A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus

Abstract

There is an urgent need for an effective, oral, direct-acting therapeutic to block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent progression to severe coronavirus disease 2019 (COVID-19). In a phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and symptom duration <7 days. Participants were randomized 1:1 to receive molnupiravir (200 mg) or placebo and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800-mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank P value = 0.013). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800-mg molnupiravir group compared with 16.7% of the placebo group at day 3 of treatment ( P = 0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients ( P = 0.034 and 0.027, respectively). Molnupiravir was well tolerated across all doses.

Computational Analysis of Molnupiravir

“…Thus, two acidic protons of the N 4 -hydroxylcytosine fragment are of great importance and play a pivotal role in a rich library of plausible tautomeric forms of molnupiravir. Notably, to the best of our knowledge, the The dire need to search for antiviral agents to combat COVID-19 has led to the emergence of studies on the effectiveness of molnupiravir against SARS-CoV-2 [9][10][11][12][13][14][15][16]. As of October 2021, it was established that oral administration of molnupiravir reduces the risk of severe disease by about 50% in comparison to placebo in patients with mild to moderate disease.…”

Molnupiravir: First Approval

“…accumulation of errors in the viral genome ultimately leading to inhibition of replication) [ 7 , 16 , 17 ]. Consistent with this mechanism of action, molnupiravir treatment was associated with numerically higher SARS-CoV-2 viral RNA error rates versus placebo in patients with COVID-19 in clinical trials [ 18 – 20 ].…”

“…Molnupiravir significantly reduced nasopharyngeal SARS-CoV-2 load in outpatients with COVID-19 in a randomized, double-blind, placebo-controlled phase II trial (NCT04405570) [ 20 ]. Patients with confirmed SARS-CoV-2 infection and symptom onset within 7 days were randomized to molnupiravir 200, 400 or 800 mg twice daily or placebo (1:1 for 200 mg and 3:1 for other doses) for 5 days.…”

“…Molnupiravir also dose-dependently decreased infectious SARS-CoV-2. On day 5, the proportion of patients positive for infectious SARS-CoV-2 in nasopharyngeal swabs was significantly lower in the 400 mg (0% of 42; p = 0.034) and 800 mg (0% of 53; p = 0.027) groups than in the placebo group (11.1% of 54) [ 20 ].…”

Development and progress in respiratory tract infections

“…Remdesivir war aufgrund seiner fehlenden oralen Verfügbarkeit keine Option für den ambulanten Bereich. Hier stehen mit Paxlovid (Pfizer), einem speziell gegen SARS-CoV-2 entwickelten Proteaseinhibitor und Molnupirvir (Merck) 2 oral applizierbare Medikamente zur Verfügung, die bei ambulanten Patienten mit Risikoprofil das Risiko der Krankenhauseinweisung signifikant reduzieren können [23,24]. Bei Molnupiravir handelt es sich um ein Nukleosidanalogon, das dieMutationsratebei der Virusreplikation so stark erhöht, dass keine replikationsfähigen Viren mehr entstehen [25].…”