お知らせ • Jul 28
Redhill Biopharma Provides Update on Development of Opaganib for Ebola Virus Disease
RedHill Biopharma Ltd. provided an update on the development of opaganib for Ebola virus disease (EVD) as the number of confirmed Bundibugyo ebolavirus (BDBV) cases and deaths has increased substantially to 3,221 cases and 1,407 deaths. Finalization of development next steps and potential partnership discussions are ongoing, including with the Emergency Task Force expert group of the African Medicines Agency (equivalent to EMA/FDA and designed to coordinate and harmonize drug approvals across Africa), the Ugandan Ministry of Health and Mbarara University of Science and Technology (MUST), alongside liaison with the Scientific Advisory Committee of the Democratic Republic of Congo (DRC). Development of opaganib for Ebola is supported by preclinical and clinical safety and efficacy data from multiple studies, including in combination with direct acting antiviral Veklury (remdesivir, Gilead Sciences). Opaganib's potential role in the ongoing Ebola outbreak as an add-on therapy to remdesivir is supported by both clinical and non-clinical data. Phase 3 severe COVID-19 clinical data showed antiviral activity when given with remdesivir, reducing mortality by 70.2% and improving median time to viral RNA clearance with no additional safety signals – with safety and tolerability demonstrated in 470 clinical trial participants. Preclinically, United States Army Medical Research Institute of Infectious Diseases (USAMRIID)-funded studies showed opaganib inhibition of EVD in human macrophages, increased survival rates in an opaganib treated group, and a synergistic effect with remdesivir. Opaganib Ebola virus disease (EVD) rationale: Phase 3 clinical antiviral activity (severe COVID-19, analogous to EVD setting) showing: 70.2% mortality reduction with opaganib given as add-on to best available standard of care (remdesivir + corticosteroids): 6.98% (n=3/43) opaganib + SoC vs. 23.4% (n=11/47) placebo + SoC (nominal p=0.034) - with no additional safety signals; Improved median time to viral RNA clearance by =4 days in opaganib-treated patients (median 10 days vs. not reached by Day 14 in placebo, HR 1.34, p=0.043); Demonstrated safety and tolerability profile in 470 clinical trial participants. Preclinical EVD activity (United States Army Medical Research Institute of Infectious Diseases (USAMRIID)-funded studies showed: Opaganib inhibition of EVD in human macrophages; Increased survival for opaganib group (one of two animal models); Synergistic effect when opaganib combined with Gilead Sciences' remdesivir (Veklury). Opaganib's potential dual mechanism of action against EVD and filovirus-class activity: Published literature explicitly validates sphingosine kinases as targets for filovirus inhibition – opaganib is an SPHK2 inhibitor that may disrupt host-cell components essential for filovirus entry and replication that are conserved across Filoviridae; Inhibits PI3K/Akt pathway (required for filovirus entry and membrane trafficking); Suppresses NLRP3 inflammasome, IL-6/TNFa secretion and S1P-mediated vascular permeability (addressing immune dysregulation and vascular leak in viral hemorrhagic fever). Clinical safety data, oral administration and ease of storage and distribution supports clinical evaluation and possible stockpiling requirements to strengthen global infectious disease preparedness and biodefense. The data, combined with the U.S. government's Biomedical Advanced Research and Development Authority (BARDA) prior selection of opaganib for joint development & funding as a medical countermeasure (MCM) to treat Ebola virus disease (EBOV), provides additional confidence that opaganib may offer a dual mechanism of action against EVD and filovirus-class activity. Opaganib is in development for multiple oncology, viral, inflammatory and diabetes and obesity-related indications. Opaganib is an investigational new drug. It has not been approved by any regulatory authority and is not available for commercial distribution. According to the Centers for Disease Control and Prevention (CDC), Ebola disease is a rare and often deadly illness, caused by infection by one of a group of four viruses, known as ebolaviruses. Transmission of the disease is mostly through contact with an infected animal (bat or nonhuman primate) or a sick or dead person infected with an ebolavirus. The course of the illness typically progresses from "dry" symptoms initially (such as fever, aches and pains, and fatigue) and then progresses to "wet" symptoms (such as diarrhea, vomiting and unexplained hemorrhaging, bleeding or bruising) as the person becomes sicker. Currently only Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn, Regeneron Pharmaceuticals Inc.), a combination of three monoclonal antibodies and Ebanga (ansuvimab-zykl, Ridgeback Biotherapeutics, LP), a single monoclonal antibody, are FDA-approved to treat EVD. Both are intravenously administered, direct acting, monoclonal antibody antivirals that bind to glycoproteins on the Ebola virus's surface to prevent the virus from entering a person's cells. There is an urgent need for host-directed small molecule therapies that may be effective against multiple strains of ebolavirus, less likely to be impacted by viral mutation, and that are easy to store, distribute and administer, especially in areas where healthcare services and infrastructures may be sub-optimal. Opaganib is a proprietary first-in-class investigational, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor drug. Potentially broad-acting, it is in development for multiple oncology, viral, inflammatory, metabolic (diabetes and obesity) and additional indications. Opaganib's suggested mechanism of action, published in the journal Drug Design, Development and Therapy, is host-directed and potentially broad-acting and is expected to maintain its effect against emerging viral variants. Opaganib is thought to work through the inhibition of multiple pathways, the induction of autophagy and apoptosis, and disruption of viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS). Opaganib has received Orphan Drug designation from the FDA for the treatment of neuroblastoma and cholangiocarcinoma. A Bayer-supported 60-patient placebo-controlled randomized Phase 2 study is ongoing to evaluate the efficacy of opaganib in combination with Bayer's darolutamide in men with metastatic castrate-resistant prostate cancer (mCRPC), testing the potentially enhancing effect of opaganib in patients with a poor prognosis. Opaganib also has a Phase 1 chemoradiotherapy study protocol ready for FDA-IND submission. Opaganib has demonstrated its safety and tolerability profile in more than 470 participants in multiple clinical studies and expanded access use, including a large global Phase 2/3 study in hospitalized patients with moderate to severe COVID-19, published in Microorganisms.