RedHill Biopharma Stock

RedHill Biopharma Ltd., a specialty biopharmaceutical company, focuses on gastrointestinal (GI) and infectious diseases.

The company focuses primarily on the commercialization in the U.S. of the GI-related products, Movantik (naloxegol), Talicia (omeprazole, amoxicillin, and rifabutin) and Aemcolo (rifamycin).

In addition, the company continues to develop its pipeline of clinical-stage therapeutic candidates, including, among others, opaganib and RHB-107 (upamostat), as potential treatments for COVID-19. It looks for opportunities to leverage its commercial presence and capabilities in the U.S. to support the potential future launch of its therapeutic candidates under development, if approved by the Food and Drug Administration (FDA), or any FDA-approved products that it may acquire the rights to in the future.

Approved and Commercial Products in the U.S.

The company has established the headquarters of its U.S. commercial operations in Raleigh, North Carolina. Its U.S. operations promote Movantik for opioid-induced constipation in adults, Talicia for the treatment of H. pylori infection in adults and Aemcolo for the treatment of travelers’ diarrhea in adults. The company also expects its U.S. operations to serve as the platform for the potential launch of its proprietary, late-clinical stage therapeutic candidates in the U.S., if approved by the FDA, and potential in-licensed or acquired commercial-stage products in the U.S.

The company continues to pursue the acquisition of additional commercial products, including, without limitation, through licensing or promotion transaction, asset purchase, joint venture with, acquisition of, or a merger with or other business combination with, companies with rights to commercial GI and other relevant assets and are continuously working to expand the U.S. managed care access and coverage to its commercial products, where appropriate. The company plans to pursue such opportunities in the U.S. and, if available, in other jurisdictions; however, it intends to focus its commercial activities in the U.S. The company promotes and commercializes three GI products in the U.S.

Movantik

The company acquired the worldwide rights (excluding Europe, Canada and Israel) to commercialize and develop Movantik (naloxegol) from AstraZeneca AB (AstraZeneca) in April 2020. Movantik is a proprietary once-daily oral peripherally-acting mu-opioid receptor antagonist (PAMORA) approved by the FDA for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g. weekly) opioid dosage escalation. The company initiated the promotion of Movantik in the second quarter of 2020. In October 2020, the company gained the rights to commercialize and develop Movantik in Israel, and thus it holds the worldwide rights to Movantik, excluding Europe and Canada.

Regulatory Status

Movantik received FDA approval in 2014 for the treatment of OIC in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g. weekly) opioid dosage escalation. In connection with its in-license for Movantik, the company agreed to assume responsibility for completing any postmarketing requirements or commitments that may be required to retain approval. Accordingly, the company is required to continue the post-marketing observational epidemiologic study to evaluate the major adverse cardiovascular events (MACE) of Movantik.

Competition

Movantik primarily competes with several branded therapies already approved and used to treat OIC, including Amitiza (lubiprostone, promoted by Takeda Pharmaceuticals) and two other oral PAMORA drugs, Relistor (methylnaltrexone bromide, promoted by Salix Pharmaceuticals, Ltd. (Salix Pharmaceuticals)) and Symproic (naldemedine, promoted by BioDelivery Sciences International, Inc.).

Talicia (Omeprazole Magnesium, Amoxicillin, and Rifabutin) Delayed-release Capsules 10 mg/250 mg/12.5 mg

Talicia is the company’s proprietary new drug approved 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, which is a proton pump inhibitor (prevents the secretion of hydrogen ions necessary for the digestion of food in the stomach), amoxicillin and rifabutin, which are antibiotics. Talicia is administered to patients orally. The company launched Talicia in the U.S. in March 2020 with its dedicated sales force.

In 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. Under its QIDP designation, Talicia is eligible for an additional five years of the U.S. market exclusivity, on top of the standard exclusivity period, for a total of eight years of market exclusivity.

Talicia is targeting a significantly broader indication than that of existing H. pylori therapies, as a treatment of H. pylori infection, regardless of ulcer status.

The company acquired the rights to Talicia pursuant to an agreement with Giaconda Limited. In December 2021, the company entered into an exclusive license agreement with Gaelan Medical Trade LLC (Gaelan Medical) for Talicia, in the United Arab Emirates (UAE).

Regulatory Status

In November 2019, Talicia was approved by the FDA and is eligible for a total of eight years of the U.S. market exclusivity.

Competition

Talicia faces competition in the U.S. from certain branded prescription therapies indicated for the treatment of H. pylori infection, including but not limited to, Pylera (sold by Allergan plc), PrevPac (sold by Takeda Pharmaceuticals) and Omeclamox-Pak (sold by Cumberland Pharmaceuticals), as well as from the generic individual components of these branded therapies and other generic antibiotics and PPIs approved for the treatment of H. pylori infection.

Aemcolo

Aemcolo, containing 194mg of rifamycin, is an orally administered, minimally absorbed antibiotic that is delivered to the colon, approved by the FDA in 2018 for the treatment of travelers’ diarrhea caused by non-invasive strains of E. coli in adults (Travelers’ Diarrhea). In October 2019, the company entered into a license agreement, as amended, with a wholly-owned subsidiary of Cosmo Pharmaceuticals N.V. (Cosmo) pursuant to which the company was granted exclusive rights to commercialize Aemcolo in the U.S. (the ‘Cosmo License Agreement’). In December 2019, the company launched the commercialization of Aemcolo in the U.S.

Regulatory Status

Aemcolo received FDA approval in 2018 for the treatment of travelers’ diarrhea caused by the noninvasive strains of Escherichia coli in adults. Cosmo transferred the Aemcolo New Drug Application (NDA) and the Investigational New Drug (IND) to RedHill Biopharma Inc. (RedHill U.S.), which were accepted on November 27, 2019. This acceptance also includes a commitment to complete any postmarketing requirements or commitments related to the NDA. There are two pediatric studies that are required to be completed to satisfy the Pediatric Research Equity Act (PREA) requirements and also with required milestone dates:

Conduct a randomized, placebo-controlled study to evaluate the safety, tolerability, and efficacy of Aemcolo (rifamycin) for the treatment of travelers’ diarrhea in children from 6 to 11 years of age.

Conduct a randomized, placebo-controlled study to evaluate the safety, tolerability, and efficacy of Aemcolo (rifamycin) for the treatment of travelers’ diarrhea in children from 12 to 17 years of age.

Therapeutic Candidates

The ongoing development programs of the company’s six therapeutic candidates, most in late-stage clinical development, include RHB-204, opaganib, RHB-107 (upamostat), RHB-104, RHB-102 (Bekinda) and RHB-106 and related research and development programs.

RHB-204

Nontuberculous Mycobacteria Infections

In November 2020, the company 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 nontuberculous mycobacteria (NTM) disease caused by MAC.

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

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

RHB-204 is a patented fixed-dose combination product of three antibiotics intended to simplify administration and optimize compliance, selected based on modelling to provide optimal balance of the potential safety and efficacy. Each capsule contains the same three antibiotics as RHB-104 (clarithromycin, clofazimine, and rifabutin), but at doses unique from RHB-104. Further, rifabutin enhances the antimicrobial activity of clarithromycin due to increased levels of clarithromycin's active metabolite. The 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.

Although each of the three components of RHB-204 is approved individually and has been tested extensively in humans (e.g. see RHB-104), the formulation and doses represented by RHB-204 is novel and has not previously been tested in humans. Initiation of the trial for pulmonary nontuberculous mycobacteria (NTM) lung infections was in November 2020. The appropriate regulatory path is under discussion.

Opaganib

Opaganib, a new chemical entity, is a proprietary, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with observed anticancer, anti-inflammatory, and antiviral activities, targeting multiple oncology, viral, inflammatory, and gastrointestinal indications. The compound originally designated as ABC294640 received an international non-proprietary name, opaganib, in the Recommended INN: List 79, 2018.

Opaganib inhibits SK2, a lipid kinase that catalyzes the formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). Opaganib’s proposed antiviral mechanism, based on pre-clinical studies conducted with the molecule, inhibits the replication of positive-strand single-stranded ribonucleic acid (RNA) viruses, of which coronavirus, and specifically SARS-CoV-2 (the virus that causes COVID-19), 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 Tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluids.

In March 2015, the company entered into an exclusive worldwide license agreement with Apogee Biotechnology Corporation (Apogee), pursuant to which Apogee granted the company the exclusive worldwide development and commercialization rights to ABC294640 (which the company then renamed to opaganib, and received an international non-proprietary name, opaganib, in 2018) and additional intellectual property for all indications.

In March 2022, the company entered into an exclusive license agreement with Kukbo Co. Ltd. (Kukbo) for opaganib for the treatment of COVID-19 in South Korea. The development of opaganib is supported by grants and contracts from the U.S. federal and state government agencies awarded to Apogee, including from the National Cancer Institute (NCI), BARDA, the U.S. Department of Defense and the FDA Office of Orphan Products Development.

ABC-201: Global Phase 2/3 Study

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

In September 2021, the company 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. The analysis of the study efficacy endpoints did show trends in favor of the opaganib arm as compared to placebo across multiple endpoints, including the primary endpoint, despite not achieving statistical significance.

In October 2021, the company 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, including 54% of the study participants.

In January 2022, the company 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 ribonucleic acid (RNA) clearance by approximately 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). This data provides clinical evidence supporting opaganib's potential antiviral activity.

In February 2022, the company 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.

Based on regulatory feedback from other territories and external advice received, the company is also planning potential emergency and marketing authorization applications in certain such countries in the first half of 2022.

The company continues to further examine and analyze the data from this study along with all the information gathered during this study, including all safety, and secondary outcome measures.

The company has submitted data packages for opaganib to the regulatory agencies in the U.S., EU, the U.K. and other territories in the fourth quarter of 2021. Discussions remain ongoing and initial guidance on a confirmatory study and potential path to approval has been received from the EU's EMA, the U.S. FDA, the U.K.'s MHRA and others. Based on regulatory feedback from other territories and external advice received, the company is also planning potential emergency and marketing authorization applications in certain such countries in the first half of 2022.

The company is also continuing its discussions with the U.S. and other government agencies and non-governmental organizations around potential funding to support the ongoing development of opaganib. Discussions are also ongoing with potential partners who are interested in the rights to opaganib in various territories.

ABC-110: the U.S. Phase 2 Study

In December 2020, the company announced that its 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.

In September 2021, the company announced the results of a preclinical study demonstrating opaganib’s efficacy in significantly decreasing renal fibrosis in a unilateral ureteral obstruction-induced renal interstitial fibrosis model. Reports suggest that over 20% of hospitalized COVID-19 patients experience acute renal failure. The aim of the in vivo efficacy study was to verify the effect of opaganib on kidney inflammation and fibrosis in a unilateral ureteral obstruction (UUO) model – a well characterized model for renal fibrosis. Results from the study showed that opaganib significantly decreased renal fibrosis.

Compassionate use

In April 2020, at the beginning of the COVID-19 pandemic, the company established a compassionate use program, providing opaganib on a compassionate-use basis to patients with severe COVID-19 in Israel and in Switzerland. A report was published in medRxiv describing the compassionate-use in Israel (2020), in which a small cohort (seven patients) with severe COVID-19 pneumonia requiring supplemental oxygen via high flow nasal cannula (HFNC) were treated with opaganib. The dose administered was 500 mg BID for up to 14 days. The outcomes of these patients were evaluated against matched controls at the same hospital center. No safety issues were observed in this small cohort. Additionally, a physician in Switzerland requested opaganib on a compassionate-use basis to treat ten COVID-19 patients. The data gathered from the physician is limited; however the outcomes suggest that the treatment was safe and well tolerated in this small cohort of patients.

ABC-108: Advanced Unresectable Cholangiocarcinoma

A Phase 2a clinical study with opaganib in patients with advanced, unresectable, intrahepatic, perihilar and extrahepatic cholangiocarcinoma is ongoing at Mayo Clinic’s major campuses in Arizona and Minnesota, the Huntsman Cancer Institute, University of Utah Health and at Emory University. In September 2018, the company 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. Preliminary data from this cohort indicated a signal of activity in a number of subjects with advanced cholangiocarcinoma. Enrollment is ongoing for a second cohort, evaluating opaganib in combination with hydroxychloroquine, an anti-autophagy agent. Opaganib received orphan drug designation from the FDA for the treatment of cholangiocarcinoma.

In October 2019, an expansion cohort for the cotreatment of opaganib and hydroxychloroquine sulfate (HCQ) was submitted to the FDA. Enrollment of this cotreatment cohort, Part 2 of the study, began in July 2020. The cohort will consist of two phases: Phase 1, an accelerated dose escalation run-in with enrollment of up to 15 patients evaluable for safety and tolerability, and Phase 2, the treatment of 20 patients evaluable in the Phase 1 determined dose to determine safety and tolerability.

Expanded Access Program (EAP) for the Treatment of Advanced Unresectable Cholangiocarcinoma

An EAP is for eligible participants who do not qualify for participation in, or who are otherwise unable to access, the ongoing clinical trial ABC-108 for advanced unresectable cholangiocarcinoma. This program is designed to provide access to opaganib for the treatment of cholangiocarcinoma prior to approval by the local regulatory agency. The company cannot predict how long this program will continue, and it may decide for various reasons, including but not limited to, resources and availability of opaganib, not to continue with the EAP.

ABC-103: Refractory or Relapsed Multiple Myeloma

A Phase 1b study with opaganib for the treatment of refractory or relapsed multiple myeloma was performed in heavily pretreated patients at Duke University Medical Center. The primary endpoints of the first portion of the study (Phase 1) were to assess safety and determine the maximum tolerated dose in this group of patients. Secondary objectives included the assessment of antitumor activity and determination of the pharmacokinetics (PK) and pharmacodynamic (PD) properties of opaganib in refractory or relapsed multiple myeloma patients. At the current stage, the company has no intention to pursue the development of opaganib for this indication.

ABC-101: Advanced Solid Tumors

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

The study included the first-ever longitudinal analysis of plasma sphingosine 1-phosphate (S1P) levels as a potential pharmacodynamic biomarker for activity of a sphingolipid-targeted drug. Administration of opaganib resulted in a rapid and pronounced decrease in levels of S1P with several patients having prolonged stabilization of disease.

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

ABC-106: Advanced Hepatocellular Carcinoma

An investigator-sponsored Phase 2 study to evaluate the safety and efficacy of opaganib as a second-line monotherapy in patients with advanced hepatocellular carcinoma (HCC) was initiated at MUSC Hollings Cancer Center, the Mayo Clinic campus at Arizona and the University of Maryland.

In September 2019, the company announced that The National Cancer Institute (NCI) grant that was previously awarded to the Medical University of South Carolina (MUSC) to support a study with opaganib in hepatocellular carcinoma (HCC) had been diverted to support a Phase 2 study with opaganib for a different indication, prostate cancer (ABC-107). At the current stage, the company has no intention to pursue the development of opaganib for the hepatocellular carcinoma (HCC) indication.

ABC-107: Prostate Cancer

The investigator-sponsored study ‘A Phase 2 Study of the Addition of opaganib to Androgen Antagonists in Patients with Prostate Cancer Progression on Enzalutamide or Abiraterone’ was initiated in March 2020 at MUSC Hollings Cancer Center and at Emory University. The study is planned to enroll up to 70 patients and is supported by the National Cancer Institute grant awarded to MUSC.

In August 2021, the company announced that based on a preliminary review of partial and unaudited data in the ongoing study, the study had met its primary endpoint of approximately six subjects demonstrating disease control (defined as stable disease or better after 16 weeks on treatment) among approximately 27 evaluable subjects.

Upon further review and analysis of the unaudited data in the ongoing study, the company reported that the study did not meet its primary endpoint in the study arm evaluating opaganib in combination with enzalutamide. Patient enrolment continues for the study’s other arm, evaluating a combination of opaganib and abiraterone. Accrual and data entry are ongoing and results for the study remain subject to further review and analysis.

Preclinical data have demonstrated both anti-inflammatory and antiviral activities of opaganib, demonstrating the potential to reduce inflammatory lung disorders, such as pneumonia, and mitigate pulmonary fibrotic damage.

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

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

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

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

ABC-109: Food Effect Study in Healthy Subjects

A Phase 1, randomized, open-label, single-dose, 3-treatment, 3-period, 6-sequence crossover study designed primarily to evaluate the effect of a standardized meal on the absorption and bioavailability of opaganib in healthy subjects, was completed in the U.S. in January 2018. The study also evaluated the effect of the administration of a solution of opaganib via nasogastric (NG) tube on the absorption and bioavailability of opaganib. Twenty-three eligible, healthy, male and female adult subjects were randomized to receive opaganib orally in a state of fast, fed or as a solution by NG tube (after tube feeding).

RHB-107 (upamostat)

In June 2014, the company signed an exclusive license agreement with Wilex AG (which later changed its name to Heidelberg Pharma AG) forRHB-107 (INN: upamostat) for all indications and for all uses. Under this agreement, the company is responsible for all development, regulatory and commercialization of RHB-107 in the entire world, excluding China, Taiwan, Macao, and Hong Kong.

RHB-107 is a proprietary, orally-administered potent inhibitor of several serine proteases, with a unique potency and specificity that suggests it may be a new non-cytotoxic approach to cancer therapy. In addition, work completed by the company demonstrated its potential use in inflammatory digestive diseases, inflammatory lung diseases and infectious diseases.

Non-Clinical and Clinical Development

Data from non-clinical studies conducted by the company 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.

Oncology

RHB-107’s safety profile has been demonstrated in approximately 200 people, including in Phase 2 studies in oncology indications and COVID-19. Several 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.

Using technologies developed since the original clinical trials were performed, the company is planning several preclinical studies, including biomarker analysis and mechanism of action studies. The company expects that the findings from these studies can help it determine the patient populations to be studied in subsequent clinical trials.

In October 2017, the FDA granted RHB-107 orphan drug designation for the treatment of pancreatic cancer. The orphan drug designation allows the company to benefit from various development incentives to develop RHB-107 for this indication, including tax credits for qualified clinical testing, waiver of a Prescription Drug User Fee Act (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.

COVID-19

RHB-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 is 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.

In March 2022, the company announced positive Phase 2 study results of Part A of the Phase 2/3 study, which enrolled a total of 61 patients who were randomized on a 1:1:1 basis to receive one of two dose levels of RHB-107 or a placebo control.

The 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 (last patient randomized November 12, 2021), with the most common variant being Delta, found in 62.5% of the patients that had next generation sequencing (NGS).

Next steps for the study will follow data submission and discussion with regulators.

Ebola Virus Disease Therapy

The company completed the first part of a preclinical in-vivo study (2 out of the 3 proposed actives). The preliminary results were evaluated in conjunction with the U.S. National Institute of Allergy and Infectious Diseases and demonstrated statistical significance of the combination of two of its molecular candidates. The second part of the study (all three actives combined) has not yet been initiated. In May 2018, the company received a new U.S. patent for its experimental Ebola therapy. The company continues to examine ways to work together with the National Institute of Health on various projects.

RHB-104

Crohn’s Disease

RHB-104 is an investigational new drug intended to treat Crohn’s disease, which is a serious inflammatory disease of the GI system that may cause severe abdominal pain and bloody diarrhea, malnutrition and potentially life-threatening complications.

RHB-104 is a patented combination of clarithromycin, clofazimine, and rifabutin, three generic antibiotic ingredients, in a single capsule. The compound was developed to treat Mycobacterium avium paratuberculosis (MAP) infections in Crohn’s disease.

The company acquired the rights to RHB-104 pursuant to an asset purchase agreement with Giaconda Limited, an Australian company.

The company continues to pursue the development program for a companion diagnostic for the detection of MAP bacteria in Crohn’s disease patients. These efforts are in part based on detecting the presence of MAP bacterial DNA in human biological specimens. It does not know if or when such a diagnostic test would become available.

The company has 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 U.S. study. The company focuses that additional clinical studies will be required to support an NDA for RHB-104, if filed.

Multiple Sclerosis (MS)

The company had previously conducted a Phase 2a proof-of-concept study with RHB-104 for relapsing-remitting multiple sclerosis. The company has no intention to pursue the development of RHB-104 for this indication.

RHB-102 (Bekinda)

RHB-102 (Bekinda) is an investigational once-daily bi-modal extended-release oral formulation of ondansetron, a member of the family of 5-HT3 serotonin receptor inhibitors. The company is developing RHB-102 (Bekinda) in multiple dosage strengths. RHB-102 (Bekinda) is under development for the intended use in the following indications, which are novel and not yet FDA-approved indications for ondansetron targeting large potential markets: acute gastroenteritis and gastritis - 24 mg strength; and irritable Bowel Syndrome with Diarrhea (IBS-D) - lower dose strength for long-term administration.

RHB-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.

Acute Gastroenteritis and Gastritis

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.

In September 2019, the company had a follow-up meeting with the FDA regarding its 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. The September 2019 meeting provided further clarity on the designs of the pediatric studies required by FDA, but the details have not yet been finalized.

Irritable Bowel Syndrome with Diarrhea (IBS-D)

In preliminary studies, ondansetron has demonstrated activity in IBS-D. 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).

In the light of the activity of ondansetron demonstrated in the preliminary studies, and because of its extended-release properties and once-daily dosing, RHB-102 (Bekinda) is a candidate for the treatment of IBS-D.

The company has initiated formulation work to formulate RHB-102 at lower dosages to help support planned pediatric studies. In December 2019, it received confirmation from the FDA that it has agreed with its Initial Pediatric Study Plan (iPSP).

RHB-106

RHB-106 is an investigational tablet intended for the preparation and cleansing of the GI tract prior to the performance of abdominal procedures, including diagnostic tests, such as colonoscopy, barium enema or virtual colonoscopy, as well as surgical interventions, such as a laparotomy.

In December 2019, the company provided a notice of termination of the worldwide exclusive license agreement it had entered into in 2014 with Salix Pharmaceuticals, Ltd. (Salix, which was later acquired by Valeant Pharmaceuticals International, Inc. (Valeant), and subsequently renamed Bausch Health Companies Inc.). As a result of the termination of the Salix licensing agreement, the company regained the exclusive worldwide rights to the RHB-106 encapsulated formulation for bowel preparation.

Strategy

The key elements of the company’s strategy are to advance its initiative to become a leading specialty biopharmaceutical company by leveraging its commercial presence in the U.S.; identify and acquire rights to products from pharmaceutical companies that have encountered cash flow or operational problems or that decide to divest one or more of their products for various reasons; identify and enter into out-licensing or collaborative agreements with third parties to develop and/or commercialize its commercial products or therapeutic candidates in territories outside the U.S.; enhance existing pharmaceutical products, including broadening their range of indications, or launching innovative and advantageous pharmaceutical products, based on existing active ingredients; where applicable, utilize the FDA’s 505(b)(2) regulatory pathway to potentially obtain more timely and efficient approval of its formulations of previously approved products; and cooperate with third parties to develop or commercialize therapeutic candidates in order to leverage the expertise of others.

License Agreement related to MAP diagnostic test for RHB-104

In December 2014, the company entered into a license agreement with the University of Minnesota (UoM) pursuant to which it was granted an exclusive license for all indications and medical uses to a patent-protected designation of certain DNA sequencing.

Intellectual Property

Patents and Patent Applications

The company has rights, either through assignment, asset purchase or in-licensing, to a total of approximately 450 issued patents and 150 patent applications. The patents and patent applications are registered in the U.S. and other key jurisdictions. In addition, the company has licensed rights to various platform technologies on a non-exclusive basis.

Movantik

Following the closing of the company’s in-license for Movantik, it has in-licensed patents and trademarks from AstraZeneca AB as part of the AstraZeneca License Agreement. The Orange Book lists six U.S. patents, two of which are directed to the approved use for the treatment of opioid-induced constipation. However, the entire licensed patent portfolio consists of ten U.S. patents, one pending patent application, over fifty foreign patents and approximately a dozen pending foreign patent applications.

Talicia: The patent portfolio protecting Talicia includes six U.S. patents, one pending U.S. patent application, and over 20 foreign patents and patent applications. The patents provide patent protection through 2034. The Orange Book lists five U.S. patents.

Aemcolo: This patent portfolio was in-licensed by the company from Cosmo Technologies Ltd. as part of its license agreement for Aemcolo. The U.S. patent portfolio consists of four issued patents and one pending patent application. The four issued patents protect the commercial product and its approved method of use. The Orange Book lists four U.S. patents.

RHB-104 – Inflammatory Bowel Disease: The patent portfolio protecting RHB-104 and its use in treating inflammatory bowel disease includes nine U.S. patents, and 33 foreign patents and patent applications, providing patent protection through 2029.

The company has also in-licensed U.S. Patent Nos. 7,074,559 and 7,867,704 from The University of Minnesota entitled ‘Mycobacterial Diagnostics’. One U.S. patent will expire in 2022, and the other U.S. patent will expire in 2026. The acquired diagnostic technology is intended for the detection of Mycobacterium avium subspecies paratuberculosis (MAP) bacterium.

RHB-104 – Multiple Sclerosis (MS): The patent portfolio protecting the use of RHB-104 for treating relapsing-remitting multiple sclerosis includes one U.S. patent and over 20 foreign patents and patent applications, providing patent protection through 2032.

RHB-204 – Nontuberculous Mycobacterium (NTM) Infections: The patent portfolio protecting RHB-204 includes one U.S. patent, one pending U.S. patent application, one European patent application, and one pending Hong Kong application, providing protection through 2041. An international patent application, due to be converted into independent country-specific patent applications in 2022, is pending.

RHB-102 (Bekinda) - Gastritis, Gastroenteritis and IBS-D: The patent portfolio protecting RHB-102 (Bekinda) and its use includes three U.S. patents, two pending U.S. patent applications, and over 30 foreign patents and patent applications, providing patent protection through 2034.

RHB-106 - Bowel Preparation: The patent portfolio protecting RHB-106 and its use includes three issued U.S. patents, and 12 foreign patents and patent applications, providing patent protection through 2033.

Opaganib - Oncology, inflammatory and GI Indications: This patent portfolio was in-licensed by the company from Apogee. Opaganib is a proprietary SK2 inhibitor, administered orally, with anti-cancer and anti-inflammatory activities, targeting a number of potential oncology, inflammatory and GI indications. These patents relate to sphingosine kinase inhibitors, pharmaceutical compositions, the methods of preparing the inhibitors, the methods of treating inflammatory diseases using the inhibitors, the methods of treating cancer using the inhibitors, and methods for inhibiting sphingosine kinase.

The patent portfolio covering opaganib includes four U.S. patents and over eighteen foreign patents and patent applications, providing patent protection through 2028.

A new patent family seeking to protect the use of opaganib plus checkpoint inhibitors to treat cancer is pending in the U.S., as well as 13 foreign jurisdictions. If patents are granted, it will provide protection for the combination treatment through 2040.

RHB-107 (upamostat; formerly Mesupron) – Oncology: The primary patent portfolio protecting the new chemical entity (WX-UK1), the pro-drug (WX-671 or RHB-107 or upamostat), formulations, including upamostat, the methods of synethesizing the compounds, and the methods of using upamostat to treat cancer, was in-licensed by the company 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 fifteen issued U.S. patents and over sixty foreign patents and patent applications, providing patent protection through 2027.

Ebola: The patent portfolio covers the company’s proprietary experimental therapy for the treatment of the Ebola virus disease. The portfolio consists of two U.S. patents, one pending U.S. patent application, five issued foreign patent applications and four pending international patents and patent applications.

SARS-CoV-2: This patent portfolio seeks covers the use of opaganib and RHB-107 for treating or preventing coronavirus infections. The portfolio consists of two issued U.S. patents, four pending U.S. patent applications and one pending PCT international patent application, providing patent protection through 2041.

RHB-108 – Combination Cancer Therapy: The company has also pursued patent protection in cancer therapy for various combination of drugs with different mechanisms of action, which achieve synergistic effects. The portfolio includes three U.S. patents, one pending U.S. patent application, four issued foreign patent applications and six foreign pending patent applications.

Trademarks

The company’s principal trademarks, including RedHill, Redhill Biopharma, Talicia, Bekinda, Yeliva, and their related logos, are registered with the United States Patent and Trademark Office. It has also filed registration applications for non-U.S. trademarks in other countries in which it does or plans to do business.

Research and Development Expenses

For the year ended December 31, 2021, the company’s research and development expenses were $29.5 million.

Government Regulations

To manufacture both new therapeutic drug candidates for clinical trials and approved therapeutic drugs for sale and distribution in the U.S., the company must follow the rules and regulations in accordance with current good manufacturing practices (cGMP) codified in 21 CFR 210 and 211. Additionally, the company is responsible for ensuring that the active pharmaceutical ingredient (API) in each therapeutic drug or therapeutic drug candidate is manufactured in accordance with the International Conference on Harmonization (ICH) Q7 guidance that has been adopted by the FDA. Further, the company is required to conduct clinical trials that present data indicating that its therapeutic drug candidates are safe and efficacious in accordance with the current good clinical practice and codified in 21 CFR 312.

In the U.S., the company is 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 (PhRMA Codes), which some states reference or incorporate in their statutes and regulations.

History

RedHill Biopharma Ltd. was founded in 2009. The company was incorporated in 2009.