In a recent phase III study published in the New England Journal of Medicine, researchers demonstrated that oral molnupiravir was effective in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapy among non-vaccinated, non-hospitalized adults at-risk for severe illness.
Study: Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. Image Credit: eamesBot / Shutterstock
The coronavirus disease 2019 (COVID-19) pandemic associated with SARS-CoV-2 has led to over 532 million confirmed cases and 6.3 million mortalities worldwide. Most COVID-19 patients, primarily older adults and those with comorbidities, e.g., diabetes mellitus, obesity, and heart diseases, require hospitalization. Numerous SARS-CoV-2 vaccines that are significantly efficacious in lowering the frequency of death and hospitalization have been authorized; nevertheless, vaccine coverage is still insufficient.
Hence, novel therapies are essential to lower the chance of COVID-19 progression. As trials have indicated that treatment should begin as soon as symptoms appear, such medications should preferably be readily accessible and easy to administer by the patients.
Molnupiravir is a small-molecule, oral antiviral N-hydroxycytidine (NHC) prodrug effective against SARS-CoV-2 infection. It has been studied in many phase I and II clinical trials. Molnupiravir at an 800-mg dose was chosen for further exploration based on dose-response analyses from phase II trials, including examination in phase III of the MOVe-OUT trial in non-hospitalized, at-risk adults with the beginning of COVID-19 symptoms or indications less than five days prior.
About the study
The current double-blind, phase III, placebo-controlled, randomized MOVe-OUT trial was designed to assess the safety and efficacy of molnupiravir treatment initiated within five days following the beginning of COVID-19 symptoms or signs in unvaccinated, non-hospitalized adults with mild to moderate laboratory-validated SARS-CoV-2 infection and a minimum of one risk element for severe COVID-19 disease. The phase III component of the MOVe-OUT trial was begun on 6 May 2021.
The trial's participants were randomly given either a placebo or 800 mg of molnupiravir twice a day for five days. The occurrence of hospitalization or death on day 29 was the key efficacy endpoint, while the prevalence of adverse reactions was the key safety endpoint. Further, a planned interim evaluation was conducted on 10 September 2021 upon 775 individuals from the target enrolment tracked through day 29. The participant recruitment continued during the interim assessment review; the last subject was recruited on 2 October 2021 and accomplished the day 29 visit on 4 November 2021.
Adults who were not hospitalized and had moderate or mild COVID-19 were eligible for the trial; moderate and mild illnesses were identified using definitions obtained from Food and Drug Administration (FDA) and World Health Organization (WHO) guidelines. Expected COVID-19-linked hospitalization within 48 hours, estimated glomerular filtration rate (eGFR) 30 ml/minute/1.73 m2 or dialysis, refusal to use contraceptive methods during the intervention phase and for a minimum of four days upon completion of the regime, pregnancy, severe neutropenia, platelet count <100,000/μL, and SARS-CoV-2 vaccination were all crucial exclusion criteria.
Results and conclusions
According to the study results, 1,433 subjects were assigned randomly to one of two groups: 717 received a placebo, and 716 received molnupiravir. The baseline features of the two cohorts were similar, except for a sex imbalance.
The effectiveness of molnupiravir was established in the interim assessment. Indeed, the likelihood of hospitalization for any reason or death at day 29 was lower with molnupiravir in 28 of 385 subjects, i.e., 7.3%, than with placebo in 53 of 377, i.e., 14.1%, harboring a difference of -6.8 percentage points. In addition, the proportion of individuals admitted to hospitals or who died on day 29 was lower in the molnupiravir cohort than in the placebo cohort, with 6.8% (48 subjects of 709) versus 9.7% (68 participants of 699), possessing a difference of -3 percentage points in the evaluation of all volunteers underwent randomization.
The results of subgroup examinations were broadly similar to the overall findings; however, the point estimate for the variance favored placebo in several subcategories, like those with proof of past SARS-CoV-2 infection, patients with low baseline viral burden, and diabetic individuals. On day 29, one fatality was observed in the molnupiravir cohort and nine in the placebo arm. Adverse reactions were reported by 216 of 710 participants in the molnupiravir cohort, i.e., 30.4%, and 231 of 701 subjects in the placebo group, i.e., 33%.
On the whole, the present work showed that early molnupiravir therapy reduced the probability of mortality or hospitalization in SARS-CoV-2-infected high-risk, unvaccinated adults. The data from the current trial illustrated that oral molnupiravir was efficacious for COVID-19 treatment in this cohort of unvaccinated non-hospitalized adults who were at threat of progressing to severe SARS-CoV-2 infection when started within five days of the initiation of COVID-19 symptoms or signs without apparent safety concerns.
- Jayk Bernal, A., Gomes da Silva, M., Musungaie, D., Kovalchuk, E., Gonzalez, A., Delos Reyes, V., Martín-Quirós, A., Caraco, Y., Williams-Diaz, A., Brown, M., Du, J., Pedley, A., Assaid, C., Strizki, J., Grobler, J., Shamsuddin, H., Tipping, R., Wan, H., Paschke, A., Butterton, J., Johnson, M. and De Anda, C., 2022. Molnupiravir for Oral Treatment of COVID-19 in Non-hospitalized Patients. New England Journal of Medicine, 386(6), pp.509-520. DOI: 10.1056/NEJMoa2116044, https://www.nejm.org/doi/full/10.1056/NEJMoa2116044