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.
SARS-CoV-2 has proven to be endemic and will continue to be prevalent in society. Although vaccines play an important role in improving a patient’s chance of experiencing a milder form of COVID-19, the continuing ability of SARS-CoV-2 to evade vaccines and monoclonal antibodies combined with the limitations of current antivirals such as drug-drug interactions, highlight the urgent need for new, oral antiviral treatment options with improved profiles.
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. Our COVID-19 strategy for bemnifosbuvir focuses on the current unmet medical needs of high-risk patients. Our goal is to deliver a safe, effective and convenient treatment option for people that remain vulnerable to hospitalization or death.
SUNRISE-3 is a randomized, double-blind, placebo-controlled, global Phase 3 trial evaluating bemnifosbuvir or placebo administered concurrently with locally available standard of care (SOC). The study has a global footprint of approximately 330 clinical trial sites in the United States, Europe, Japan and rest of the world. Patients are being randomized 1:1 to receive either bemnifosbuvir 550 mg twice-daily (BID) plus locally available SOC or placebo BID plus locally available SOC for five days.
This trial is comprised of two patient population cohorts derived from the type of SOC received. These are the “Supportive Care Population” which will assess bemnifosbuvir as monotherapy (primary analysis) when the patient does not qualify for an authorized oral antiviral treatment or is in a region where oral antivirals are not locally available and the “Combination Antiviral Population” which will assess combination therapy being bemnifosbuvir plus SOC if the SOC includes treatment with other COVID-19 antivirals (secondary analysis).
The primary endpoint of the study is all-cause hospitalization or death through Day 29 in the Supportive Care Population in approximately 2,200 patients. Secondary endpoints in both the Supportive Care Population and the Combination Antiviral Population include: COVID-19 complications, medically attended visits, symptom rebound / relapse and viral load rebound.
The patients enrolling in the SUNRISE-3 trial are those at the highest risk for COVID-19 disease progression, consisting of patients ≥70 years old (regardless of other risk factors), patients ≥55 years old with one or more risk factors, patients ≥50 years old with two or more risk factors and patients ≥18 years old with certain risk factors including immunocompromised conditions, all regardless of COVID-19 vaccination status. Patients with decreased renal function are also eligible for the trial.
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.
AT-511, the free base of bemnifosbuvir, has been shown to be a potent inhibitor of SARS-CoV-2 in vitro. Recent in vitro results demonstrated that AT-511 retained potent antiviral activity against all tested SARS-CoV-2 Omicron subvariants including XBB. AT-511 has previously demonstrated in vitro potent antiviral activity against other variants of concern and/or of interest, including Alpha, Beta, Gamma, Epsilon, Delta and Omicron subvariants BA.1, BA.2, BA.4, BA.5 and XBB
We are also advancing an internal discovery program focused on identifying a second-generation protease inhibitor that we may potentially combine with bemnifosbuvir for combination treatment of COVID-19. We are seeking to discover a protease inhibitor that is highly potent and well tolerated with limited drug-drug interactions and does not require a pharmacokinetic booster (e.g., ritonavir). The optimization of lead compounds is ongoing.
The rationale for advancing this potential combination is based upon both historical precedents for treating serious viral diseases with combination treatments that include agents with different mechanisms of action targeting different points in the viral replication cycle and the results from the in vitro study we have conducted in an HCoV-229E surrogate model. In this in vitro study, the antiviral activity of AT-511, the free base of bemnifosbuvir in combination with the protease inhibitor, nirmatrelvir, showed an additive antiviral effect.
These data suggest a potential benefit of the combination of bemnifosbuvir and a protease inhibitor for the treatment of SARS-CoV-2 infection.