Candidates: Opaganib (Yeliva®, ABC294640) and RHB-107, in combination and individually

Types: Opaganib is a first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. RHB-107 is a first-in-class, orally-administered inhibitor of S1 family of trypsin-like serine proteases with potential for use in multiple oncology, gastrointestinal and inflammatory indications.

2021 Status: PRIMARY ENDPOINT MISSED—RedHill Biopharma acknowledged September 14 that its global Phase II/III study assessing opaganib in patients hospitalized with severe COVID-19 pneumonia (NCT04467840) did not meet its primary endpoint, according to preliminary topline data. The primary endpoint of the study was the proportion of patients breathing room air without oxygen support by Day 14.

While an analysis showed trends that favored the opaganib arm vs. placebo across multiple endpoints, including the primary endpoint, the outcomes failed to achieve statistical significance. RedHill added that analysis of the topline data was ongoing, and was suggesting an increased benefit to opaganib in a subset of patients at earlier stages of the disease on low flow oxygen support.

The multi-center, randomized, double-blind, parallel-arm, placebo-controlled Phase II/III study enrolled 475 participants with severe COVID-19 pneumonia requiring hospitalization and treatment with supplemental oxygen. Subjects were randomized at a 1:1 ratio to receive either opaganib or placebo, on top of standard-of-care therapy.

Proof of Concept Study—A team of U.S. and Israeli researchers posted a proof of concept preprint August 29 on medRxiv showing that 14 days after treatment with opaganib in 40 moderate to severe patients with COVID-19 pneumonia, 11 of 22 patients treated with opaganib (50%) and 4 of 18 patients treated with placebo (22%) no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6% of patients, respectively, were discharged from the hospital. The relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms: “These findings support further evaluation of opaganib in this population.”

‘Strong’ Delta Inhibition in Tissue Model—RedHill on August 26 announced preliminary preclinical results for opaganib showing “strong” inhibition of Delta variant replication in a 3D tissue model of human bronchial epithelial cells (EpiAirway™) while maintaining cell viability at relevant concentrations. Working with the University of Louisville Center for Predictive Medicine, opaganib was studied for its in vitro efficacy vs. Delta—research that followed studies showing opaganib to have also inhibited the Alpha, Beta, and Gamma SARS-CoV-2 variants.

RedHill added that opaganib’s global 475-patient Phase II/III trial (NCT04467840) in hospitalized patients with COVID-19 has completed its treatment and follow up phase, and study topline results are upcoming.

2021 Status: RedHill on June 21 presented positive Phase II safety and efficacy data for oral opaganib in hospitalized patients with COVID-19 pneumonia at the World Microbe Forum (WMF) 2021. Results and post hoc analyses of data from the 40-patient U.S. Phase II study (NCT04414618) were presented in a poster (#5574) showing:

  • About 50% of the 22 patients treated with opaganib reached room air by Day 14 compared to 22% of the 18 patients in the placebo group. The benefit of reaching room air by Day 14 for patients on opaganib was maintained regardless of whether the patients were receiving dexamethasone and/or remdesivir, RedHill said.
  • 86.4% of patients treated with opaganib were discharged from hospital by Day 14 compared to 55.6% of patients treated with placebo.
  • Median time to discharge was 6 days for the opaganib group compared to 7.5 days for the placebo group.
  • 81.8% of opaganib patients achieved a 2-point improvement in the WHO Ordinal Scale compared to 55.6% of patients in the placebo group – achieved in a median time of 6 days versus 7.5 days, respectively.
  • No significant differences in safety-related measures between the two groups (with diarrhea being the main treatment-emergent difference in tolerability).

On June 7, RedHill said it completed enrollment and randomized the last patient in the global Phase II/III study with opaganib in patients hospitalized with severe COVID-19 pneumonia (NCT04467840). A total of 475 patients were randomized, more than the planned 464.

The primary endpoint of the study is the proportion of patients breathing room air without oxygen support by Day 14. The study captures additional important outcome measures in the follow up period of up to 6 weeks, such as the time to hospital discharge, improvement according to the World Health Organization Ordinal Scale for Clinical Improvement and incidence of intubation and mortality.

In addition to ongoing discussions with the FDA and other regulators, RedHill said it has also met with the European Medicines Agency to plan a European pathway to regulatory review and approval.

RedHill said an evaluation of blinded blended intubation and mortality rates to date “is encouraging as compared to reported rates of mortality from large platform studies such as RECOVERY (NCT04381936), and other studies in similar patient populations.” The company also noted that four independent Data Safety Monitoring Board (DSMB) recommendations to continue the study had already been already provided following unblinded safety and futility reviews.

In one instance January 29, RedHill said, that the independent Data Safety Monitoring Board (DSMB) for the company’s global Phase II/III trial (NCT04467840) of opaganib in patients with severe COVID-19, unanimously recommended to continue the study following a pre-scheduled futility review of unblinded efficacy data from the first 135 patients treated in the study and safety data from the first 175 patients. The trial is is ongoing, with patients enrolled in more than 30 sites in multiple countries.

A day earlier, RedHIll announced a manufacturing agreement with Cosmo Pharmaceuticals to further expand manufacturing capacity for opaganib, to address prospective demand subsequent to potential global emergency use authorizations.

2020 Status: RedHill rang out 2020 with positive topline safety and efficacy results from its U.S. Phase II trial (NCT04414618) assessing opaganib in patients hospitalized with severe COVID-19 pneumonia. The trial’s opaganib-treated arm showed a greater improvement in reaching room air within 14 days (52.6% vs. 22.2%); greater improvement in reduction to 50% supplemental oxygen by Day 14 (89.5% vs. 66.7%); a higher proportion of patients discharged by Day 14 (73.7% vs. 55.6%) and a greater reduction in the median total oxygen requirement (AUC) over 14 days (68.0% vs. 46.7%), the company said December 31.

RedHill said November 16 that its U.S. Phase II trial (NCT04414618) assessing opaganib in patients hospitalized with severe COVID-19 pneumonia has completed enrollment of the last patient in the study—which is not powered for statistical significance. The trial has enrolled 40 patients in clinical sites across the U.S. Topline data is expected “in the coming weeks,” the company said.

Patients in the study were randomized at a 1:1 ratio to receive either opaganib or placebo on top of standard-of-care. The primary objective of the study is to evaluate the reduction in total oxygen requirement over the course of treatment for up to 14 days. Secondary endpoints include time to 50% reduction in oxygen requirements, the proportion of patients without fever at Day 14, and proportion with negative nasal swabs at Day 14.

RedHill also said its ongoing global Phase II/III trial (NCT04467840) evaluating opaganib in patients hospitalized with severe COVID-19 pneumonia is approximately 50% enrolled. The global trial is expected to undergo its first pre-planned safety analysis “in the coming days,” RedHill said. With topline data set to be reported in the first quarter of 2021.

On September 22, RedHill said that it received approval from the Brazilian Health Regulatory Agency (ANVISA) for the Phase II/III trial. The global multi-center, randomized, double-blind, parallel-arm, placebo-controlled study continues to enroll with a target of up to 270 patients requiring hospitalization and treatment with supplemental oxygen, the company said. Brazil has joined Israel, the U.K., Italy, Russia and Mexico in approving the study, with further expansion ongoing and progressing “rapidly,” RedHill said.

Subjects are being randomized 1:1 to receive either opaganib or placebo, plus standard-of-care therapy. The primary endpoint is a statistically significant reduction in patients requiring intubation and mechanical ventilation by day 14.

RedHill also said it was in talks with unspecified U.S. government agencies to obtain potential funding to support the rapid advancement of opaganib toward potential emergency use approval.

On August 27, RedHill said its U.S. Phase II study assessing opaganib in patients hospitalized with severe COVID-19 pneumonia will continue without change after successfully passing the first scheduled independent Safety Monitoring Committee (SMC) review. The SMC reviewed unblinded safety data from the first 12 patients treated for at least seven days.

The study is more than 50% enrolled, with enrollment expected to be completed “in the coming weeks,” RedHill said. The next scheduled SMC review will take place once 24 patients complete at least seven days of treatment. More than 140 people have been treated with opaganib, according to the company.

Also in August, RedHill received approval from the Italian Medicines Agency (AIFA) and the Mexican Federal Committee for the Protection against Sanitary Risks (COFEPRIS) for the company’s Clinical Trial Authorization (CTA) application for the Phase II/III trial.

“If the studies are successful, we aim to apply for emergency use authorizations as early as the fourth quarter of this year,” said Gilead Raday, RedHill’s Chief Operating Officer.

According to RedHill, a Phase IIa study (NCT04414618) designed to assess opaganib in the U.S. is approximately 75% enrolled, and set to complete enrollment “in the coming weeks.” In August, a pre-scheduled independent Safety Monitoring Committee recommended that the study continue without change. The randomized, double-blind, placebo-controlled study is set to enroll up to 40 patients with severe COVID-19 pneumonia requiring hospitalization and supplemental oxygen. Should data be positive, it will support potential aplications for emergency use authorization in the fourth quarter. RedHill acknowledged, however, that the trial is not powered for statistical significance.

In July, RedHill submitted Clinical Trial Applications (CTAs) to COFEPRIS and the Brazilian Health Regulatory Agency (ANVISA) for the Phase II/III trial.

Earlier in June, RedHill announced publication of a preprint study in medRxiv a day earlier in which four Israeli researchers reported that five severe COVID-19 patients treated with opaganib under compassionate use plus standard of care showed substantial benefit in both clinical outcomes and inflammatory markers compared to a matched case-control group of 18 patients from the same hospital. All patients in the opaganib-treated group were discharged from hospital on room air, without requiring mechanical ventilation, compared with 33% of control group patients who required mechanical ventilation. The median time to weaning from high-flow nasal cannula was 10 days in the opaganib-treated group, vs. 15 days in the control group.

In April, RedHill reported preliminary data from six moderate-to-severe COVID-19 patients treated with opaganib under its compassionate use program in Israel, and subsequently analyzed.

The six were hospitalized and previously treated with standard-of-care (mostly hydroxychloroquine). All six showed objective significant measurable clinical improvement within days of starting treatment with opaganib, the company said, including a decrease in required supplemental oxygenation, higher lymphocyte counts, a sign of improvement from virus-induced lymphopenia, and decreased C-reactive protein (CRP) levels.

Five of the six patients were weaned from oxygen, and three were discharged from the hospital within days of treatment initiation. The sixth patient, whose therapy was initiated more recently, is improving, RedHill said. Not included in the analysis was a seventh patient treated with opaganib for one day, and earlier treated with hydroxychloroquine and azithromycin, who suffered from diarrhea that was resolved quickly after cessation of all therapies.

The company has agreed to provide RHB-107 in non-clinical studies for activity against SARS-CoV-2, through an agreement with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). RHB-107 was selected for in vitro testing after NIAID evaluated data on the drug’s possible mechanism of action and potential activity against SARS-CoV-2.

Approximately 160 patients at three Italian hospitals will be treated with opaganib under an expanded access program (EAP) allowing immediate compassionate use of the drug, RedHill also said April 6.

RedHill said March 11 it was exploring opaganib and RHB-107 individually and in combination with hydroxychloroquine and other compounds as a COVID-19 treatment, based on preclinical data and literature indicating potential anti-viral activity. Opaganib was originally developed by Apogee Biotechnology, which received U.S. federal and state grants and contracts toward development. RedHill has licensed rights to RHB-107 from Heidelberg Pharma (formerly Wilex) worldwide except China, Taiwan, Macao, and Hong Kong.

COVID-19: 300 Candidates and Counting

To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types:


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