Molnupiravir (Lagevrio) is a potent ribonucleoside analog that blocks SARS-CoV-2 replication by acting as a competitive substrate of virally-encoded RNA-dependent RNA polymerase.
Molnupiravir (Lagevrio) is the first-ever investigational oral antiviral therapy for the treatment of SARS-CoV-2 (COVID-19) in non-hospitalized adult patients. It is a potent ribonucleoside analog that blocks SARS-CoV-2 replication by acting as a competitive substrate of virally-encoded RNA-dependent RNA polymerase. The inhibition is what leads to rapid mutations of the virus over multiple viral replication cycles resulting in an antiviral effect.1
Molnupiravir was invented at Drug Innovations at Emory (DRIVE), LLC—a not-for-profit biotechnology company wholly owned by Emory University—and is being developed by Merck & Co, Inc, in collaboration with Ridgeback Biotherapeutics.2
Current outpatient therapies for COVID-19 include monoclonal antibodies (casirivimab-imdevmiab,bamlanivumab-etesevimab or sotrovimab), which are subcutaneous or intravenous injections.3 This means that although considered as outpatient therapy, patients will still need to go to an ambulatory setting for assistance in administration by a health professional, which creates a logistical barrier for patients and health systems.
Merck has applied to the FDA for an Emergency Use Authorization (EUA). The submission is supported by hopeful results from the planned interim analysis of the ongoing MOVe-OUT clinical trial.4
MOVe-OUT is an ongoing phase 3, randomized, placebo-controlled, double-blinded, multi-site study that aims to investigate the efficacy and safety of molnupiravir in non-hospitalized adult patients with mild to moderate COVID-19.4 The current primary outcomes of the study are the percentage of participants who are hospitalized and/or die, the percentage with adverse events (AEs), and the percentage who discontinue study intervention due to an AE.
The secondary outcomes of the study were time to sustained resolution or improvement of each targeted sign/symptom at 29 days, time to progression of each sign/symptom, and WHO 11-point outcomes score on a scale to categorize clinical progression up to 29 days. Inclusion criteria include adults above 18 years of age, with confirmed documentation of positive COVID-19 test results through polymerase chain reaction (PCR) testing with a sample collection <10 days prior to the day of randomization and who had the initial onset of signs/symptoms attributable to COVID-19 within 5 days of study randomization.2,4
Exclusion criteria include patients who are on dialysis with estimated glomerular filtration rate <30 mL/min/1.73m2 and have critical COVID-19 with respiratory failure or are on noninvasive positive pressure ventilation or extracorporeal membrane oxygenation.2,4 Eligible participants are then randomized to be given 1:1 ratio of molnupiravir 200 mg or placebo, 3:1 of molnupiravir (400 mg or 800 mg), or placebo oral capsules every 12 hours for 5 days respectively.2,4
In the planned interim analysis of this phase 3 trial, 775 patients who were initially enrolled in the MOVe-OUT trial were formatted by 385 in the molnupiravir group and 385 in the placebo group.4 Results show that molnupiravir reduced the risk of hospitalization or death by approximately 50% in all subgroups.
Twenty-eight patients (7.3%) in the molnupiravir group were hospitalized through day 29 versus 53 patients (14.1%) in the placebo group who were either hospitalized or died; p= 0.0012.4 With an absolute risk reduction of 6.8%, relative risk reduction of 48%, and number needed to treat of 15, this agent provides compelling data to support its use in the management of COVID-19.
In an analysis of the 40% participants who had available viral sequencing data, molnupiravir was found to perform with consistent efficacy across the viral variants of COVID-19, Gamma, Delta, and Mu. For key secondary outcome measures, the AEs between molnupiravir (35%) and placebo (40%) were comparable and the molnupiravir group (1.3% vs 3.4%) had fewer participants discontinuing the study due to an AE.4
Although the phase 3 MOVe-OUT trial is not anticipated to be complete until May 2022, the positive results from the interim analysis show great promise for molnupiravir. Recently, the European Medicines Agency has also begun to initiate a rolling review for molnupiravir for the treatment of COVID-19 in adult patients.2
The initiation could lead to the clinical viability necessary for the use in the European Union. In November 2021, the United Kingdom became the first to approve molnupiravir.5
As Merck has committed to allowing global access of molnupiravir, they have agreed to enter into a non-exclusive licensing agreement to accelerate the process of the availability in low- and middle-income countries. Merck has also put in an EUA to the FDA for approval of molnupiravir for at-risk adults. This would allow the option for the first orally-administered treatment for COVID-19 at home for patient convenience.2
About the Authors
Kevin Nguyen, PharmD, is a PGY-1 pharmacy resident at Albert Einstein Medical Center Philadelphia, Pennsylvania.
Nathan Nguyen, PharmD candidate 2023 at Temple University School of Pharmacy.
Mya Yee, PharmD candidate 2023 at Temple University School of Pharmacy.
Katherine Kim, PharmD candidate 2023 at Temple University School of Pharmacy.