A Phase 2 Randomized Trial Evaluating the Antiviral Activity and Safety of the Direct-Acting Antiviral Bemnifosbuvir in Ambulatory Patients with Mild or Moderate COVID-19 (MOONSONG Study)

Abstract

Bemnifosbuvir is an oral antiviral drug with a dual mechanism of action targeting viral RNA polymerase, with in vitro activity against SARS-CoV-2. We conducted a phase 2, double-blind study evaluating the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. Patients were randomized 1:1 to bemnifosbuvir 550 mg or placebo (cohort A) and 3:1 to bemnifosbuvir 1,100 mg or placebo (cohort B); all doses were given twice daily for 5 days. The primary endpoint was a change from baseline in the amount of nasopharyngeal SARS-CoV-2 viral RNA by reverse transcription PCR (RT-PCR). The modified intent-to-treat infected population comprised 100 patients (bemnifosbuvir 550 mg, n = 30; bemnifosbuvir 1,100 mg, n = 30; cohort A placebo, n = 30; cohort B placebo, n = 10). The primary endpoint was not met: the difference in viral RNA adjusted means at day 7 was -0.25 log₁₀ copies/mL between bemnifosbuvir 550 mg and cohort A placebo (80% confidence interval [CI], -0.66 to 0.16; P = 0.4260), and -0.08 log₁₀ copies/mL between bemnifosbuvir 1,100 mg and pooled placebo (80% CI, -0.48 to 0.33; P = 0.8083). Bemnifosbuvir 550 mg was well tolerated. Incidence of nausea and vomiting was higher with bemnifosbuvir 1,100 mg (10.0% and 16.7% of patients, respectively) than pooled placebo (2.5% nausea, 2.5% vomiting). In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity on nasopharyngeal viral load as measured by RT-PCR compared with placebo in patients with mild/moderate COVID-19. The trial is registered at ClinicalTrials.gov under registration number NCT04709835. IMPORTANCE COVID-19 continues to be a major global public health challenge, and there remains a need for effective and convenient direct-acting antivirals that can be administered outside health care settings. Bemnifosbuvir is an oral antiviral with a dual mechanism of action and potent in vitro activity against SARS-CoV-2. In this study, we evaluated the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity compared with placebo as assessed by nasopharyngeal viral loads. The negative predictive value of nasopharyngeal viral load reduction for clinical outcomes in COVID-19 is currently unclear, and further evaluation of bemnifosbuvir for COVID-19 may be warranted despite the findings observed in this study.

Keywords: AT-527; COVID-19; SARS-CoV-2; bemnifosbuvir; direct-acting antiviral.

FIG 1

Patient disposition. The mITTI population is defined as all patients that received at least 1 dose of study treatment and had at least 1 positive SARS-CoV-2 RT-PCR test result during the study. The safety population was defined as all patients who received at least 1 dose of study treatment. ITT, intent-to-treat population; mITTI, modified intent-to-treat infected population; RT-PCR, reverse transcription PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

FIG 2

Adjusted change from baseline in the amount of SARS-CoV-2 virus RNA by RT-PCR. (A) Cohort A and cohort A placebo. (B) Cohort B and pooled placebo (modified intent-to-treat infected population). CI, confidence interval; LSM, least-squares mean; NE, not evaluable; RT-PCR, reverse transcription PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

FIG 3

Change from baseline in the amount of SARS-CoV-2 virus RNA by RT-PCR at specified time points in key subgroups (cohort A versus cohort A placebo). RT-PCR, reverse transcription PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, standard error.

FIG 4

Change from baseline in the amount of SARS-CoV-2 virus RNA by RT-PCR at specified time points plot in key subgroups (cohort B versus pooled placebo). RT-PCR, reverse transcription PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, standard error.

FIG 5

Exploratory analysis: adjusted change from baseline in the amount of SARS-CoV-2 infectious virus titer at specified time points. (A) Cohort A versus cohort A placebo. (B) Cohort B versus pooled placebo. Only patients that had at least one positive test result during the study were included. CI, confidence interval; LSM, least-squares mean; NE, not evaluable; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

FIG 6

(A and B) Post hoc analysis: adjusted change from baseline in the amount of SARS-CoV-2 (A) virus RNA by RT-PCR and (B) infectious virus titer at specified time points; cohort B versus cohort B placebo. (B) Only patients that had at least one positive test result during the study were included. CI, confidence interval; LSM, least-squares mean; NE, not evaluable; RT-PCR, reverse transcription PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.