RedHill Biopharma’s Opaganib Demonstrates Complete Inhibition of SARS-CoV-2

RedHill Biopharma Ltd. recently 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. Opaganib is a first-in-class, orally administered, sphingosine kinase-2 (SK2) selective inhibitor with dual anti-inflammatory and anti-viral activity that targets a host cell component, unaffected by viral mutation, thus minimizing the likelihood of resistance. Opaganib is currently being evaluated in global Phase 2/3 and US Phase 2 clinical studies for the treatment of severe COVID-19 pneumonia.

Working in collaboration with the University of Louisville Center for Predictive Medicine, opaganib was studied in a 3D tissue model of human bronchial epithelial cells (EpiAirway) that morphologically and functionally resembles the human airway and is similar to the model used to discover SARS-CoV-2. This study was designed to evaluate the in vitro efficacy of opaganib in inhibiting SARS-CoV-2 infection and included a positive control of remdesivir, a drug with known antiviral activity.

Results from this study showed a clear and compelling antiviral effect of opaganib against SARS-CoV-2. Opaganib demonstrated the most potent activity compared to all compounds tested, including the positive control, remdesivir. Treatment of cells infected with SARS-CoV-2 resulted in a dose-dependent inhibition of virus production without compromising cell membrane integrity, a measure of cell viability and drug safety, further demonstrating opaganib’s promising potential for treating patients with COVID-19.

Opaganib at 1 mg/ml (a pharmacologically relevant concentration) completely inhibited viral replication as measured after three days of incubation. This potent opaganib activity compares favorably with remdesivir data as the active control in the RedHill study which is consistent with published remdesivir data.  Data from the study is planned to be submitted to a peer-reviewed journal.

“Opaganib’s previously demonstrated anti-inflammatory activity, combined with our now proven specific anti-SARS-CoV-2 viral activity, provides a unique dual mechanism of action with the potential to greatly benefit COVID-19 patients by inhibiting the key drivers of disease progression – viral replication and lung inflammation,” said Mark L. Levitt, MD, PhD, Medical Director at RedHill. “These compelling data, using a physiologically relevant human respiratory tissue model, demonstrate opaganib’s potential to strongly inhibit SARS-CoV-2 viral replication, validating the hypotheses underlying our ongoing global Phase 2/3 and US Phase 2 clinical studies and further supporting their rationale. Accordingly, we are accelerating progress toward our goal of generating a robust data package to potentially support emergency use authorizations for COVID-19.”

The ongoing global multi-center, randomized, double-blind, parallel-arm, placebo-controlled Phase 2/3 study (NCT04467840) evaluating opaganib for the treatment of patients with severe COVID-19 pneumonia continues to enroll with a target of up to 270 patients requiring hospitalization and treatment with supplemental oxygen. The study recently received approval in Israel and has been approved in the United Kingdom, Italy, Russia and Mexico, with further expansion progressing.

In parallel, the randomized, double-blind, placebo-controlled US Phase 2 study (NCT04414618) with opaganib in patients with severe COVID-19 pneumonia is more than 50% enrolled, with enrollment set to be completed in the coming weeks. Recently, a pre-scheduled independent Safety Monitoring Committee recommended that the study continue without change. The study, which is not powered for statistical significance, is set to enroll up to 40 patients requiring hospitalization and supplemental oxygen.

The company is in discussions with US government agencies around potential funding to support the rapid advancement of opaganib toward potential emergency use approval.

In addition to opaganib, RedHill’s in-vitro study evaluated the antiviral activity of its Phase-2 stage investigational drug, RHB-107 (upamostat), a serine protease inhibitor active against a number of human serine proteases, with results demonstrating potent inhibition of SARS-CoV-2 viral replication. A US Phase 2/3 study with RHB-107 in an outpatient setting is planned to be initiated later this year.

“Host cellular proteases play a critical role in the process of SARS-CoV-2 entry into cells, specifically responsible for activating the SARS-CoV-2 spike (S) protein, which is a prerequisite for the fusion of viral and host cell membranes during viral entry,” said Terry F. Plasse MD, Medical Director at RedHill. “RHB-107 demonstrated excellent antiviral activity, with viral replication being strongly inhibited in a dose-dependent manner at pharmacologically relevant concentrations. As with opaganib, RHB-107 (upamostat) is orally bioavailable and therefore potentially suitable for both inpatient and out-patient settings.”

The results from the preclinical studies of opaganib and RHB-107 are preliminary and were provided to the Company by an independent third-party following an initial independent analysis and remain subject to additional review and analysis of the data and potentially supportive experiments.

Opaganib, a new chemical entity, is a proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer, anti-inflammatory, and antiviral activities, targeting multiple oncology, viral, inflammatory, and gastrointestinal indications.

Opaganib received Orphan Drug designation from the US FDA for the treatment of cholangiocarcinoma and is being evaluated in a Phase 2a study in advanced cholangiocarcinoma and in a Phase 2 study in prostate cancer. Opaganib is also being evaluated in a global Phase 2/3 study and a US Phase 2 study for the treatment of coronavirus (COVID-19).

Preclinical data have demonstrated both anti-inflammatory and antiviral activities of opaganib, with the potential to reduce lung inflammatory disorders, such as pneumonia, and mitigate pulmonary fibrotic damage. Opaganib demonstrated potent antiviral activity against SARS-CoV-2, the virus that causes COVID-19, completely inhibiting viral replication in an in vitro model of human lung bronchial tissue. 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.

Opaganib was originally developed by US-based Apogee Biotechnology Corp. and completed multiple successful preclinical studies in oncology, inflammation, GI, and radioprotection models, as well as a Phase 1 clinical study in cancer patients with advanced solid tumors and an additional Phase 1 study in multiple myeloma.

Under a compassionate use program, COVID-19 patients (as classified by the WHO ordinal scale) were treated with opaganib in a leading hospital in Israel. Data from the treatment of these first patients with severe COVID-19 with opaganib have been published. Analysis of treatment outcomes suggested substantial benefit to patients treated with opaganib under compassionate use in both clinical outcomes and inflammatory markers as compared to a retrospective matched case-control group from the same hospital. All patients in the opaganib-treated group were discharged from hospital without requiring mechanical ventilation, whereas 33% of the matched case-control group required mechanical ventilation. Median time to weaning from high-flow nasal cannula was reduced to 10 days in the opaganib-treated group, as compared to 15 days in the matched case-control group.

The development of opaganib has been supported by grants and contracts from US federal and state government agencies awarded to Apogee Biotechnology Corp., including from the NCI, BARDA, the US Department of Defense and the FDA Office of Orphan Products Development.

The ongoing studies with opaganib are registered on www.ClinicalTrials.gov, a web-based service by the US National Institute of Health, which provides public access to information on publicly and privately supported clinical studies.

RHB-107 is a proprietary, first-in-class, orally-administered potent inhibitor of several serine proteases, with demonstrated antiviral and potential tissue-protective effects. This combined antiviral and potential tissue-protective action make it a strong candidate for evaluation as a treatment for COVID-19 infection. In addition, RHB-107 has potential in targeting cancer, inflammatory lung diseases and gastrointestinal diseases, and has undergone several Phase 1 studies and two Phase 2 studies, demonstrating its clinical safety profile in over 300 patients. RedHill acquired the exclusive worldwide rights to RHB-107, excluding China, Hong Kong, Taiwan and Macao, from Germany’s Heidelberg Pharmaceuticals (formerly WILEX AG) for all indications.

RedHill Biopharma Ltd. is a specialty biopharmaceutical company primarily focused on gastrointestinal diseases. RedHill promotes the gastrointestinal drugs, Movantikfor opioid-induced constipation in adults, Talicia for the treatment of Helicobacter pylori (H. pylori) infection in adults, and Aemcolo for the treatment of travelers’ diarrhea in adults. RedHill’s key clinical late-stage development programs include: (i) RHB-204, with a planned pivotal Phase 3 study for pulmonary nontuberculous mycobacteria (NTM) infections; (ii) opaganib (Yeliva), a first–in–class SK2 selective inhibitor targeting multiple indications with a Phase 2/3 program for COVID-19 and Phase 2 studies for prostate cancer and cholangiocarcinoma ongoing; (iii) RHB-104, with positive results from a first Phase 3 study for Crohn’s disease; (iv) RHB-102 (Bekinda), with positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D; (v) RHB-107, a Phase 2-stage first-in-class, serine protease inhibitor, targeting cancer and inflammatory gastrointestinal diseases and is also being evaluated for COVID-19 and (vi) RHB-106, an encapsulated bowel preparation. For more information, visit www.redhillbio.com.