Bemnifosbuvir has a unique mechanism of action, with dual targets including chain termination (RdRp) and NiRAN inhibition, which has the potential to create a high barrier to resistance.
Although vaccines play an important role in improving a patient’s chance of experiencing a milder form of disease, as COVID-19 evolves combined with waning immunity from vaccination and prior infection, there will be a continuing need for novel, orally available treatment options. Increased transmissibility of new variants will continue to fuel surges and can be life-threatening, especially to those at high risk.
Our most advanced product candidate, bemnifosbuvir, is an oral direct-acting antiviral, which is being developed as monotherapy and potential combination therapy for COVID-19. Bemnifosbuvir’s unique mechanism of action, which targets two sites within the RNA-dependent RNA polymerase and results in termination of RNA synthesis and inhibition of NiRAN activity, has the potential to create a high barrier to viral resistance.
Complementary medical intervention to vaccination similar to the influenza paradigm (Tamiflu®)
Significant advantages vs antibodies:
Highly-conserved target has potential to enable antiviral activity in the presence of multiple variants
Antiviral activity against potential future coronaviruses beyond SARS-CoV-2 anticipated
In a topline analysis of data from the MORNINGSKY trial, which was closed out early, the primary endpoint, time to symptom alleviation, was not achieved. However, a 71% reduction in hospitalization (2.9% versus 10%) was observed (p=0.047, unadjusted, exploratory) in the bemnifosbuvir arm (n=137) versus placebo (n=70). There were no deaths in the trial. Hospitalization and death are study endpoints have been preferred by the U.S. Food and Drug Administration and other regulatory authorities.
The MORNINGSKY trial enrolled a broad patient population of whom approximately 50% were high risk and 50% were standard risk; 28% of patients were vaccinated; and 56% were seropositive at baseline. Consistent with previous studies, bemnifosbuvir 550 mg twice-daily (BID) was generally safe and well tolerated. There were no drug-related serious adverse events. Adverse events leading to treatment discontinuation were 3% for bemnifosbuvir versus 7% for placebo and there were no gastrointestinal-related events leading to treatment discontinuation.
Final clinical results from the Phase 2 hospitalized study in high-risk patients (n=83) suggest potential clinical benefits. The overall rate of disease progression was low, which had an impact on the ability to assess the primary endpoint of progression of respiratory insufficiency (PRI) rate. The results showed a 7.5% PRI rate for bemnifosbuvir 550 mg BID versus a 10% PRI rate for placebo (primary endpoint). The respiratory events associated with progression were less severe in the bemnifosbuvir treated patients as compared to those receiving placebo. There were 3 deaths in the study, no deaths were reported in patients treated with bemnifosbuvir versus 3 deaths reported with placebo.
Final virology results (secondary endpoint) were consistent with previously reported interim data from this study. Bemnifosbuvir was generally safe and well tolerated with no drug related serious adverse events and no adverse events leading to treatment discontinuation.
The global Phase 2 trial was a randomized, double-blind, placebo-controlled, multi-center study to evaluate bemnifosbuvir in patients with moderate COVID-19 in the hospital setting. The key inclusion criteria for this study were adult patients 18 years or older with risk factors such as obesity, diabetes, asthma and hypertension. Study objectives were to assess safety, tolerability, clinical and antiviral efficacy. Patients were randomized within five days of symptom onset to receive either bemnifosbuvir (550 mg BID in Part A; 1100 mg BID in Part B) or placebo for five days. In total, 81 patients were randomized in Part A (41 patients in the 550 mg BID arm; 40 patients in placebo arm) and 2 patients were randomized in Part B (0 patients in 1100 mg BID arm; 2 patients in placebo arm). The evolving nature of the standard of care resulted in the in the early close out of the study which limited the Part B enrollment.
AT-511, the free base of bemnifosbuvir, has been shown to be a potent inhibitor of SARS-CoV-2 in vitro. New results demonstrate bemnifosbuvir retained potent antiviral activity against the SARS-CoV-2 variant Omicron (BA.1). In vitro results evaluating antiviral activity against all variants of concern and/or of interest have previously included Alpha, Gamma, Epsilon, Delta.