{"url_path":"/sec/rdhl/10-k/2026/item-4","section_key":"item-4","section_title":"Item 4 INFORMATION ON THE COMPANY**","topic":"sec","document":{"doc_type":"20-F","doc_date":"2026-04-27","source_url":"https://www.sec.gov/Archives/edgar/data/1553846/0001104659-26-049055-index.html","accession_number":"0001104659-26-049055","cik":"0001553846","ticker":"RDHL","issuer_name":"RedHill Biopharma Ltd.","edgar_url":"https://www.sec.gov/Archives/edgar/data/1553846/0001104659-26-049055-index.html","primary_entity_key":"0001553846","primary_entity_name":"RedHill Biopharma Ltd."},"word_count":28353,"has_tables":true,"body_markdown":"**ITEM 4.          INFORMATION ON THE COMPANY**\n\n**A.          History and Development of the Company**\n\nOur 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.\n\nIn 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.”\n\nThe 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.\n\nOur 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.\n\nOur 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.\n\n**B.           Business Overview**\n\nWe 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.\n\nWe 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.\n\n65\n\n[Table of Contents](#TOC)\n\nAmong 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.\n\nOur 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.\n\n**Our Strategy**\n\nOur 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.\n\nKey elements of our strategy are to:\n\n●Identify and enter into out-licensing or collaborative agreements with third parties to (i) develop and/or commercialize Talicia® outside the U.S. through Talicia Holdings; and (ii) develop and/or commercialize future commercial products or therapeutic candidates through Talicia Holdings or controlled entities, and with partners where applicable;\n\n●Enhance existing pharmaceutical products, including broadening their range of indications, or launching innovative and advantageous pharmaceutical products, based on existing active ingredients. Because there is a large knowledge base regarding existing products, the preclinical, clinical and regulatory requirements needed to obtain marketing approval for enhanced formulations are relatively well-defined. In particular, clinical trial designs, inclusion criteria and endpoints previously accepted by regulators may sometimes be re-used. In addition to reducing costs and time to market, we believe that targeting therapeutics with proven safety and efficacy profiles provides us with a better prospect of clinical success;\n\n●Seek creative and resource-efficient ways to advance our pipeline and commercial strategy despite liquidity constraints, including through grants, government and institutional partnerships, collaborations, and other funding mechanisms- including opportunistic transactions with entities that have available cash but limited operations - that align with our limited resources;\n\n●Identify and acquire or in-license rights to FDA approved or other commercial-stage products, including from pharmaceutical companies seeking to divest or out-license non-core assets, subject to securing appropriate external funding, strategic financing, and/or structured acquisition terms. We focus on products addressing significant clinical needs, with existing or potential revenue generation, strong market potential and IP or regulatory protection, and also seek to diversify our portfolio by acquiring products based on different technologies. Any commercialization of acquired products may be executed through Talicia Holdings, where appropriate, or through controlled entities, and with partners where applicable. We source these opportunities through our broad industry network;\n\n●Where applicable, utilize the FDA’s 505(b)(2) regulatory pathway to potentially obtain more timely and efficient approval of our formulations of previously approved products. Under the 505(b)(2) process, we are able to seek FDA approval of a new dosage form, strength, route of administration, formulation, dosage regimen, or indication of a pharmaceutical product that has previously been approved by the FDA. This process enables us to partially rely on the FDA findings of safety or efficacy for previously approved drugs, thus avoiding the duplication of\n\n66\n\n[Table of Contents](#TOC)\n\ncostly and time-consuming preclinical and various human studies. See “Item 4. Information on the Company – B. Business Overview – Government Regulations – Section 505(b)(2) New Drug Applications”;\n\n●Cooperate with third parties to develop or commercialize therapeutic candidates in order to share costs and leverage the expertise of others; and\n\n●Consider potential acquisitions of other companies with or without commercial products, including combinations or strategic partnerships with companies that may have complementary assets, capabilities, or financial resources.\n\nThe 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.\n\n**Commercial Operations in the U.S.**\n\nWe 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.\n\nAs 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.\n\nWe 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.\n\n*Talicia*® *(omeprazole magnesium, amoxicillin, and rifabutin) delayed-release capsules 10.3 mg/250 mg/12.5 mg*\n\nTalicia® 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.\n\nChronic 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, 15th ed. U.S. Dep. of Health and Human Services. 2021. Helicobacter pylori (Chronic Infection)).\n\n67\n\n[Table of Contents](#TOC)\n\nGastric 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).\n\nWe 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.”\n\nOn 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.\n\nIn 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.”\n\nOn 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.”\n\nIn 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.\n\n*Regulatory Status*\n\nOn November 1, 2019, Talicia® was approved by the FDA and was granted a total of eight years of U.S. market exclusivity.\n\nIn 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.\n\n​\n\n68\n\n[Table of Contents](#TOC)\n\nIn 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.  \n\nIn 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®.\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\n*Market and Competition*\n\n*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.\n\nResistance 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.\n\n​\n\n69\n\n[Table of Contents](#TOC)\n\nTalicia® 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).\n\nTalicia® 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).\n\nVarious 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.\n\n70\n\n[Table of Contents](#TOC)\n\n**Our Therapeutic Candidates**\n\n*Summary*\n\nThe 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.\n\n​\n\n​\n\n** **\n\n​\n\n**Potential Advantages**\n\n \n\n​\n\n​\n\n​\n\n​\n\n**Over Most Existing**\n\n​\n\n​\n\n​\n\n​\n\n**Name of Therapeutic**\n\n​\n\n​\n\n​\n\n**Treatments, if**\n\n​\n\n**Development**\n\n​\n\n​\n\n**Candidate**\n\n**  ​ ​ ​**\n\n**Proposed Indication**\n\n**  ​ ​ ​ ​**\n\n**Approved**\n\n**  ​ ​ ​**\n\n**Stage**\n\n**  ​ ​ ​ ​**\n\n**Rights to the Product**\n\nOpaganib\n\n​\n\nProstate cancer\n\n​\n\n​\n\nOral administration, first-in-class SK2 selective inhibitor, sensitizes prostate cancer cells to androgen receptor signal inhibitors (e.g. darolutamide)\n\n​\n\nInvestigator-sponsored Phase 2 study in the U.S completed.\n\n​\n\nInvestigator-initiated phase 2 study in combination with Bayer’s darolutamide – recruiting in Australia (Daro-Lipid Trial)\n\n​\n\nWorldwide exclusive license\n\nOpaganib\n\n​\n\nPatients hospitalized with severe COVID-19 pneumonia\n\n​\n\nOral administration, first-in-class SK2 selective inhibitor, with anti-inflammatory, antiviral and anti-cancer activities\n\n​\n\nData received from the U.S. Phase 2/3 study; Data offers a  compelling rationale for further investigation in acute respiratory distress syndrome (ARDS), with data from the Phase 2/3 COVID-19 study to support a potential Phase 2/3 study in ARDS\n\n​\n\nWe filed patent applications to protect the proposed commercial use\n\nOpaganib\n\n​\n\nHost directed anti-viral\n\n​\n\nOral administration, first-in-class SK2 selective inhibitor, with anti-inflammatory and anti-viral activities\n\n​\n\nPreclinical stage; RedHill is seeking ongoing collaborations for further development in Ebola and other viral diseases\n\n​\n\nWorldwide exclusive license\n\nOpaganib\n\n​\n\nNuclear radiation protection\n\n​\n\nOral, small molecule pill that is stable with a more than five-year shelf-life, easy to administer and distribute, supporting, if approved, potential central stockpiling by governments\n\n​\n\nIn vivo studies completed, supported by U.S. government-funding and additional validation experiments planned\n\n​\n\nWorldwide exclusive license\n\nRHB-204 & RHB-104 (RHB-204 is the next-generation, optimized formulation of RHB-104)\n\n​\n\nModerate to severe Crohn’s disease in *Mycobacterium avium subspecies paratuberculosis*-positive (MAP+) patients\n\n​\n\nOral drugs with novel mechanisms of action (targeting suspected underlying cause of Crohn’s disease); RHB-104 demonstrated improved clinical benefit in this indication\n\n​\n\nRHB-104: First Phase 3 study successfully completed; supportive results from the open-label extension\n\nRHB-204: Phase 2 study planned\n\n​\n\nWe filed patent applications internationally directed to the proposed commercial formulation and use\n\nRHB-102 (Bekinda®) 24 mg\n\n​\n\nAcute gastroenteritis and gastritis\n\n​\n\nNo other approved 5-HT3 serotonin receptor inhibitor for this indication; offers once-daily dosing\n\n​\n\nFirst Phase 3 study in the U.S. completed; confirmatory Phase 3 study designed\n\n​\n\nWe filed patent applications internationally to protect the proposed commercial formulation and its use\n\nRHB-102 (Bekinda®) 12 mg\n\n​\n\nDiarrhea-predominant irritable bowel syndrome (IBS-D)\n\n​\n\nPotential 5-HT3 serotonin receptor inhibitor with potential for improved safety with maintained efficacy\n\n​\n\nPhase 2 in the U.S. completed; Two pivotal Phase 3 studies planned\n\n​\n\n​\n\nWe filed patent applications internationally to protect the proposed commercial formulation and its use\n\nRHB-102 (Bekinda®) 24 mg\n\n​\n\nOncology support (management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy)\n\n​\n\nReduced number of drug administrations, potential for improved compliance and adherence\n\n​\n\nMAA planned in  U.K (being pursued by our partner, Hyloris)\n\n​\n\nWe filed patent applications internationally to protect the proposed commercial formulation and its use.\n\nRHB-107 (upamostat; formerly Mesupron)\n\n​\n\nOutpatients infected with SARS-CoV-2 (COVID-19 disease)\n\n​\n\nOral administration, inhibitor of human serine proteases with antiviral activity and established safety profile\n\n​\n\nPart A of Phase 2/3 study completed. Included in a multi-site Phase 2 platform trial supported by the U.S.-Government  study, which was terminated\n\n​\n\nWe filed patent applications to protect the proposed commercial use\n\nRHB-107 (upamostat; formerly Mesupron) and opaganib\n\n​\n\nAdvanced unresectable cholangiocarcinoma\n\n​\n\nCombination of (RHB-107 (upamostat)) and (opaganib )\n\n​\n\nPreclinical\n\n​\n\nWe filed patent applications internationally directed to the proposed commercial use\n\n​\n\n71\n\n[Table of Contents](#TOC)\n\n*Opaganib*\n\nOpaganib, 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.\n\nOpaganib 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.\n\nOpaganib’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.\n\nOn 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.”\n\nThe 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.\n\n*Market and Competition*\n\nOpaganib 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.\n\nCholangiocarcinoma (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\n\n72\n\n[Table of Contents](#TOC)\n\nin 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).\n\nThe 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.\n\nAdditional 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.\n\nAccording 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.\n\nCLL 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.\n\nMost 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).\n\nA 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\n\n73\n\n[Table of Contents](#TOC)\n\nregimens (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.  \n\nIn 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.\n\nGI-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.\n\nTo 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.\n\nCOVID-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,*\n\n74\n\n[Table of Contents](#TOC)\n\n*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.\n\nThere 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.\n\n*Clinical Development*\n\n*COVID-19*\n\nPreclinical 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.\n\nPreliminary 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.\n\nIn 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.\n\n*ABC-201: Global Phase 2/3 Study*\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\n75\n\n[Table of Contents](#TOC)\n\nThese 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.\n\nAnalyses 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:\n\n●**Mortality**: Opaganib treatment resulted in a statistically significant 62% reduction in mortality (7/117 patients treated with opaganib vs. 21/134 for placebo; nominal p-value=0.019, Relative Risk 2.6) (Sensitivity Analysis: 5/117 vs. 16/134, 64% efficacy benefit; nominal p-value=0.033, Relative Risk - 2.8).\n\nA 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.\n\n●**Reaching Room Air by Day 14 (primary endpoint of the study)**: 77% of opaganib-treated patients reached room air by Day 14 vs. 63.5% for placebo – an efficacy benefit of 21% with opaganib (nominal p-value=0.033).\n\n●**Median time to discharge**: Patients treated with opaganib showed median time of 10 days to discharge vs. 14 days for the placebo arm, resulting in a saving of four days hospitalization per opaganib patient and saving a total of 524 cumulative days of hospitalization across the group by Day 42, nominal p-value=0.0195.\n\n●**Safety**: Overall adverse events were balanced between the opaganib and placebo groups, suggesting good safety, with no new safety signals emerging, further supporting potential use in this patient population and earlier stage populations.\n\nIn 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.\n\nIn 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).\n\nThe 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).\n\nSafety data for the Phase 2/3 clinical trial showed good tolerability of opaganib, with balanced adverse events between the study arms.\n\nIn 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\n\n76\n\n[Table of Contents](#TOC)\n\nmortality 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.\n\nGuidance 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.\n\nPreclinical 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.\n\n*ABC-110: U.S. Phase 2 Study*\n\nIn 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.\n\nThe data from the study was published in May 2022 in Open Forum Infectious Diseases.  \n\n*ABC-108: Advanced Unresectable Cholangiocarcinoma*\n\nA 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.\n\nIn 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.\n\nA 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.\n\nThe 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.\n\n77\n\n[Table of Contents](#TOC)\n\nIn 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.\n\n*Neuroblastoma*\n\nIn 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.\n\n*EAP for the Treatment of Advanced Unresectable Cholangiocarcinoma*\n\nAn 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.\n\n*ABC-101: Advanced Solid Tumors*\n\nA 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.\n\nTwenty-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.\n\nThe 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.\n\nThe 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.\n\n*ABC-107: Prostate Cancer*\n\nThe 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.\n\n78\n\n[Table of Contents](#TOC)\n\nThis 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.\n\nThe 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.\n\nOn 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.\n\n●The 60-patient placebo-controlled randomized Phase 2 study will evaluate the efficacy of opaganib in combination with Bayer’s darolutamide in men with mCRPC, testing the potentially enhancing effect of opaganib in overcoming resistance to standard of care androgen receptor pathway inhibition (ARPI) treatment in patients with a poor prognosis.\n\n●The study is being financially supported by Bayer (ETR: BAYN) and the Ramsay Hospital Research Foundation, and will be led by Professor Lisa Horvath from Chris O’Brien Lifehouse and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).\n\n●The study will utilize a companion lipid biomarker test (PCPro) to select mCRPC patients who have a poor prognosis due to standard of care treatment and who may benefit from an opaganib + darolutamide combination treatment approach. Primary endpoint will be improved 12-month radiographic progression-free survival (rPFS).\n\n*ABC-104: Oncology Support, Radioprotectant: Prevention of Radiation-Associated Mucositis in the Treatment of Head and Neck Cancer*\n\nA Phase 1b study to evaluate opaganib as a radioprotectant in head and neck cancer patients undergoing therapeutic radiotherapy is currently on hold.\n\n​\n\n79\n\n[Table of Contents](#TOC)\n\n*Chronic Lymphocytic Leukemia (CLL)*\n\nIn 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.\n\n*Nuclear Radiation Protection Development Program*\n\nIn 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:\n\n●Protection of normal tissue, including gastrointestinal, from radiation damage due to ionizing radiation exposure or cancer radiotherapy.\n\n●Improvement of antitumor activity, response to chemoradiation, and enhancement of tolerability and survival.\n\nDevelopment 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.\n\nIn 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.\n\nIn 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.\n\nResults 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.\n\nIn 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.\n\n*Ebola*\n\nIn 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.\n\n80\n\n[Table of Contents](#TOC)\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\n*ABC-105: Moderate to Severe Ulcerative Colitis (“UC”)*\n\nA 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.\n\n*ABC-109: Food Effect Study in Healthy Subjects*\n\nA 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.\n\n​\n\n81\n\n[Table of Contents](#TOC)\n\nThe following chart summarizes the clinical trial history and status of opaganib:\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n**Planned**\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n**Development**\n\n​\n\n**Purpose of**\n\n​\n\n​\n\n​\n\n**number of**\n\n​\n\n**Nature and**\n\n​\n\n​\n\n**Clinical trial**\n\n​\n\n**phase of the**\n\n​\n\n**the clinical**\n\n​\n\n**Clinical**\n\n​\n\n**subjects of**\n\n​\n\n**status of**\n\n​\n\n​\n\n**name**\n\n** **\n\n**clinical trial**\n\n** **\n\n**trial**\n\n** **\n\n**trial site**\n\n** **\n\n**the trial**\n\n** **\n\n**the trial**\n\n**Schedule**\n\nDaro-Lipid Trial\n\n​\n\nPhase 2\n\n​\n\nA combination study of opaganib in addition to darolutamide in people with poor prognostic metastatic castration resistant prostate cancer (mCRPC) based on a companion circulating lipid biomarker, PCPro\n\n​\n\nMulticenter study\n\n​\n\n60\n\n​\n\nOngoing\n\n​\n\nBeing conduct by ANZUP- no expected completion date yet\n\nABC-201\n\n​\n\nPhase 2/3\n\n​\n\nA study for the treatment of Opaganib in patients with severe COVID-19 pneumonia\n\n​\n\nMulticenter study\n\n​\n\n464\n\n​\n\nCompleted\n\n​\n\nResults reported in 2022\n\nABC-110\n\n​\n\nPhase 2\n\n​\n\nA study for the treatment of opaganib in patients with severe COVID-19 pneumonia\n\n​\n\nMulticenter study across the U.S.\n\n​\n\n40\n\n​\n\nCompleted\n\n​\n\nResults reported in 2021\n\nABC-108\n\n​\n\nPhase 2a\n\n​\n\nA study for the treatment of advanced, unresectable intrahepatic, perihilar and extrahepatic cholangiocarcinoma with opaganib and co-treatment with opaganib and HCQ\n\n​\n\nMulticenter study across the U.S.\n\n​\n\n65\n\n​\n\nCompleted\n\n​\n\nEnded- pending completion of CSR\n\nABC-107 (103193 MUSC Study ID)\n\n​\n\nPhase 2\n\n​\n\nAn add-on study for prostate cancer patients who progressed on enzalutamide or abiraterone. The proportion of patients with disease control during treatment with opaganib  and enzalutamide or abiraterone will be measured\n\n​\n\nMedical University of South Carolina, Charleston, U.S. and Emory University, Atlanta, Georgia, U.S.\n\n​\n\n65\n\n​\n\nCompleted\n\n​\n\nEnded- publication pending\n\nABC-103\n\n​\n\nPhase 1b/2\n\n​\n\nSafety and efficacy study in patients with refractory or relapsed multiple myeloma that have previously been treated with proteasome inhibitors and immunomodulatory drugs\n\n​\n\nDuke University, North Carolina, U.S.\n\n​\n\nEnded\n\n​\n\nEnded after Phase 1\n\n​\n\nCompleted 2022; reported\n\nABC-101\n\n​\n\nPhase 1\n\n​\n\nSafety, PK and pharmacodynamic study in patients with advanced solid tumors\n\n​\n\nMedical University of South Carolina, Charleston, U.S.\n\n​\n\n22\n\n​\n\nCompleted. Final results indicate the study drug is well tolerated and can be safely administered to cancer patients\n\n​\n\nCompleted 2015\n\nABC-106\n\n​\n\nPhase 2\n\n​\n\nInvestigator-Sponsored Safety and Efficacy Study in Patients with Advanced Hepatocellular Carcinoma Who Have Progressed on Sorafenib\n\n​\n\nMedical University of South Carolina, Charleston, U.S. and collaborating sites (Multicenter, U.S.)\n\n​\n\nFrom 12 to 39\n\n​\n\nWithdrawn and replaced with ABC-107 in prostate cancer (103193 MUSC Study ID)\n\n​\n\nWithdrawn\n\nABC-104\n\n​\n\nPhase 1b\n\n​\n\nSafety and efficacy study in the prevention of mucositis in combination with radiotherapy for treatment of squamous head and neck carcinoma\n\n​\n\nMulticenter study across the U.S.\n\n​\n\nUp to 32\n\n​\n\nTBD\n\n​\n\nTBD\n\nABC-105\n\n​\n\nPhase 2\n\n​\n\nA study for the treatment of moderate to severe ulcerative colitis\n\n​\n\nMulticenter study\n\n​\n\nUp to 94\n\n​\n\nTBD\n\n​\n\nTBD\n\nABC-109\n\n​\n\nPhase 1\n\n​\n\nAssessment of the effect of food on the absorption and bioavailability of opaganib; also as a solution via nasogastric (NG) tube under fed conditions\n\n​\n\nICON Early Phase Services, San-Antonio, TX, U.S.\n\n​\n\n23 \n\n​\n\nCompleted\n\n​\n\nCompleted 2018\n\n​\n\nWe 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”.\n\n*Other Preclinical studies*\n\nIn 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\n\n82\n\n[Table of Contents](#TOC)\n\nureteral obstruction (UUO) model – a well characterized model for renal fibrosis. Results from the study showed that opaganib significantly decreased renal fibrosis.\n\nOpaganib 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.\n\nIn 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.\n\nIn 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.\n\n*RHB-204*\n\nRHB-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).\n\n*Crohn’s Disease*\n\nRHB-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).\n\nCrohn’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.\n\nTo 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\n\n83\n\n[Table of Contents](#TOC)\n\nsince 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.\n\nA 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.\n\n*Market and Competition*\n\nAccording 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).\n\nTherapeutic 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.\n\nCurrently, 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.\n\nUnlike 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.\n\n*Nontuberculous Mycobacteria Infections*\n\nIn 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).\n\nThe 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\n\n84\n\n[Table of Contents](#TOC)\n\ntreatment 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.\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\nRHB-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.\n\n*Market and Competition*\n\nPulmonary 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).\n\nNTM 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.\n\nAccording 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.\n\n85\n\n[Table of Contents](#TOC)\n\nIn 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.\n\nA 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.\n\n*Clinical Development*\n\nAlthough 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.\n\nIn 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.\n\nThe 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.\n\nInitiation 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:\n\n​\n\n​\n\n**  ​ ​ ​**\n\n​\n\n  ​ ​ ​\n\n​\n\n  ​ ​ ​\n\n​\n\n  ​ ​ ​\n\n**Planned**\n\n  ​ ​ ​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n​\n\n**number of**\n\n​\n\n​\n\n​\n\n​\n\n**Development**\n\n​\n\n**Purpose of**\n\n​\n\n**Clinical**\n\n​\n\n**subjects of**\n\n​\n\n**Status of**\n\n**Trial name**\n\n​\n\n**phase**\n\n​\n\n**the trial**\n\n​\n\n**trial sites**\n\n​\n\n**the trial**\n\n​\n\n**the trial**\n\nTBD\n\n​\n\nPhase 2\n\n​\n\nTo evaluate the efficacy of RHB-204 in *Mycobacterium avium subspecies paratuberculosis-positive* (MAP+) moderate to severe Crohn’s disease\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nPlanned\n\nCleaR-MAC Trial\n\n​\n\nPhase 3\n\n​\n\nEvaluate the efficacy and safety of RHB-204 in adult subjects with documented MAC lung infection.\n\n​\n\nUp to 40\n\n​\n\n125\n\n​\n\nTerminated\n\n​\n\n86\n\n[Table of Contents](#TOC)\n\n*RHB-104*\n\n*Crohn’s Disease*\n\nRHB-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.\n\nIn 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.”\n\nWe 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.”\n\n*Clinical Development*\n\nA 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.\n\nIn 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.\n\nIn 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.\n\nIn 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.\n\nOur 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\n\n87\n\n[Table of Contents](#TOC)\n\nsecondary 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.\n\nIn 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.\n\nIn 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).\n\nRHB-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.\n\nIn 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.\n\nFurther 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.\n\nWe 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.\n\nWe believe that additional clinical studies will be required to support an NDA for RHB-104, if filed.\n\n88\n\n[Table of Contents](#TOC)\n\nThe following chart summarizes the clinical trial history and status of RHB-104 studies and its earlier individual active agents:\n\n​\n\n**  ​**\n\n​\n\n  ​\n\n​\n\n  ​\n\n​\n\n  ​\n\n**Planned**\n\n  ​\n\n​\n\n  ​\n\n​\n\n​\n\n​\n\n**Development**\n\n​\n\n​\n\n​\n\n​\n\n​\n\n**number of**\n\n​\n\n**Nature and**\n\n​\n\n​\n\n**Clinical trial**\n\n​\n\n**phase of the**\n\n​\n\n**Purpose of the**\n\n​\n\n**Clinical**\n\n​\n\n**subjects of**\n\n​\n\n**status of**\n\n​\n\n​\n\n**author/designation**\n\n​\n\n**clinical trial**\n\n​\n\n**clinical trial**\n\n​\n\n**trial site**\n\n​\n\n**the trial**\n\n​\n\n**the trial**\n\n​\n\n**Schedule**\n\nBorody 2002\n\n​\n\nPhase 2a\n\n​\n\nExamining the effect of the treatment on Crohn’s disease patients\n\n​\n\nCenter for Digestive Disease, Australia\n\n​\n\n12\n\n​\n\nPerformed\n\n​\n\nCompleted 2002\n\nBorody 2005\n\n​\n\nPhase 2\n\n​\n\nExamining the effect of the treatment on Crohn’s disease patients\n\n​\n\nCenter for Digestive Disease, Australia\n\n​\n\n52\n\n​\n\nPerformed\n\n​\n\nCompleted 2005\n\nSelby\n\n​\n\nPhase 3\n\n​\n\nExamining the effect of the treatment with the product on Crohn’s disease patients\n\n​\n\n20 clinical centers in Australia\n\n​\n\n213\n\n​\n\nThe trial was performed and indicated promising improvement rates, although it did not meet the main trial objective, as defined\n\n​\n\nPublished in 2007\n\nBiovail PK Study 2007\n\n​\n\nPK Study\n\n​\n\nOptimize the formulation of RHB-104 on a PK basis\n\n​\n\nToronto, Ontario\n\n​\n\n24\n\n​\n\nThe trial compared two formulations to determine the optimum formulation for RHB-104\n\n​\n\nCompleted 2007\n\nMAP US Study\n\n​\n\nPhase 3\n\n​\n\nAssess the safety and efficacy of RHB-104 in Crohn’s disease patients\n\n​\n\nU.S., Canada. Israel, Australia, New Zealand, and Europe\n\n​\n\n331\n\n​\n\nCompleted\n\n​\n\nCompleted 2020\n\nMAP US2 Study\n\n​\n\nPhase 3\n\n​\n\nAssess the safety and efficacy of RHB-104 in Crohn’s disease patients\n\n​\n\nU.S., Canada, Israel, New Zealand, and Europe\n\n​\n\n54\n\n​\n\nCompleted\n\n​\n\nCompleted 2021\n\nDrug-Drug Interaction Study\n\n​\n\nPK Study\n\n​\n\nTo assess the net PK effect of multiple doses of RHB-104 on CYP3A4 enzymes in healthy volunteers\n\n​\n\nAlgorithme Pharma, Canada\n\n​\n\n36\n\n​\n\nEnded\n\n​\n\nEnded 2014\n\nFood Effect Study\n\n​\n\nPK Study\n\n​\n\nDetermine the effect of food on the bioavailability of RHB-104 in healthy volunteers\n\n​\n\nAlgorithme Pharma, Canada\n\n​\n\n84\n\n​\n\nCompleted\n\n​\n\nCompleted 2014\n\n​\n\nWe cannot predict with certainty our development costs, and such costs may be subject to change. See “Item 3. Key Information – D. Risk Factors – Risks Related to Our Financial Condition and Capital Requirements.”\n\n*Multiple Sclerosis (“MS”)*\n\nMS is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system of uncertain etiology that exhibits characteristics of both infectious and autoimmune pathology.\n\nWe had previously conducted a Phase 2a proof-of-concept study with RHB-104 for relapsing-remitting multiple sclerosis. At the current stage, we have no intention to pursue the development of RHB-104 for this indication.\n\n89\n\n[Table of Contents](#TOC)\n\n*RHB-102 (Bekinda*®*)*\n\nRHB-102 (Bekinda®) is an investigational, once-daily, bi-modal release, oral formulation of ondansetron, a leading member of the family of 5-HT3 serotonin receptor inhibitors. RHB-102 (Bekinda®) is under development in multiple dosage strengths for the intended use in the following indications:\n\n1)GLP-1/GIP receptor agonist therapy-associated GI side effects\n\n2)Acute gastroenteritis and gastritis – 24 mg strength\n\n3)Irritable bowel syndrome with diarrhea (IBS-D) – lower dose strength, at 12 mg for long-term administration\n\n4)Oncology support (management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, also referred to as CINV and RINV) – 24 mg strength in the UK by our partner, Hyloris Pharmaceuticals that holds the worldwide rights excluding North America to develop and commercialize RHB-102\n\nOn February 16, 2023, the Company announced that following a positive pre-MAA meeting and subject to manufacturing-related activities it is considering plans and path to submit a Marketing Authorisation Application (MAA) to the UK’s MHRA seeking approval for RHB-102 (Bekinda®) for oncology support in adults and children over the age of 12. Data to support the submission was generated from several clinical studies, including the successful U.S. Phase III GUARD study with RHB-102 24 mg for acute gastroenteritis and gastritis.\n\nOn February 25, 2025, we announced that we entered into an exclusive worldwide development and commercialization licensing agreement, excluding North America, with Hyloris for RHB-102 (Bekinda®). We intend to continue the development for FDA approval in the U.S, if granted, for RHB-102. Hyloris will be responsible for all development, regulatory, and commercialization activities related to RHB-102 in its territories across all indications including acute gastroenteritis and gastritis, IBS-D, and oncology support. See “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – License Agreement with Hyloris Pharmaceuticals.”\n\nRHB-102 (Bekinda®) utilizes a technology called CDT® that uses salts to provide an extended-release of ondansetron. The CDT® platform enables extended drug release (i.e., the measured rate of introduction of active drug) at a relatively low manufacturing cost. The proposed commercial formulation and its use are protected by Company-filed patents and pending patent applications and are being pursued internationally.\n\n*GLP-1/GIP Receptor Agonist Therapy-Associated GI Side Effects*\n\nGI intolerance is the primary clinical limitation of GLP-1-based therapies which are used for the treatment of type 2 diabetes and obesity and is commonly characterized by symptoms such as nausea, vomiting, diarrhea and constipation. Clinical trial data indicates that approximately 40% to 70% of patients usually develop GI adverse events (AEs) during treatment with GLP-1 receptor agonists, with other rates reaching as high as 85% (Gorgojo-Martínez et al., 2023). GI AEs, which vary by the type of GLP-1 receptor agonist or GLP-1/GIP agent used, typically occur during treatment initiation or dose escalation and are a leading cause of treatment discontinuation. Literature reports that up to 12% of patients treated with GLP-1 receptor agonists experience GI AE-related treatment interruptions in clinical trials compared to approximately 2% of placebo-treated patients. Persistence rates in real world clinical practice have been reported to range between 40% to 60% at 180 days and between 34% to 67% at 360 days of treatment (Gorgojo-Martínez et al., 2023).\n\n*Market and Competition*\n\nThe total GLP-1 agonist market was valued at approximately $53.7 billion in 2024 and is projected to reach around $182 billion in 2031 with the launch of new candidates (GlobalData. GLP-1R Agonists – Label Extensions/Drug Repurposing: Market Overview. April 2025). According to the KFF Health Tracking Poll, approximately one in eight Americans (12%) report having ever used a GLP-1 medication, with 6% of Americans identifying as current users (Montero et al., 2024).\n\n90\n\n[Table of Contents](#TOC)\n\nStrategies used to mitigate GI side effects can include adjustments to dose titrations of the therapy as well as dietary modifications and use of supportive medications such as antiemetics and antidiarrheals depending on the symptom(s).\n\nGiven the prevalence of GI side effects and treatment discontinuation associated with GLP-1-based therapies, there remains an opportunity to improve tolerability of existing treatments and effectively manage GI AEs to enhance patient experience and reduce treatment discontinuation.RHB-102 (Bekinda®), a bimodal once-daily oral formulation of ondansetron, has the potential to improve titration success for GLP-1-based therapies, enabling patients to reach and maintain doses for optimal clinical outcomes.\n\n*Clinical Development*\n\nIn January 2026, we announced development progress for RHB-102 (Bekinda®) in multiple GI indications, including its development, via the accelerated FDA 505(b)(2) route, as a once-daily oral ondansetron therapy for GLP-1/GIP receptor agonist therapy-associated GI side effects, such as nausea, vomiting and diarrhea. A Phase 2 proof-of-concept study evaluating RHB-102(Bekinda®) for GLP-1/GIP receptor agonist-associated GI intolerance has been designed.\n\n*Acute Gastroenteritis and Gastritis*\n\nAcute gastroenteritis and gastritis both involve inflammation of the mucous membranes of the GI tract. Symptoms of gastroenteritis and gastritis include nausea, vomiting, diarrhea, and abdominal pain. Acute gastroenteritis and gastritis are major causes of emergency room visits, particularly for pediatrics. If approved, RHB-102 (Bekinda®) could potentially decrease the number of emergency room visits for patients suffering from acute gastroenteritis and gastritis by offering them an effective and long-lasting treatment, which can be taken in the comfort of their home.\n\n*Market and Competition*\n\nAcute gastroenteritis is a common illness in the U.S., with an estimated 179 million cases occurring annually (Schmidt et al., *Emerg Infect Dis*, 2022). Viral pathogens are the most common identifiable cause, led by norovirus, which accounts for an estimated 19 to 21 million cases per year and contributes substantially to healthcare utilization, including hospitalizations, emergency department visits and outpatient clinic visits (CDC – Norovirus Facts and Stats, 2024).\n\nManagement of acute gastroenteritis is primarily supportive, centered on rehydration through oral or intravenous fluids, while drug therapy is mainly used to manage symptoms such as nausea, vomiting, and diarrhea. Medications frequently used in acute care settings include antiemetics such as ondansetron, which is widely used off label for this indication. Additional medications may include antiemetics such as metoclopramide and prochlorperazine, and antimotility agents to decrease stool output, such as loperamide.\n\nA single dose of RHB-102 (Bekinda®) is intended to treat nausea and vomiting over a time window of approximately 24 hours. If approved for such use, this would be potentially advantageous for acute gastroenteritis and gastritis patients as it could help eliminate the need to take additional drugs (tablets) during the day or receiving intravenously administered drugs.RHB-102 (Bekinda®) could also be prescribed by primary care physicians to patients early on, potentially preventing emergency room visits, dehydration and the need to provide IV fluids. To the best of our knowledge, no other 5-HT3 serotonin receptor inhibitors are approved by the FDA or are in advanced clinical development for the treatment of acute gastroenteritis and gastritis in the U.S. If approved, RHB-102 (Bekinda®) will compete with several prescription and OTC antiemetic drugs, including but not limited to, dimenhydrinate, Nauzene®, and Emetrol®, as well as off-label use of ondansetron and other 5-HT3 inhibitors. RHB-102 (Bekinda®) may also be exposed to potentially competitive products that may be under development to treat acute gastroenteritis.\n\n*Clinical Development*\n\nIn June 2017, we announced positive top-line results from the randomized, double-blind, placebo-controlled Phase 3 study (the “GUARD study”) with RHB-102 (Bekinda®) 24 mg for acute gastroenteritis and gastritis. The study successfully met its primary endpoint and RHB-102 (Bekinda®) 24 mg was found to be safe and well tolerated in this indication. The GUARD study evaluated the efficacy and safety of RHB-102 (Bekinda®) 24 mg in treating acute gastroenteritis and\n\n91\n\n[Table of Contents](#TOC)\n\ngastritis in 321 adults and children over the age of 12. The primary endpoint of the study was the proportion of patients without further vomiting, without rescue medication, and who were not given intravenous hydration from 30 minutes post first dose of the study drug until 24 hours post-dose, compared to placebo. In September 2017, we met with the FDA to discuss the study results and the clinical and regulatory path toward potential marketing approval of RHB-102 (Bekinda®) 24 mg in the U.S. Following the guidance provided at the meeting and additional guidance provided thereafter, we are currently advancing preparations toward a confirmatory Phase 3 study to support a potential NDA with RHB-102 (Bekinda®) 24 mg for acute gastroenteritis and gastritis.\n\nFinal results from the GUARD study showed improvement to the primary efficacy outcome by 21% in the ITT population; 65.6% of RHB-102 (Bekinda®) treated patients as compared to 54.3% of placebo patients (p=0.04; n=192 in the RHB-102 (Bekinda®) group and n=129 in the placebo group). In the Per Protocol (PP) population, which included patients who met all protocol entry criteria and for which the diagnosis of gastroenteritis was confirmed (n=177 in the RHB-102 (Bekinda®) group and n=122 in the placebo group), RHB-102 (Bekinda®) improved the efficacy outcome by 27%; 69.5% of patients in the RHB-102 (Bekinda®) group vs. 54.9% in the placebo group, (p=0.01). An imbalance in baseline nausea was noted, with worse nausea in the RHB-102 (Bekinda®) treated group. In a post hoc analysis, when results were adjusted for baseline nausea, the p-value for the ITT population was 0.0152, and for the PP population was 0.0037. RHB-102 (Bekinda®) 24 mg was also shown to be safe and well tolerated; electrocardiogram results showed no adverse changes with treatment. The benefit observed with RHB-102 (Bekinda®) is evident across the spectrum of severity of nausea at baseline, including in patients with very severe nausea, suggesting that the drug works regardless of the initial severity of gastroenteritis.\n\nThe lead investigator for the Phase 3 study was Dr. Robert A. Silverman, MD, MS, Associate Professor at the Hofstra North Shore-LIJ School of Medicine and an emergency medicine specialist.\n\nIn September 2019, we had a follow-up meeting with the FDA regarding our efforts to design a study acceptable to the agency to seek the FDA’s approval for pediatric labeling for RHB-102 (Bekinda®), as required by the FDA pursuant to the Pediatric Research Equity Act.\n\nThe following chart summarizes the clinical trial history and status of RHB-102 (Bekinda®) for gastroenteritis and gastritis:\n\n​\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n**Planned**\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n​\n\n​\n\n​\n\n**Development**\n\n​\n\n​\n\n​\n\n​\n\n​\n\n**number of**\n\n​\n\n**Nature and**\n\n​\n\n​\n\n**Clinical trial**\n\n​\n\n**phase of the**\n\n​\n\n**Purpose of the**\n\n​\n\n**Clinical**\n\n​\n\n**Subjects**\n\n​\n\n**status of**\n\n​\n\n​\n\n**Name**\n\n​\n\n**clinical trial**\n\n​\n\n**clinical trial**\n\n​\n\n**trial site**\n\n​\n\n**of the trial**\n\n​\n\n**the trial**\n\n​\n\n**Schedule**\n\nGUARD Study\n\n​\n\nPhase 3\n\n​\n\nRandomized double-blind placebo-controlled Phase 3 study in acute gastroenteritis and gastritis\n\n​\n\n21 sites in the U.S.\n\n​\n\n321\n\n​\n\nEvaluated the safety and efficacy of RHB-102 (Bekinda®) in acute gastroenteritis and gastritis\n\n​\n\nCompleted 2017\n\nTBD\n\n​\n\nConfirmatory Phase 3\n\n​\n\nSupport a potential NDA with RHB-102 (Bekinda®) 24 mg for acute gastroenteritis and gastritis\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nWe 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.”\n\n*Irritable Bowel Syndrome with Diarrhea (IBS-D)*\n\nIrritable bowel syndrome (IBS) is a multifactorial disorder marked by recurrent abdominal pain or discomfort and altered bowel function. According to the Mayo Clinic, certain factors that alter GI function can contribute to IBS symptoms, including stress, prior gastroenteritis, and changes in the gut microbiome, bile acids and short-chain fatty acids, which may stimulate 5-HT3 serotonin release and increase colonic permeability and motility.\n\n92\n\n[Table of Contents](#TOC)\n\nIn preliminary studies, ondansetron has demonstrated activity in IBS-D (Garsed K, Chernova J, Hastings M, et al. Gut Published Online First December 12, 2013). Unlike alosetron (a currently approved 5-HT3 antagonist in IBS-D), ondansetron has not been noted to cause ischemic colitis (FDA labeling for Lotronex® (alosetron), 2010; FDA labeling for Zofran® (ondansetron), 2014).\n\nIn light of the activity of ondansetron demonstrated in the preliminary studies described above, and because of its extended-release properties and once-daily dosing, we believe RHB-102 (Bekinda®) is a promising candidate for the treatment of IBS-D.\n\n*Market and Competition*\n\nIBS is one of the most common GI disorders. According to GlobalData, the number of diagnosed prevalent cases of IBS (age>=18) in the 16 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) is estimated at approximately 76 million in 2025. Of the three subtypes of IBS, IBS-D is the most prevalent diagnosed subtype according to Pimentel M (Am J Manag Care, 2018), accounting for 40% of the patient population.\n\nTo the best of our knowledge, there is one other 5-HT3 serotonin receptor inhibitor indicated for the treatment of IBS-D in the U.S., alosetron, marketed under the brand name Lotronex® by Sebela Pharmaceuticals and also available in generic versions marketed by other companies. However, alosetron is approved only for the treatment of IBS in women with severe chronic IBS-D and has been associated with serious gastrointestinal side effects. The active ingredient in RHB-102 (Bekinda®), ondansetron, is approved by the U.S. FDA as an oncology support antiemetic and has a good safety profile. If RHB-102 (Bekinda®) is approved for the treatment of IBS-D in the U.S., it may offer improved safety while maintaining efficacy, with the potential to become a preferred 5-HT3 serotonin receptor inhibitor treatment for patients suffering from IBS-D. Ramosetron, another 5-HT3 serotonin receptor inhibitor is marketed for the treatment of IBS in Japan, South Korea, China and India (marketed under the brand name Irribow® by Astellas Pharma Inc. in Japan and is available in generic versions marketed by other companies in South Korea, China and India). Ramosetron is also marketed for the treatment of chemotherapy-induced nausea and vomiting in Japan, South Korea, China, India and Indonesia and for postoperative nausea and vomiting in South Korea and India. To the best of our knowledge, there is currently no clinical development of ramosetron for marketing approval in the U.S. for the treatment of IBS-D. If approved, RHB-102 (Bekinda®) will also compete with several other prescription drugs indicated for the treatment of IBS-D, including Xifaxan® (rifaximin), marketed in the U.S. by Salix Pharmaceuticals, and Viberzi® (eluxadoline), marketed in the U.S. by Allergan plc., now AbbVie Inc. Additional prescription drugs and over-the-counter products may also be used to manage symptoms of IBS-D and may represent additional competition, as well as investigational products in development for IBS-D in the U.S. that may represent future competition.\n\n*Clinical Development*\n\nIn January 2018, we announced positive final results from the Phase 2 clinical study of RHB-102 (Bekinda®) 12 mg for the treatment of IBS-D. The randomized, double-blind, placebo-controlled Phase 2 study evaluated the efficacy and safety of RHB-102 (Bekinda®) 12 mg in 126 subjects over 18 years old at 16 clinical sites in the U.S. The study successfully met its primary endpoint, improving the primary efficacy outcome of stool consistency.\n\nRHB-102 (Bekinda®) was also shown to be safe and well tolerated in this indication. No serious adverse events or new or unexpected safety issues were noted in the study. In September 2018, we announced that we concluded a positive End-of-Phase 2 Type B meeting with the FDA discussing the clinical and regulatory pathway toward potential FDA approval of RHB-102 (Bekinda®) for the treatment of IBS-D, which requires the conduct of two pivotal Phase 3 studies with RHB-102 (Bekinda®) for the treatment of IBS-D.\n\nThe primary endpoint of the trial was the proportion of patients in each treatment group with response in stool consistency on study drug as compared to baseline. Response was defined as per FDA guidelines for the indication. Additional endpoints were analyzed including:\n\n●proportion of patients in each treatment group who are pain responders, per FDA guidance definition;\n\n93\n\n[Table of Contents](#TOC)\n\n●proportion of patients in each treatment group who are overall responders, per FDA guidance definition; and\n\n●differences between treatment groups in:\n\noabdominal pain,\n\noabdominal discomfort,\n\nofrequency of defecation, and\n\noincidence and severity of adverse events.\n\nThe RHB-102 (Bekinda®)12 mg Phase 2 study successfully met its primary endpoint, improving the primary efficacy outcome of stool consistency response (in accordance with the FDA guidance definition) by an absolute difference of 20.7%, with 56.0% responders of subjects treated with RHB-102 (Bekinda®) (n=75) vs. 35.3% responders of the placebo subjects (n=51) (p=0.036). While not powered for statistical significance of the secondary efficacy endpoints, the study suggested clinically meaningful improvement in both secondary efficacy endpoints of abdominal pain response and overall response (combined stool consistency and abdominal pain response). Final results from the Phase 2 study demonstrated that RHB-102 (Bekinda®) 12 mg improved the overall worst abdominal pain response rate by 11.5% vs. placebo (50.7% with RHB-102 (Bekinda®) 12 mg (n=75) vs. 39.2% with placebo (n=51); (p=0.278)) and the overall response improved by an absolute difference of 14.5% in favor of the RHB-102 (Bekinda®) 12 mg arm (40.0% with RHB-102 (Bekinda®) 12 mg (n=75) vs. 25.5% with placebo (n=51); (p=0.135)).\n\nRHB-102 (Bekinda®) 12 mg was also shown to be safe and well tolerated. No serious adverse events or new or unexpected safety issues were noted in the study. In September 2018, we announced that we concluded a positive End-of-Phase 2/Pre-Phase 3 (Type B) meeting with the FDA discussing the clinical and regulatory pathway toward potential FDA approval of RHB-102 (Bekinda®) 12 mg for the treatment of IBS-D, which requires the conduct of two pivotal Phase 3 studies with RHB-102 (Bekinda®) for the treatment of IBS-D.\n\nWe have initiated formulation work to formulate RHB-102 at lower dosages to help support planned pediatric studies. In December 2019, we received confirmation from the FDA that it has agreed with our Initial Pediatric Study Plan (iPSP).\n\nThe following chart summarizes the clinical trial history and status of RHB-102 (Bekinda®) for IBS-D:\n\n​\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n**Planned**\n\n**  ​ ​ ​**\n\n​\n\n**  ​ ​ ​**\n\n​\n\n​\n\n​\n\n**Development**\n\n​\n\n​\n\n​\n\n​\n\n​\n\n**number of**\n\n​\n\n**Nature and**\n\n​\n\n​\n\n**Clinical trial**\n\n​\n\n**phase of the**\n\n​\n\n**Purpose of the**\n\n​\n\n**Clinical**\n\n​\n\n**Subjects**\n\n​\n\n**status of**\n\n​\n\n​\n\n**Name**\n\n​\n\n**clinical trial**\n\n​\n\n**clinical trial**\n\n​\n\n**trial site**\n\n​\n\n**of the trial**\n\n​\n\n**the trial**\n\n​\n\n**Schedule**\n\n-\n\n​\n\nPhase 2\n\n​\n\nRandomized double-blind placebo-controlled Phase 2 study in IBS-D\n\n​\n\n16 sites in the U.S.\n\n​\n\n126\n\n​\n\nEvaluating the safety and efficacy of RHB-102 (Bekinda®) 12 mg in IBS-D\n\n​\n\nCompleted 2018\n\nTBD\n\n​\n\nPhase 3\n\n​\n\nRandomized double-blind placebo-controlled Phase 3 study in IBS-D\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nTBD\n\n​\n\nWe cannot predict with certainty our development costs and such costs may be subject to change. See “Item 3. Key Information – D. Risk Factors – Risks Related to Our Financial Condition and Capital Requirements.”\n\n*RHB-107 (upamostat; formerly Mesupron)*\n\nAs mentioned under “Item 4. Information on the Company – B. Business Overview – Acquisition, Commercialization and License Agreements – License Agreement for RHB-107” (upamostat; formerly Mesupron)”, on June 30, 2014, we signed an exclusive license agreement with Wilex AG (which later changed its name to Heidelberg Pharma AG) for RHB-107 (INN: upamostat; formerly Mesupron) for all indications and for all uses. Under this agreement, we are responsible for all development, regulatory and commercialization of RHB-107 in the entire world, excluding China, Taiwan, Macao, and Hong Kong.\n\n94\n\n[Table of Contents](#TOC)\n\nRHB-107 is a proprietary, first-in-class, orally administered potent inhibitor of several serine proteases, with a unique potency and specificity. In addition to its original development as a potential cancer therapy, work completed by us demonstrated its potential use in inflammatory digestive diseases, inflammatory lung diseases and infectious diseases. Furthermore, RHB-107 shows promise as a potential host-directed anti-viral with applications in pandemic preparedness, including COVID-19 and potentially, influenza.\n\n*Market and Competition*\n\nRHB-107 is currently being developed for the treatment of non-hospitalized symptomatic COVID-19 and is planned to undergo evaluation in influenza and has previously undergone non-clinical and clinical studies in several oncological indications, including metastatic breast cancer and advanced non-metastatic pancreatic cancer.\n\n*Non-Clinical and Clinical Development*\n\nData from non-clinical studies conducted by us indicate that WX-UK1, the active metabolite of RHB-107, is a specific and potent inhibitor of several human serine proteases (e.g., trypsin-3, trypsin-2, trypsin-1, matriptase-1, and trypsin-6), some of which have been shown to play a role in inflammatory digestive diseases and lung diseases. Additional non-clinical studies indicated that several members of the type II transmembrane serine proteases (TTSPs), some of which are important factors in the spread of infectious diseases, were inhibited by WX-UK1.\n\nRHB-107’s safety profile has been demonstrated in approximately 300 participants, including in Phase 2 studies in oncology indications and COVID-19.  \n\n*Oncology*\n\nSeveral Phase 1 studies and two Phase 2 proof-of-concept studies have been completed with RHB-107 in cancer patients. The first Phase 2 trial in locally advanced non-metastatic pancreatic cancer and the second trial in metastatic breast cancer established the therapeutic candidate’s safety and tolerability profile. The Phase 2 trials with RHB-107 in both indications failed to demonstrate significant improvement in either progression-free survival or overall survival.\n\nNone of the prior studies used any molecular markers to target certain patient populations. Using technologies developed since the original clinical trials were performed, we are currently considering several preclinical studies, including biomarker analysis and mechanism of action studies. We expect that the findings from these studies can help us determine the patient populations to be studied in subsequent clinical trials.\n\nIn October 2017, the FDA granted RHB-107 orphan drug designation for the treatment of pancreatic cancer. The orphan drug designation allows us to benefit from various development incentives to develop RHB-107 for this indication, including tax credits for qualified clinical testing, waiver of a PDUFA upon submission of a potential marketing application and, if approved, a seven-year marketing exclusivity period (subject to certain exceptions) for the treatment of pancreatic cancer.\n\n*COVID-19*\n\nRHB-107 was studied in a 3D tissue model of human bronchial epithelial cells (EpiAirway™) which morphologically and functionally resembles the human airway and is similar to the model used to discover SARS-CoV-2. The study was designed to evaluate the *in vitro* efficacy of RHB-107 in inhibiting SARS-CoV-2 infection and included a positive control of camostat. Results from the study demonstrated strong inhibition of SARS-CoV-2 viral replication.\n\nIn 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.\n\n95\n\n[Table of Contents](#TOC)\n\n*RHB-107-01: Global Phase 2/3 Study*\n\nA 2-part, Phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study with RHB-107 randomized its last patient into Part A of the study November 12, 2021. The study aimed at evaluating treatment in patients with symptomatic COVID-19 early in the course of the disease, with a once-daily oral treatment that can be prescribed and used in the non-hospitalized patient population. The Phase 2 part of the study was designed to evaluate safety for dose selection and to provide preliminary assessment of parameters to be used for efficacy evaluation in Part B. A total of 61 patients were enrolled in Part A and randomized on a 1:1:1 basis to receive one of two dose levels of RHB-107 or a placebo control and was predominantly conducted in the U.S. (60/61 patients) as well as South Africa.\n\nRHB-107 was administered once daily for 14 days, with patients receiving follow-up for eight weeks from first dosing. The primary endpoints were time to sustained recovery from symptomatic illness compared to placebo, as well as safety and tolerability of RHB-107. Several secondary and exploratory endpoints are also being assessed. In February 2021, we announced that the first patient had been dosed in the study.\n\nIn March 2022, we announced the positive Phase 2 study results of Part A of the Phase 2/3 study. Although not powered for efficacy assessment, the study showed highly promising efficacy results delivering a 100% reduction in hospitalization due to COVID-19, with zero patients on RHB-107 hospitalized with COVID-19 (0/41) compared to 15% on the placebo-controlled arm requiring hospitalization (3/20) (nominal p-value=0.0317). Furthermore, the study showed an 87.8% reduction in reported new severe COVID-19 symptoms, with only one patient on RHB-107 (2.4%, 1/41) compared to 20% (4/20) of patients on the placebo-controlled arm experiencing new COVID-19 related severe symptoms (nominal p-value=0.036).\n\nThe study met its primary outcome measure, demonstrating a favorable safety and tolerability profile of RHB-107. Study arms were well balanced with respect to baseline disease severity, risk factors and vaccination status. Patients were also tested for the specific viral strain, with the most common variant being Delta, found in 62.5% of the patients that had next generation sequencing (NGS). The second part of the study was never carried out, as RHB-107 was accepted for testing into the ACESO study described below.\n\nIn July 2023, we announced that RHB-107 had been accepted for inclusion in the U.S. Department of Defense- supported Austere environments Consortium for Enhanced Sepsis Outcomes’ (ACESO) PROTECT multinational platform trial for early COVID-19 outpatient treatment. The ACESO PROTECT study was funded primarily by the U.S. Department of Defense, and conducted by researchers from ACESO and partner organizations, and administered by the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF).\n\nThe ACESO PROTECT study was an adaptive, randomized, double blind, multi-site Phase 2 platform trial that sought to evaluate the safety and efficacy of RHB-107 for early outpatient COVID-19 treatment. The study was conducted as part of a master protocol evaluating promising investigational products for safety and efficacy as early outpatient treatment and post-exposure prophylaxis for COVID-19. RHB-107 was the first and only drug to enter the platform and was evaluated in the early treatment arm of the study. The study was planned for a duration of approximately 18 months, but due to challenges in enrollment and U.S. government funding limitations, enrollment was discontinued after a total of only 92 of the planned 300 participants were enrolled. 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, the study did not reach statistical significance. Whether the lack of significant results were due to true lack of efficacy or accrual of fewer than one third of the planned number of patients is unknown.\n\n*Ebola Virus Disease Therapy*\n\nIn 2022, in collaboration with the Therapeutic Discovery Branch of the USAMRIID (US Army Medical Research Institute of Infectious Diseases) to evaluate opaganib and RHB-107 in high throughput antiviral screening. We completed *in-vitro* studies against different strains of Ebola virus, including SUDV, Sudan ebolavirus (Boniface), Ebola Virus Disease, EBOV (Makona), and additional viral infectious diseases, including Marburg virus disease, MARV (Ci67), and Rift Valley fever RVFZ (ZH-501). Initial data from high-content imaging assays, provided further support for activities of Redhill candidates against these viral diseases.\n\n96\n\n[Table of Contents](#TOC)\n\nIn December 2023, we announced opaganib and RHB-107 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.\n\n**Acquisition, Commercialization and License Agreements**\n\n*Acquisition of Talicia*®*, RHB-104, and RHB-106*\n\nOn August 11, 2010, we entered into an asset purchase agreement with Giaconda Limited, a publicly-traded Australian company, pursuant to which Giaconda Limited transferred all of its patents, tangible assets, production files, regulatory approvals and other data related to the “Heliconda”, “Myoconda” and “Picoconda” products to us. We renamed these products Talicia®, RHB-104, and RHB-106, respectively. Giaconda Limited further transferred to us products in process, product samples and raw materials, as well as certain rights of first refusal with respect to intellectual property in relation to digestive condition treatments. The agreement excluded the transfer of the rights to two products of Giaconda Limited that are not related to Talicia®, RHB-104, and RHB-106. However, to the extent that the intellectual property associated with these two other products may be required for the research, development, manufacture, registration, import/export, use, commercialization, distribution, sale or offer for sale of any of Talicia®, RHB-104, and RHB-106, Giaconda Limited granted us an exclusive worldwide assignable right to such intellectual property for such purposes. The closing of this transaction occurred on August 26, 2010.\n\nWe paid Giaconda Limited in consideration for the assets purchased by us an initial amount of $500,000. We and Giaconda Limited also agreed that, until the expiration of the last patent transferred to us with respect to each product, we will pay to Giaconda Limited 7% of net sales from the sale of the relevant product/s by us and 20% of the consideration (including royalties received by us) from sublicensees, in each case, only after we recoup the amounts and expenses exceeding an approved budget.\n\nUnder the agreement, Giaconda Limited agreed that neither it, nor the developer of the products, nor any of their respective affiliates may compete with us or assist others to compete with us with respect to the products and acquired technology for the period provided for in the agreement.\n\nThe agreement provides that, should we elect not to proceed with the registration proceedings, or the maintenance of any patent transferred to us, we will notify Giaconda Limited and Giaconda Limited will have the right to proceed with the registration, maintenance, development and commercialization of such patent at its expense. Should Giaconda Limited exercise such right, it will be entitled to all amounts received in connection with sales relating to such patent.\n\nThe agreement also requires us to make a good faith, continuous and commercially reasonable effort to allocate appropriate financial resources to prepare, initiate and complete the clinical development of the products (with the exception of Picoconda by virtue of the Salix license agreement dated February 27, 2014) and file an application for regulatory marketing approval in accordance with industry standards. Development failures, negative regulatory decisions, or other reasons beyond our control will not constitute a breach of this obligation. Should we breach this obligation with respect to the development of any of the products and fail to cure the breach within 90 days from the date that Giaconda Limited sends us a default notice, Giaconda Limited may buy back all of the intellectual property rights with respect to such product for the original purchase price, plus the related development costs incurred by us through the date of the buy-back.\n\nIn connection with the license agreement with Salix (later acquired by Bausch Health), dated February 27, 2014, described below, we amended the asset purchase agreement and related agreements by excluding from the non-compete undertakings of Giaconda Limited and certain of its affiliate products, technology, and related activities in the purgative field and excluded from such non-compete undertakings certain of Giaconda Limited’s affiliates. Subsequently, we recognized revenues in 2014 and paid Giaconda Limited an additional amount of $1 million. On February 27, 2014, we amended the asset purchase agreement with Giaconda Limited to cancel the buyback right and agreed that we would pay Giaconda Limited 20% of all amounts received by us from Bausch Health under the license agreement, without first recouping amounts and expenses and notwithstanding the expiration of any relevant patents.\n\n97\n\n[Table of Contents](#TOC)\n\nLicense Agreement with Hyloris Pharmaceuticals\n\nIn February 2025, we entered into an exclusive worldwide development and commercialization licensing agreement, excluding North America, with Hyloris Pharmaceuticals SA (“Hyloris”) for RHB-102 (Bekinda®). Under the terms of the agreement, Hyloris paid us an upfront payment of $0.1 million, in addition to up to $60 million in potential milestone payments, contingent upon achieving specified commercial targets, plus up to mid-20s percent royalties on revenues, subject to certain cost recoupments, with minimum annual payments to us, in return for exclusive rights to RHB-102 across all indications and territories outside the United States, Canada, and Mexico. We intend to continue the development for FDA approval in the U.S, if granted, for RHB-102. Hyloris will be responsible for all development, regulatory, and commercialization activities related to RHB-102 in its territories across all indications including acute gastroenteritis and gastritis, IBS-D, and oncology support.\n\nLicense Agreement with Kukbo\n\nIn March 2022, we entered into the Exclusive License Agreement with Kukbo Co. Ltd. (“Kukbo”) for opaganib for the treatment of COVID-19 in South Korea. Under the terms of the Exclusive License Agreement, Kukbo was required to pay an upfront payment of $1.5 million and we are also eligible for milestone payments and royalties on net sales of oral opaganib in South Korea.\n\nOn 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 a subscription agreement, dated October 25, 2021 (the “Subscription Agreement”), in exchange for the ADSs we were to issue to Kukbo, and in delivering to us the $1.5 million due under the Exclusive License Agreement. Kukbo thereafter filed counterclaims with various allegations such as breach of contract, misrepresentation, and the breach of the duty of good faith and fair dealing, among other claims. On November 20, 2023, we entered into a Contingency Fee Agreement with our legal firm, Haynes and Boone, LLP (“H&B”), under which certain legal costs related to the Kukbo litigation will be assumed by H&B. On December 2, 2024, we were awarded a judgment of approximately $8 million, including $6.5 million in principal and approximately $1.5 million in accrued interest, plus costs, in a summary judgment by the Supreme Court of the State of New York, New York County in our legal proceedings against Kukbo. 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.\n\nOn 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.\n\nIn addition, we 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.\n\nWe intend to vigorously pursue the recovery of attorneys’ fees and the collection of the judgment.\n\n98\n\n[Table of Contents](#TOC)\n\n*License Agreement with Gaelan Medical*\n\nIn December 2021, we entered into an exclusive license agreement (the “License Agreement”) with Gaelan Medical Trade LLC (“Gaelan Medical”) for Talicia® in the United Arab Emirates (UAE). Under the terms of the License Agreement, we received in April 2022 an upfront payment of $2 million. In addition, we are eligible for additional milestone payments as well as tiered royalties up to mid-teens on net sales of Talicia® in the UAE. Gaelan Medical received the exclusive rights to commercialize Talicia® in the UAE. Gaelan Medical shall be responsible for obtaining and maintaining regulatory approvals, as well as to conduct any and all required clinical and other studies. In March 2022, we signed an amendment to the License Agreement, according to which Gaelan Medical may sublicense or assign any of its rights or obligations under the License Agreement. In connection with the License Agreement, we and Gaelan Medical entered into a supply agreement, according to which, we will exclusively manufacture (by a third party CMO) and supply Talicia® to Gaelan Medical during the term of the agreement. On August 1, 2023, we announced that Gaelan Medical had received marketing approval for Talicia® in the UAE and that Gaelan Medical has 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.\n\n*Additional License Agreement related to MAP diagnostic test for RHB-104*\n\nOn December 27, 2014, we entered into a license agreement with the University of Minnesota (UoM) pursuant to which we were granted an exclusive license for all indications and medical uses to a patent-protected designation of certain DNA sequencing.\n\n*Transaction with Cumberland*\n\nOn October 20, 2025, we announced that we had entered into definitive agreements with Cumberland relating to Talicia®. The transaction was effected through Talicia Holdings, our recently formed subsidiary established to hold the global rights to Talicia® and oversee its commercialization worldwide, including through partnerships.\n\nUnder a Stock Purchase Agreement between Talicia Holdings and Cumberland, Cumberland agreed to invest $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% equity interest in Talicia Holdings. We retained 70% ownership. Talicia Holdings is jointly controlled by RedHill and Cumberland under accompanying governance arrangements that provide for equal board representation and joint decision-making on key matters. In addition, under a related shareholders agreement, the transfer of shares by either us or Cumberland is subject to a right of refusal by the other party, and each party is subject to non-competition and non-solicitation obligations for so long as such party owns shares in Talicia Holdings.\n\nConcurrently, Talicia Holdings and Cumberland entered into a five-year Exclusive Joint Commercialization Agreement for Talicia® in the United States.  Under the agreement, the parties will jointly commercialize Talicia® in the U.S., through a joint commercialization committee with equal representation and joint decision-making to oversee commercialization, pricing, contracting, sales and marketing activities related to Talicia®. Net revenues from U.S. sales of Talicia® will be shared equally between the parties. As part of the agreement, Talicia Holdings granted Cumberland an exclusive license to use Talicia Holdings’ intellectual property solely for the joint commercialization of Talicia® under the agreement, and sublicensing or co-promotion by Cumberland requires Talicia Holdings’ prior written consent.\n\nCumberland will deploy its national sales organization to promote Talicia® and will conduct trade operations, including handling sales promotion, warehousing and distribution in the U.S., in accordance with Committee-approved plans, and will fund significant commercialization activities approved by the Committee. Talicia Holdings will oversee market access, marketing, regulatory approvals, and medical affairs activities, as well as manufacturing, quality, and supply of the product, bearing the related cost of goods.\n\n​\n\n99\n\n[Table of Contents](#TOC)\n\n**Sale of Movantik**®**to HCRM**\n\nOn February 2, 2023, RedHill U.S. and the Company (together, “RedHill Group”) entered into an Asset Purchase Agreement (the “APA”) and related agreements with HCRM. The APA provides for the sale of RedHill Group’s assets exclusively related to RedHill Group’s exploitation of Movantik® to an affiliate of HCRM in exchange for the extinguishment and termination of all Obligations (as defined in the Credit Agreement) (other than certain indemnification obligations), including the loans, all accrued and unpaid interest thereon, the revenue interest, the prepayments premiums and exit fees (the “Transaction”). The related agreements, each dated as of February 2, 2023, included the Sixth Amendment to the Credit Agreement and Collateral Documents (the “Collateral Amendment”), the Escrow Agreement (the “Escrow Agreement”), the Transition Services Agreement (the “TSA”) and the Supply Agreement (the “Supply Agreement”). The closing of the transaction pursuant to the APA occurred on February 2, 2023 (the “Closing”).\n\n*Asset Purchase Agreement.*HCRM acquired all assets exclusively related to RedHill Group’s exploitation of Movantik® and, generally, assumed all liabilities related to the business arising after the Closing (as defined in the APA). Pursuant to the Supply Agreement (described in more detail below), certain supply contracts will either be terminated or assigned to Movantik Acquisition Co., an affiliate of HCRM (“Movantik Acquisition” or “Buyer”), after the Closing. The APA extinguished all Obligations (as defined in the Credit Agreement) under the Credit Agreement (other than certain indemnification obligations that survive the termination) including the loans, all accrued and unpaid interest thereon, the revenue interest, the prepayment premiums, and exit fees.\n\n*Collateral Amendment.  *All Obligations under the Credit Agreement (including the loans, all accrued and unpaid interest thereon, the revenue interest, the prepayment premiums and exit fees) terminated as of the Closing, except for those obligations that were expressly intended to survive termination of the Credit Agreement, including certain indemnification obligations. Upon Closing, collateral, consisting of (i) the Escrow Account, (ii) Talicia®-related assets, (iii) our former Aemcolo®-related assets and (iv) accounts receivable related to Movantik® accrued as of the Closing, continued to secure “Go-Forward Obligations” consisting of indemnification obligations under the APA and the Credit Agreement and scheduled pre-closing liabilities relating to Movantik®. The value of such liens and security interests were capped at the value of our pre-closing liabilities relating to Movantik®, and all such liens and security interests were fully released upon the first to occur of (i) the payment of scheduled pre-closing liabilities related to Movantik® other than certain specified long-dated liabilities and (ii) the first date 90 days after the Closing on which RedHill Israel has at least $16.9 million in cash and cash equivalents on hand. Both HCRM and its affiliates and RedHill Group provided each other with a broad release of any claims they have against each other arising prior to the Closing.\n\n*Escrow Agreement.* At the Closing, Buyer deposited $16 million, which was equal to the amount of cash collateral against which HCRM exercised remedies under the Credit Agreement, into the Escrow Account overseen by the Bank of New York Mellon, acting as an escrow agent. Additionally, from and after the Closing, RedHill U.S. was required to deposit all cash received from accounts receivable related to Movantik accrued as of the Closing into the Escrow Account. Funds from the Escrow Account could only be used to pay certain scheduled pre-closing liabilities related to Movantik® that were retained by RedHill U.S. under the terms of the APA. RedHill U.S. and Buyer established a “Joint Escrow Committee” to oversee the release of funds from the Escrow Account to pay the scheduled liabilities in an agreed order of priority. Unless earlier terminated by mutual agreement of RedHill U.S. and Buyer, the Escrow Agreement was to remain in effect until the time that all scheduled pre-Closing liabilities relating to Movantik® were paid.\n\n*Transition Services Agreement.* RedHill U.S. agreed to provide Buyer certain services, including financial services, regulatory services, pharmacovigilance services, medical information services, quality assurance services, commercial services (including calls by sales agents), project management services, contract transfer services and supply chain services. RedHill U.S. received payment of fees for each service type, calculated as a specified FTE rate plus out-of-pocket costs and pass-through costs incurred during the term of the TSA in which services were provided, in addition to certain pre-determined milestone payments. Effective October 1, 2023, all services under the agreement were terminated.\n\n*Supply Agreement.*RedHill U.S. facilitated supply of Movantik® from third-party suppliers at cost to Buyer on Buyer’s behalf to provide Buyer with the opportunity to establish, with the assistance of RedHill U.S., its own manufacturing capabilities and supply chain for Movantik. Effective October 2, 2023, the Supply Agreement was terminated.\n\n100\n\n[Table of Contents](#TOC)\n\nOn July 15, 2024, we signed a Global Termination Agreement with Movantik Acquisition Co., Valinor Pharma, LLC, and HCR Redhill SPV, LLC, affiliates of HCRM. As a result of the agreement, we received approximately $9.9 million in cash. This amount was in settlement of liabilities related to Movantik® that were allocatable to HCRM and its affiliates under their agreements with us. As the cash received was less than the total net amount of these liabilities (approximately $12.2 million), we recognized a loss of approximately $2.3 million resulting from the termination agreement, presented under “Other expenses” in our consolidated statements of comprehensive income (loss) in our financial statements included elsewhere in this Annual Report. We also gained full control over an additional $0.7 million previously held in a restricted account and settlement of trade balances resulting from the transition services. The agreement terminated all existing credit ties with the agreement parties, removed the lien on Talicia® and restored full control over cash collections back to us.\n\n**License Agreement for Talicia**®**in New Middle East Markets**\n\nIn 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 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. Certain of the milestone and royalty-related payments are subject to regulatory approvals, commercial launches, and the passage of time.  In connection with the Talicia Holdings transactions, we transferred to Talicia Holdings our rights to all future proceeds and receivables under this arrangement, while retaining certain receivables existing as of the transaction date.\n\n**Expanded Access Program (EAP)**\n\nWe have adopted an Expanded Access Program (“EAP”), allowing patients with life-threatening diseases potential access to our investigational new drugs that have not yet received regulatory marketing approval. Expanded access (sometimes referred to as “compassionate use”) is possible outside of our clinical trials, under certain eligibility criteria, when a certain investigational new drug is needed to treat a life-threatening condition and when there is some clinical evidence suggesting that the drug might be effective for that condition. Patients who qualify for our EAP do not meet the eligibility criteria or are incapable of participating in our clinical trials for such therapeutic candidate or there is no clinical trial accessible to such patients. Following the adoption of the program, we continue to receive patient requests to obtain access to our investigational drugs. Subject to the evaluation of eligibility and all other necessary regulatory, reporting and other conditions and approvals required in all relevant jurisdictions, we provide certain patients with access to an investigational new drug under the EAP.\n\n**Intellectual Property**\n\nOur success depends in part on our ability to obtain and maintain proprietary protection for our technology and therapeutic candidates, its therapeutic applications, and related technology and know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights. Our policy is to seek to protect our proprietary position by, among other methods, filing U.S. and foreign patent applications related to our proprietary technology, inventions, and improvements that are important to the development of our business. We also rely on our trade secrets, know-how, and continuing technological innovation to develop and maintain our proprietary position. We vigorously defend our intellectual property to preserve our rights and gain the benefit of our technological investments.\n\n*Patents and Patent Applications*\n\nWe have rights, either through assignment, asset purchase or in-licensing, to a total of approximately 181 issued patents and 38 patent applications. The patents and patent applications are registered in the U.S. and other key jurisdictions, the details of each family of patents being provided below. In addition, we have licensed rights to various platform technologies on a non-exclusive basis.\n\n101\n\n[Table of Contents](#TOC)\n\nThe patent positions of companies such as ours are generally uncertain and involve complex legal and factual questions. Our ability to maintain and solidify our proprietary position for our technology will depend on our success in obtaining effective claims and enforcing those claims once granted.\n\n*Talicia*®\n\nThe patent portfolio protecting Talicia® currently includes eight U.S. patents, two pending U.S. patent applications, and over 27 foreign patents. The patents currently provide patent protection through 2034 and 2042. The Orange Book currently lists seven U.S. patents.\n\n*Opaganib - Oncology, inflammatory, viral and GI Indications*\n\nWe in-licensed several patents from Apogee and also generated new intellectual property. Opaganib is a first-in-class, proprietary SK2 inhibitor These patents relate to sphingosine kinase inhibitors, pharmaceutical compositions, methods of preparing the inhibitors, methods of treating inflammatory diseases using the inhibitors, methods of treating cancer using the inhibitors, and methods for inhibiting sphingosine kinase.\n\nThe patent portfolio covering opaganib includes six U.S. patents and over 28 foreign patents and patent applications, providing patent protection through 2026 and 2030.\n\nA patent portfolio covering the use of opaganib plus checkpoint inhibitors to treat cancer includes three foreign patents as well as applications pending in the U.S. as well as 11 foreign jurisdictions, providing protection for the combination treatment through 2040.\n\n*SARS-CoV-2*\n\nThis patent portfolio covers the use of opaganib and RHB-107 for treating or preventing coronavirus infections. The portfolio currently consists of eight issued U.S. patents, there issued foreign patents, and 10 pending foreign patent applications, providing patent protection through 2041.\n\n*RHB-107 (upamostat; formerly Mesupron) – Oncology*\n\nThe primary patent portfolio protecting the new chemical entity (WX-UK1), the pro-drug (“WX-671” or “RHB-107” or “upamostat”), formulations comprising upamostat, methods of synthesizing the compounds, and methods of using upamostat to treat cancer, was in-licensed by us from Wilex AG, now known as Heidelberg Pharma AG. RHB-107 is a first-in-class protease inhibitor administered by oral capsule. The portfolio includes three issued U.S. patents, providing patent protection through 2026 and 2027.\n\n*RHB-104 – Inflammatory Bowel Disease*\n\nThe patent portfolio protecting RHB-104 and its use in treating inflammatory bowel disease currently includes nine U.S. patents and 18 foreign patents, providing patent protection through 2029.\n\nWe have also in-licensed U.S. Patent No. 7,867,704 from The University of Minnesota entitled “Mycobacterial Diagnostics”, expiring in 2026. The acquired diagnostic technology is intended for the detection of Mycobacterium avium subspecies paratuberculosis (MAP) bacterium.\n\n*RHB-104 – Multiple Sclerosis*\n\nThe patent portfolio protecting the use of RHB-104 for treating relapsing-remitting multiple sclerosis includes one U.S. patent and over 11 foreign patents, providing patent protection through 2032.\n\n102\n\n[Table of Contents](#TOC)\n\n*RHB-102 (Bekinda*®*) - Gastritis, Gastroenteritis, IBS-D and Oncology support*\n\nThe patent portfolio protecting RHB102 (Bekinda®) and its use currently includes three U.S. patents and 22 foreign patents, providing patent protection through 2034 and 2035.\n\n*RHB-204 – Nontuberculous Mycobacterium (NTM) Infections*\n\nThe patent portfolio protecting RHB-204 currently includes one U.S. patent and 8 pending international patent applications, providing patent protection through 2041.\n\n*Ebola*\n\nThe patent portfolio covers RedHill’s proprietary experimental therapy for the treatment of the Ebola virus disease. The portfolio consists of five U.S. patents, one pending U.S. patent application, four foreign patents and one pending foreign patent application providing patent protection through 2035.\n\n*RHB-108 – Combination Cancer Therapy*\n\nRedHill has also pursued patent protection in cancer therapy for various combination of drugs with different mechanisms of action which achieve synergistic effects. Currently, the portfolio includes four U.S. patents, three foreign patents and two foreign pending patent applications.\n\n*Trademarks*\n\nOur principal trademarks, including RedHill®, Redhill Biopharma®, Talicia®, Bekinda™, Yeliva®, and their related logos, are registered or pending with the United States Patent and Trademark Office. We have also filed registration applications for non-U.S. trademarks in other countries in which we do or plan to do business. Brand names appearing in this annual report are trademarks of RedHill Biopharma Ltd. except for:\n\n●trademarks used or that may be or have been used under license by RedHill or its affiliates, such as Aemcolo®, a trademark of Cosmo Technologies Ltd. On July 9, 2024, we announced the mutual decision with Cosmo to voluntarily terminate the Cosmo License Agreement, and it was officially terminated on October 8, 2024.\n\n●trademarks used or that may be or have been used under license by RedHill or its affiliates, such as Movantik®, a trademark of AstraZeneca AB.\n\nNot all trademarks related to investigational agents have been authorized as of the date of this annual report by the relevant health authorities; for instance, the Bekinda™ and Yeliva® products have not been approved by the FDA.\n\n103\n\n[Table of Contents](#TOC)\n\n**Government Regulations**\n\nPharmaceutical companies are subject to extensive regulation by national, state and local agencies such as the FDA in the U.S., the Ministry of Health in Israel, or the EMA in Europe. The manufacture, clinical trials, distribution, marketing and sale of pharmaceutical products are subject to government regulation in the U.S. and various foreign countries. To manufacture both new therapeutic drug candidates for clinical trials and approved therapeutic drugs for sale and distribution in the U.S., we must follow the rules and regulations in accordance with current cGMP codified in 21 CFR 210 and 211. Additionally, we are responsible for ensuring that the API in each therapeutic drug or therapeutic drug candidate is manufactured in accordance with ICH Q7 guidance that has been adopted by the FDA. Further, we are required to conduct clinical trials that present data indicating that our therapeutic drug candidates are safe and efficacious in accordance with the current good clinical practice and codified in 21 CFR 312. If we do not comply with applicable requirements, we may be fined, the government may refuse to approve our marketing applications or not allow us to manufacture or market our products, and we may be criminally prosecuted. We and our contract manufacturers and clinical research organizations may also be subject to regulations under other federal, state and local laws, including, but not limited to, the U.S. Occupational Safety and Health Act, the Resource Conservation and Recovery Act, the Clean Air Act and import, export and customs regulations as well as the laws and regulations of other countries. Further, the U.S. government has increased its enforcement activity regarding fraud and abuse and illegal marketing practices in the healthcare industry. As a result, pharmaceutical companies must ensure their compliance with the Foreign Corrupt Practices Act and federal healthcare fraud and abuse laws, including the False Claims Act.\n\nThese regulatory requirements impact our operations and differ in one country to another, so that securing the applicable regulatory approvals of one country does not imply the approval in another country. However, securing the approval of a more stringent body, i.e., the FDA, may facilitate receiving the approval by a regulatory authority in a different country where the regulatory requirements are similar or less stringent. The approval procedures involve high costs and are manpower intensive, usually extend over many years and require highly skilled and professional resources.\n\n*FDA Approval Process for New Molecular Entities*\n\nOur therapeutic drug candidates are classified as New Molecular Entities. The steps required to be taken before therapeutic drug candidate may be marketed in the U.S. generally include:\n\n●completion of pre-clinical laboratory and animal testing;\n\n●the submission to the FDA of an investigational new drug, or IND, application which must be evaluated and found acceptable by the FDA before human clinical trials may commence;\n\n●performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed drug therapeutic candidate for its intended use; and\n\n●the submission and approval of an NDA.\n\nClinical studies are conducted under protocols detailing, among other things, the objectives of the study, what types of patients may enter the study, schedules of tests and procedures, drugs, dosages, and length of study, as well as the parameters to be used in monitoring safety, and the efficacy criteria to be evaluated. A protocol for each clinical study and any subsequent protocol amendments must be submitted to the FDA as part of the IND.\n\nIn all the countries that are signatories of the Helsinki Declaration (including Israel), the prerequisite for conducting clinical trials (on human subjects) is securing the preliminary approval of the competent authorities of that country to conduct medical experiments on human subjects in compliance with the other principles established by the Helsinki Declaration.\n\nThe clinical testing of a therapeutic drug candidate generally is conducted in three sequential phases prior to approval, but the phases may overlap or be combined. However, safety information should be submitted before the initiation of a subsequent clinical phase. A fourth, or post-approval phase may include additional clinical studies. The phases are generally as follows:\n\n104\n\n[Table of Contents](#TOC)\n\n*Phase 1.* In Phase 1 clinical studies, the therapeutic drug candidate is tested in a small number of healthy volunteers, though in cases where the therapeutic drug candidate may make the volunteer ill, clinical patients with the targeted condition may be used. These “dose-escalation” studies are designed to evaluate the safety, dosage tolerance, metabolism and pharmacologic actions of the therapeutic drug candidate in humans, side effects associated with increasing doses, and, in some cases, to gain early evidence on efficacy. The number of participants included in Phase 1 studies is generally in the range of 20 to 80.\n\n*Phase 2*. In Phase 2 studies, in addition to safety, the sponsor evaluates the efficacy of the therapeutic drug candidate on targeted indications to determine dosage tolerance and optimal dosage and to identify possible adverse effects and safety risks. Phase 2 studies typically are larger than Phase 1 but smaller than Phase 3 studies and may involve several hundred participants.\n\n*Phase 3*. Phase 3 studies typically involve an expanded patient population at geographically-dispersed test sites and involve control groups taking a reference compound or a placebo (an inactive compound identical in appearance to the study compound). They are performed after preliminary evidence suggesting the effectiveness of the therapeutic candidate has been obtained and are designed to evaluate clinical safety and efficacy further, to establish the overall benefit-risk relationship of the therapeutic candidate and to provide an adequate basis for a potential product approval. Phase 3 studies usually involve several hundred to several thousand participants.\n\n*Phase 4. *Phase 4 clinical trials are postmarketing studies designed to collect additional safety data as well as potentially expand a product indication. Postmarketing commitments may be required of, or agreed to by, a sponsor after the FDA has approved a therapeutic drug candidate for marketing. These studies are used to gain additional information from the treatment of patients in the intended therapeutic indication and to verify a clinical benefit in the case of drugs approved under accelerated approval regulations. If the FDA approves a product while a company has ongoing clinical trials that were not necessary for approval, a company may be able to use the data from these clinical trials to meet all or part of any Phase 4 clinical trial requirement. These clinical trials are often referred to as Phase 4 post-approval or postmarketing commitments. Failure to promptly conduct Phase 4 clinical trials could result in the inability to deliver the product into interstate commerce, misbranding charges, and civil monetary penalties.\n\nClinical trials must be conducted in accordance with the FDA’s GCP requirements. The FDA may order the temporary or permanent discontinuation of a clinical study at any time or impose other sanctions if it believes that the clinical study is not being conducted in accordance with FDA requirements or that the participants are being exposed to an unacceptable health risk. An institutional review board, or IRB, generally must approve the clinical trial design and patient informed consent at study sites that the IRB oversees and also may halt a study, either temporarily or permanently, for failure to comply with the IRB’s requirements, or may impose other conditions. Additionally, some clinical studies are overseen by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board or committee. The FDA recommends that a data safety monitoring board should be used to perform regular interim analysis for long-term clinical studies where safety concerns may be unusually high. This group recommends whether or not a trial may move forward at designated checkpoints based on access to certain data from the study. The clinical study sponsor may also suspend or terminate a clinical trial based on evolving business objectives or competitive climate.\n\nAs a therapeutic candidate moves through the clinical testing phases, manufacturing processes are further defined, refined, controlled and validated. The level of control and validation required by the FDA would generally increase as clinical studies progress. We and the third-party manufacturers on which we rely for the manufacture of our therapeutic drugs and therapeutic drug candidates and their respective API are subject to requirements that drugs be manufactured, packaged and labeled in conformity with cGMP. In addition to our third-party API manufacturers, we are responsible for ensuring that our third-party excipient manufacturers conform to cGMP requirements. To comply with cGMP requirements, manufacturers must continue to spend time, money and effort to meet requirements relating to personnel, facilities, equipment, production and process, labeling and packaging, quality control, recordkeeping, and other requirements.\n\n105\n\n[Table of Contents](#TOC)\n\nAssuming completion of all required testing in accordance with all applicable regulatory requirements, detailed information on the therapeutic candidate is submitted to the FDA in the form of an NDA, requesting approval to market the product for one or more indications, together with payment of a user fee, unless waived. An NDA includes all relevant data available from pertinent nonclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information on the chemistry, manufacture, control and proposed labeling, among other things. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the therapeutic candidate for its intended use to the satisfaction of the FDA.\n\nIf an NDA submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the Prescription Drug User Fee Act, or PDUFA, the FDA’s goal is to complete its initial review and respond to the applicant within ten months of a completed submission for 90% of the submissions received, unless the application relates to an unmet medical need in a serious or life-threatening indication, in which case the goal may be within six months of a completed NDA submission. However, PDUFA goal dates are not legal mandates, and the FDA response may occur several months beyond the original PDUFA goal date. Further, the review process and the target response date under PDUFA may be extended if the FDA requests or the NDA sponsor otherwise provides additional information or clarification regarding information already provided in the NDA. The NDA review process can, accordingly, be very lengthy. During its review of an NDA, the FDA may refer the application to an advisory committee for review, evaluation, and recommendation as to whether the application should be approved. The FDA is not bound by the recommendation of an advisory committee, but it typically follows such recommendations. Data from clinical studies are not always conclusive, and the FDA or any advisory committee it appoints may interpret data differently than the applicant.\n\nAfter the FDA evaluates the NDA and conducts a pre-approval inspection of all manufacturing facilities where the drug therapeutic candidate or its API will be produced, it will either approve commercial marketing of the drug therapeutic candidate with prescribing information for specific indications or issue a complete response letter indicating that the application is not ready for approval and stating the conditions that must be met in order to secure approval of the NDA. If the complete response letter requires additional data and the applicant subsequently submits that data, the FDA nevertheless may ultimately decide that the NDA does not satisfy its criteria for approval. The FDA could also approve the NDA with a Risk Evaluation and Mitigation Strategies, or REMS, plan to mitigate risks, which could include medication guides, physician communication plans, or elements to ensure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling, development of adequate controls and specifications, or a commitment to conduct postmarketing testing. The FDA may also request a Phase 4 clinical trial to further assess and monitor the product’s safety and efficacy after approval. Regulatory approval of products for serious or life-threatening indications may require that participants in clinical studies be followed for long periods to determine the overall survival benefit of the drug therapeutic candidate.\n\nIf the FDA approves one of our therapeutic drug candidates, we will be required to comply with a number of post-approval regulatory requirements. We would be required to report to the FDA, among other things, certain adverse reactions and production problems, and provide updated safety and efficacy information and comply with requirements concerning advertising and promotional labeling for any of our products. Also, quality control and manufacturing procedures must continue to conform to cGMP after approval, and the FDA periodically inspects manufacturing facilities to assess compliance with cGMP, which imposes extensive procedural, substantive and recordkeeping requirements. If we seek to make certain changes to an approved therapeutic drug, such as certain manufacturing changes, we may need the FDA to review and approve before the change can be implemented. For example, if we change the manufacturer of a product or its API, the FDA may require stability or other data from the new manufacturer, which will take time and is costly to generate, and the delay associated with generating this data may cause interruptions in our ability to meet commercial demand, if any. At their discretion, physicians may prescribe approved pharmaceutical products for indications that pharmaceutical products have not been approved for use by the FDA. However, we may not label or promote pharmaceutical products for an indication that has not been approved. Securing FDA approval for new indications of an approved therapeutic drug requires a Section 505(b)(2) filing, is similar to the process for approval of the original indication and requires, among other things, submitting data from adequate and well-controlled studies that demonstrate the product’s safety and efficacy in the new indication. Even if such studies are conducted, the FDA may not approve any change in a timely fashion, or at all.\n\n106\n\n[Table of Contents](#TOC)\n\nWe rely on, and expect to continue to rely on, third parties for the manufacture of clinical and future commercial, quantities of our therapeutic candidates. Future FDA and state inspections may identify compliance issues at these third-party facilities that may disrupt production or distribution or require substantial resources to correct. In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved NDA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing. Newly discovered or developed safety or efficacy data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and may also require the implementation of other risk management measures. Many of the foregoing could limit the commercial value of an approved product or require us to commit substantial additional resources in connection with the approval of a product. Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.\n\n*Section 505(b)(2) New Drug Applications*\n\nAs an alternate path to FDA approval of new indications or new formulations of previously-approved therapeutic drugs, a company may file a Section 505(b)(2) NDA, instead of a “stand-alone” or “full” NDA, somewhat similar to the process for approval of the original indication or reference drug and requires, among other things, submitting data from adequate and well-controlled studies that demonstrate the product’s safety and efficacy in the new indication. Even if such studies are conducted, the FDA may not approve any change in a timely fashion, or at all. Section 505(b)(2) of the Food, Drug, and Cosmetic Act was enacted as part of the Drug Price Competition and Patent Term Restoration Act of 1984, otherwise known as the Hatch-Waxman Amendments. Section 505(b)(2) was enacted to allow a company to avoid duplicative testing by permitting the applicant to leverage previously performed pertinent clinical and non-clinical studies into the current NDA submission. Some examples of therapeutic drug candidates that may be allowed to follow a 505(b)(2) path to approval are candidates that have a new dosage form, strength, route of administration, formulation or indication.\n\nThe Hatch-Waxman Amendments permit the applicant to rely upon certain published nonclinical or clinical studies conducted for an approved product or the FDA’s conclusions from a prior review of such studies. The FDA may require companies to perform additional studies or measurements to support any changes from the approved product. The FDA may then approve the new product for all or some of the labeled indications for which the reference product has been approved, as well as for any new indication supported by the NDA. While references to nonclinical and clinical data not generated by the applicant or for which the applicant does not have a right of reference are allowed, all development, process, stability, qualification and validation data related to the manufacturing and quality of the new product must be included in an NDA submitted under Section 505(b)(2).\n\nTo the extent that the Section 505(b)(2) applicant is relying on the FDA’s conclusions regarding studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the FDA’s Orange Book publication. Specifically, the applicant must certify that: (i) the required patent information has not been filed; (ii) the listed patent has expired; (iii) the listed patent has not expired but will expire on a particular date and approval is sought after patent expiration; or (iv) the listed patent is invalid or will not be infringed by the new product. The Section 505(b)(2) application also will not be approved until any non-patent exclusivity, such as exclusivity for obtaining approval of a new chemical entity, listed in the Orange Book for the reference product has expired. Thus, the Section 505(b)(2) applicant may invest a significant amount of time and expense in the development of its products only to be subject to significant delay and patent litigation before its products may be commercialized.\n\n*Orphan Drug Designation*\n\nThe Orphan Drug Act of 1983, or Orphan Drug Act, encourages manufacturers to seek approval for products intended to treat “rare diseases and conditions” with a prevalence of fewer than 200,000 patients in the U.S. or for which there is no reasonable expectation of recovering the development costs for the product. For products that receive orphan drug designation by the FDA, the Orphan Drug Act provides tax credits for clinical research, FDA assistance with protocol design, eligibility for FDA grants to fund clinical studies, waiver of the FDA application fee, and a period of seven years of marketing exclusivity for the product following FDA marketing approval.\n\n107\n\n[Table of Contents](#TOC)\n\n*GAIN Act*\n\nThe FDA’s Generating Antibiotic Incentives Now (GAIN) Act is intended to encourage the development of new antibiotic drug therapeutic candidates for the treatment of serious or life-threatening infections. For products that receive QIDP designation under the Act, the Act provides Fast-Track development status with an expedited development pathway and Priority Review status, which potentially provides shorter review time by the FDA of a future potential marketing application. Following FDA approval, an additional five years of U.S. market exclusivity applies, received on top of the standard exclusivity period.\n\n*Other Healthcare Laws and Compliance Requirements*\n\nIn the U.S., we are subject to various federal and state laws and regulations regarding fraud and abuse in the healthcare industry, as well as industry standards and guidance, such as the codes issued by the Pharmaceutical Research and Manufacturers of America (or “PhRMA Codes”), which some states reference or incorporate in their statutes and regulations. These laws, regulations, standards, and guidance may impact, among other things, our sales and marketing activities and our relationships with healthcare providers and patients. In addition, we may be subject to patient privacy regulations by both the federal government and the states in which we conduct our business. The laws that may affect our ability to operate include but are not limited to:\n\n●the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order, or recommendation of, an item or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs;\n\n●federal civil and criminal false claims laws and civil monetary penalty laws, including the False Claim Act, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from the federal government, including Medicare, Medicaid, or other third-party payors, that are false or fraudulent;\n\n●HIPAA, which imposes federal criminal and civil liability for executing, or attempting to execute, a scheme to defraud any healthcare benefit program and making false statements relating to healthcare matters;\n\n●the federal transparency laws, including the Physician Payments Sunshine Act, that requires applicable manufacturers of covered drugs to disclose payments and other transfers of value provided to physicians and teaching hospitals and physician ownership and investment interests;\n\n●HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and its implementing regulations, also imposes certain requirements relating to the privacy, security, and transmission of individually identifiable health information; and\n\n●state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers, state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines, state laws that require pharmaceutical manufacturers to report certain pricing or payment information, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and are not preempted by HIPAA, thus complicating compliance efforts.\n\nThe Healthcare Reform Law broadened the reach of the fraud and abuse laws by, among other things, amending the intent requirement of the federal Anti-Kickback Statute and certain other criminal healthcare fraud statutes. Specifically, a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. In addition, the Healthcare Reform Law provides that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act or the civil monetary penalties statute. Many states have adopted laws similar to the federal Anti-Kickback Statute, some of which apply to the referral of patients for healthcare items or services reimbursed by any source, not only federal healthcare programs such as the Medicare and Medicaid programs.\n\n108\n\n[Table of Contents](#TOC)\n\nDue to the breadth of some of these laws, it is possible that some of our, or our subsidiaries’, collaborators’, or affiliates’, current or future practices might be challenged under one or more of these laws. In addition, there can be no assurance that we would not be required to alter one or more of our practices to comply with these laws. Evolving interpretations of current laws or the adoption of new federal or state laws or regulations could adversely affect the arrangements we, or our subsidiaries, collaborators, or affiliates, may have with sales personnel, healthcare providers, and patients. Our risk of being found in violation of these laws is increased by the fact that some of these laws are open to a variety of interpretations. If our past or present operations, practices, or activities are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, exclusion from participation in government healthcare programs, such as Medicare and Medicaid, imprisonment, damages, fines, disgorgement, contractual remedies, reputational harm, diminished profits, and future earnings, if any, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.\n\n**C.          Organizational Structure**\n\nOur wholly-owned subsidiary, Redhill Biopharma Inc., was incorporated in Delaware on January 19, 2017. Talicia Holdings, the Company’s joint venture with Cumberland, was incorporated in Delaware on September 12, 2025.\n\n**D.          Property, Plant and Equipment**\n\nWe lease approximately 418 square meters of office space and five parking spaces in the “Platinum” building at 21 Ha’arba’a Street, Tel-Aviv, Israel. In December 2025, we entered into an amendment to our lease agreement, pursuant to which the lease term was extended, and the leased premises were reduced from approximately 826 square meters to approximately 418 square meters. The term under the amended lease agreement expires on January 31, 2031. We have an option to extend the lease term for an additional five years.\n\nThe yearly gross rental expenses were approximately $420,000 per year prior to the December 2025 amendment. Following the reduction in leased space, the annual gross rental expenses are approximately $298,000 per year commencing in 2026.\n\nThese offices have served as our corporate headquarters since April 2011.\n\nOur U.S. office lease expired on July 31, 2024, with all related rental obligations fully settled."}