Decoding Molnupiravir for Non hospitalized COVID-19 Patients

In the Covid-19 pandemic, a substantial portion of patients need hospitalization, predominantly older adults and persons with preexisting conditions (e.g., obesity, diabetes mellitus (DM), and serious cardiac conditions). Several authorized vaccines can reduce the incidence of hospitalization and death; however, vaccine coverage remains insufficient. Antiviral therapies that reduce the risk of Covid-19 progression are needed. Molnupiravir is a small-molecule ribonucleoside prodrug of N hydroxycytidine (NHC), which has activity against SARS-COV-2 and other RNA viruses and a high barrier to the development of resistance.

A phase 2-3, double-blind, parallel-group, randomized placebo-controlled trial evaluated the safety and efficacy of molnupiravir (800 mg) in non-hospitalized adults with Covid-19.

Key inclusion criteria were SARS-COV-2 infection that had been laboratory-confirmed no more than 5 days earlier, the onset of signs or symptoms no more than 5 days earlier, at least one sign or symptom of Covid-19, and at least one risk factor for the development of severe illness from Covid-19 (age >60 years; active cancer; CKD; COPD; obesity (BMI 2 301; heart failure, coronary artery disease, or cardiomyopathies; or DM). 1433 participants were randomly assigned in a 1:1 ratio to receive either molnupiravir (n=716 patients, 800 mg delivered as four 200-mg capsules) or identical placebo (n=717 patients), administered orally twice daily for 5 days.

The primary efficacy endpoint was the incidence of hospitalization for any cause or death through day 29. The primary safety endpoint was the incidence of adverse events. Safety outcomes, including percentages of participants with adverse events. Secondary efficacy endpoints were based on the WHO 11-point Clinical Progression Scale and on patients who reported Covid-19 signs and symptoms through day 29.

Planned interim analysis included 775 participants (54.1% of the all-randomized sample) enrolled at 78 sites in 15 countries and underwent randomization. All-randomized analysis sample included a total of 1433 participants, enrolled at 107 sites from 20 countries. The results were as followed;

Baseline Characteristic:

Overall, 47.7% of participants had onset of signs or symptoms 3 days or less before randomization and 44.5% had moderate Covid-19.

The most common risk factors were obesity (73.7%), age over 60 years (17.2%), and DM (15.9%).

SARS-CoV-2 nucleocapsid antibodies at baseline, indicating recent or previous infection (not vaccination), were reported among 19.8% of participants.

The three most common SARS-CoV-2 variants were B.1.617.2 (delta; 58.1%), B.1.621 (mu; 20.5%), and P.1(gamma; 10.7%).

Almost all the participants (98.3%; 70g in the molnupiravir group and 699 in the placebo group) were included in the modified intention-to-treat population.

Efficacy:

An interim analysis; The risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 17.3%]) than with placebo (53 of 377 (14.1%]) (difference, -6.8% points; 95%CI, -11.3 to-2.4; P=0.001).

In the analysis of all participants, a Lower percentage of participants were hospitalized or died through day 29 in the molnupiravir group than in the placebo group (6.8%[48 of 709] vs. 9.7% 168 of 6991; difference, -3.0% points; 95% CI, -5.9 to-0.1).

The rate of hospitalization or death through day 29 was ~ 31% lower with molnupiravir than with placebo (HR, 0.69; 95%CI, 0.48 to 1.01).

One death was reported in the molnupiravir group (29-day all-cause mortality, 0.1%) and 9 deaths in the placebo group (29-day all-cause mortality, 1.3%) risk of death that was lower by 89% (95% CI, 14 to 99) with molnupiravir than with placebo.

Based on WHO Clinical Progression Scale, a greater percentage of participants in the molnupiravir group showed improved outcomes by day 5, with the largest differences observed by days 10 and 15 compared to the placebo group.

For most Covid-19 signs and symptoms, sustained abatement or resolution was more likely and progression of signs or symptoms was less likely in molnupiravir than in the placebo group.

Virology

All-randomized analysis, 1093 of 1408 participants (77.6%) in the modified intention-to-treat population had quantifiable RNA confirmed in nasopharyngeal samples at baseline, and of those, samples from 964 participants (88.2%) had been tested at day 5.

Molnupiravir treatment was associated with greater reductions from baseline in mean viral load than placebo at days 3, 5 (end-of-treatment visit), and 10.

Safety

Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.

Most frequently reported AE;

Occurred in 22% of participants in either group - Covid-19 pneumonia (occurred in 6.3% molnupiravir group vs 9.6% placebo group), diarrhea (2.3% vs. 3.0%), and bacterial pneumonia (2.0% vs. 1.6%); worsening of Covid-19 was reported as an AE in 7.9% as compared with 9.8%.

Occurring in 21% of participants in either group - related to the trial regimen were diarrhea (1.7% vs. 2.1%), nausea (1.4% vs. 0.7%), and dizziness (1.0% vs. 0.7%).

One participant each in the molnupiravir and placebo groups met the prespecified criteria for a postbaseline platelet count below 50,000 per microliter.

Early treatment with molnupiravir was found effective for COVID-19 treatment, without evident safety concerns, when initiated within 5 days after the onset of signs or symptoms in non-hospitalized, unvaccinated adults who were at risk for progression to severe disease.

Reference: Jayk BernalA, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V. Martín-Quirós A Caraco Y, Williams-DiazA, Brown ML DuJ, Pedley A. Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2021 Dec 16. doi: 10.1056/NEJMoa2116044. Early treatment with molnupiravir was found.