies in North America and Europe. PharmaNet was subsequently acquired by inVentiv Health which became Syneos Health (“Syneos”), and our agreements were transferred to Syneos.

In October 2012, we entered into an agreement with our Canadian service provider, which, in turn, entered into a back-to-back agreement with a Canadian manufacturer to complete the manufacturing and supply of RHB-104 for our clinical trials. In addition, we entered into additional manufacturing agreements directly with the Canadian manufacturer.

In July 2018, we announced positive top-line results from the first Phase 3 study with RHB-104 for Crohn’s disease (the “MAP US study”), a randomized, double-blind, placebo-controlled first Phase 3 study with RHB-104 for Crohn’s disease. The Phase 3 study enrolled 331 subjects with moderately to severely active Crohn’s disease (defined as Crohn’s Disease Active Index (“CDAI”) between 220 and 450) in the U.S., Canada, Europe, Australia, New Zealand, and Israel. Subjects were randomized 1:1 to receive RHB-104 or placebo as an add-on therapy to baseline standard-of-care medications, including 5-ASAs, corticosteroids, immunomodulators or anti-TNF agents.

Our MAP US study successfully met its primary endpoint, as well as key secondary endpoints. Top-line results in the intent-to-treat (ITT) population demonstrated superiority of RHB-104 over placebo in achieving remission at week 26, defined as CDAI value of less than 150, the primary endpoint of the study. The proportion of patients meeting the primary endpoint was significantly greater in the RHB-104 group compared to placebo at week 26 (37% vs. 23%, p= 0.007). Moreover, while the secondary endpoints were not powered for significance in this induction of remission trial, key

secondary endpoints were nevertheless met with statistically and clinically meaningful outcomes, demonstrating consistent benefit to Crohn’s disease patients treated with RHB-104. RHB-104 was found to be generally safe and well tolerated.

In October 2018, we reported additional positive data from the MAP US study, including subgroup analysis of treatment with and without anti-TNF agents, presented at the United European Gastroenterology Week 2018.

In October 2019, we announced full week 52 results of blinded treatment in the MAP US study at the American College of Gastroenterology, which were consistent with the previously reported interim positive outcomes from the study. The study continued to meet its primary endpoint of clinical remission, defined as CDAI value of less than 150, at week 26 (36.7% vs. 22.4%, p=0.0048), key secondary endpoints of maintenance of remission at weeks 16 and 52 (25.9% vs. 12.1%, p=0.0016) and, notably, durable clinical remission on all visits, week 16 through 52 (18.7% vs. 8.5%, p=0.0077) (in all cases, data presented as RHB-104 vs. placebo).

RHB-104 was found to be generally safe and well tolerated, with an overall balance in the type and frequency of adverse events between RHB-104 and placebo. RHB-104 was associated with a lower incidence of Clostridiodies (Clostridium) difficile infections compared with placebo. In the analysis of the complete safety information for the study, a top-line electrocardiogram monitoring report for the MAP US study, which was shared with the FDA, demonstrated evidence of progressive prolongation of the QTcF (corrected QT interval by Frederica’s formula) interval across visits, with the largest mean placebo-corrected ΔQTcF (∆∆QTcF) of 30.6ms at week 52 of treatment. Clofazimine, as well as clarithromycin (another active component of RHB-104), are known to be associated with QT prolongation.

In October 2019, we also announced supportive top-line results from an open-label extension Phase 3 study (the “MAP US2 study”), which was conducted to evaluate the safety and efficacy of RHB-104 in subjects who remain with active Crohn’s disease (CDAI ≥ 150) after 26 weeks of blinded study therapy in the Phase 3 MAP US study. These subjects had the opportunity to receive treatment with RHB-104 for a 52-week period in the open-label MAP US2 study. A total of 54 subjects entered the open-label extension study in the U.S., Canada, Europe, Israel, and New Zealand, and 30 subjects completed 52 weeks of treatment with RHB-104. The MAP US2 study’s primary endpoint is disease remission at week 16, defined as CDAI of less than 150. Top-line results from the MAP US2 study demonstrated 28% clinical remission with RHB-104 at week 16 and 22% remission at week 52. Of the MAP US2 subjects who were previously randomized to the placebo arm (as an add-on to standard-of-care therapies) in the MAP US study and treated with RHB-104 for the first time in the MAP US2 study, 32% achieved remission at week 16.

Further development of RHB-104 will likely require a validated lab test for the detection of MAP bacteria in Crohn’s disease patients. Efforts to develop such a test are in part based on reliably detecting the presence of MAP bacterial DNA in human biological specimens. We are currently collaborating with two leading scientific academic centers for the provision of cutting-edge MAP detection diagnostics as part of RHB-204 development program to support the planned Phase 2 study in MAP-positive Crohn’s disease patients. We do not know if or when such a diagnostic test would become available. Additional FDA guidance on the potential path to approval of RHB-104 is to be obtained prior to initiation of further clinical studies.

We have conducted several supportive studies with the current formulation of RHB-104, including a population pharmacokinetic study that was conducted as part of the Phase 3 MAP US study.

We believe that additional clinical studies will be required to support an NDA for RHB-104, if filed.

The following chart summarizes the clinical trial history and status of RHB-104 studies and its earlier individual active agents: