On this page:
- Clinical Information
- Clinical Evidence
This page undergoes regular review and was last comprehensively reviewed on October 3, 2022. Some sections may reflect more recent updates.
Molnupiravir (brand name Lagevrio) has been FDA-authorized for emergency use to treat mild-to-moderate COVID-19 since December 2021. It is a readily bioavailable prodrug of a ribonucleoside analogue that interferes with multiple SARS-CoV-2 viral processes, including replication. It also acts potently against several other RNA viruses, including Ebola, influenza, MERS-CoV and Venezuelan equine encephalitis virus.
In human airway epithelial cells, molnupiravir has potent effect against SARS-CoV-2, reducing viral production with an in vitro IC50 of 0.024 µM, without observed cytotoxicity (Sheahan, April 2020). In mice and ferret models of SARS-CoV-2, molnupiravir has shown efficacy in prevention and treatment of infection, laying a strong foundation and rationale for clinical studies (Cox, January 2021; Wahl, March 2021).
The molnupiravir emergency use authorization (EUA) covers adults 18 years of age and older who are at high risk for progressing to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by FDA are not accessible or clinically appropriate. If it is decided to give molnupiravir, treatment should begin as soon as possible after diagnosis and within 5 days of symptom onset.
A course of molnupiravir consists of 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days.
In ambulatory adult patients with mild-to-moderate COVID-19 at high risk for progression to severe disease who have no other treatment options, IDSA guidelines suggest molnupiravir be initiated within 5 days of symptom onset (conditional recommendation, low certainty of evidence). NIH guidelines also suggest molnupiravir only when other antiviral options cannot be used (class CIII recommendation).
In a Phase 1 randomized controlled single and multiple ascending dose pharmacokinetic study, molnupiravir had rapid appearance in plasma of ß-d-N4-hydroxycytidine (NHC, also called EIDD-1931) with a time of peak concentrations 1 to 1.75 hours after the dose and plasma concentrations which exceeded those expected to be efficacious based on preclinical data (Holman, August 2021; Painter, March 2021).
Phase 2 studies to examine safety, tolerability and antiviral effect followed, in both outpatients with COVID-19 (Study MK-4482-006, also known as EIDD-2801-2003) and inpatients (the ongoing END-COVID study):
- Study MK-4482-006 assessed safety, tolerability and antiviral effect of molnupiravir given within 7 days of symptom onset in nonhospitalized adults with confirmed COVID-19. A total of 202 participants were randomized to receive molnupiravir (200 mg, 400 mg or 800 mg twice daily for 5 days) versus placebo (N=23, 62, 55 and 62 in the respective groups). Endpoints included the time to undetectable levels of nasopharyngeal viral RNA (by RT-PCR) and time to elimination of replication-competent (i.e., infectious) virus from nasopharyngeal secretions. The drug was well tolerated; rates of any adverse event were 48% in the molnupiravir 200 mg recipients, 32.3% in the 400 mg recipients, 20% in the 800 mg recipients and 29% in placebo recipients, with similar very low rates of drug discontinuation across the groups. At day 3 after treatment initiation, there was lower recovery of virus from recipients of molnupiravir 800 mg (1.9%) versus placebo (16.7%) (p=0.02). This effect was also seen at day 5 (0% virus recovery in 400 mg or 800 mg recipients; 11.1% in placebo recipients; p=0.03). The time it took to clear viral RNA was also shorter in participants who got 800 mg of molnupiravir as compared to placebo (p=0.01). The END-COVID study in hospitalized patients with COVID-19 is still enrolling participants, with results anticipated soon (Fischer, June 2021 – preprint, not peer-reviewed).
Several Phase 3 trials of molnupiravir have been initiated for COVID-19:
- MOVe-AHEAD, an ongoing Phase 3, placebo-controlled trial of molnupiravir for prevention of COVID-19 within households, will enroll approximately 1,332 adults who are currently residing in the same household with someone who tested positive for SARS-CoV-2 and is symptomatic. The study excludes anyone with past COVID infection. The trial will examine the primary endpoints of safety and percentage of participants with symptomatic laboratory-confirmed COVID-19 through day 14.
- MOVe-OUT (also called MK-4482-002), a Phase 2/3 randomized, placebo-controlled trial of efficacy, safety and PK of molnupiravir in preventing hospitalization or death among outpatients with PCR-confirmed COVID-19 (see description of study results below).
- MOVe-IN, a phase 2/3 randomized, placebo-controlled study of safety, efficacy and PK of molnupiravir among hospitalized patients with COVID-19. Notably, there was a slight imbalance in mortality between the study groups in the MOVe-IN study: The number of deaths in groups assigned 200 mg, 400 mg and 800 mg of molnupiravir, respectively, were four (5.5%), eight (11%) and three (4.2%), as compared to two (2.7%) in the placebo group. An interim analysis of the MOVe-IN study data concluded that there was no meaningful benefit of molnupiravir in hospitalized patients, and at that time, the study was stopped.
In October 2021, Merck and Ridgeback announced submission of an FDA EUA application for oral molnupiravir based on preliminary MOVe-OUT trial data. In November 2021, the companies announced by press release further analyses from the entire cohort of 1,433 enrolled participants indicating that the rate of hospitalization or death was 68/699 (9.7%) in the placebo group and dropped to 6.8% (48/709) in the molnupiravir group. The absolute risk reduction was 3.0% (95% CI: 0.1, 5.9; nominal p-value=0.0218) and the relative risk was 0.70 (95% CI: 0.49, 0.99), so the relative risk reduction was revised from 50% to 30%. Overall, there were 9/699 (1.2%) deaths in the placebo group and 1/709 (0.14%) in the group given molnupiravir (FDA Briefing Document, November 2021). In November 2021, the FDA Advisory Committee voted narrowly (with 13 in favor and 10 opposed) that the benefits of the drug outweigh its risks when used for the treatment of mild-to-moderate COVID-19 in nonpregnant, nonhospitalized people within 5 days of the onset of symptoms.
Efforts are underway to supply molnupiravir (once approved for emergency use) to governments of high-income countries as well as low- and middle-income countries. The manufacturer (in North America, Merck & Co., Inc. holds the rights to the trademark "Merck," but globally the company trades under the name MSD) has committed to nonexclusive voluntary licensing agreements with eight generic manufacturers, with a goal of distributing molnupiravir to 100 low- and middle-income countries. Notably, the same week that the MOVe-OUT trial results were announced, two Indian generic manufacturers (Aurobindo Pharma Ltd. and MSN Laboratories) announced that they would end trials of a generic version of molnupiravir in patients with moderate COVID-19 (defined as COVID-positive with oxygen saturation of >90%), due to a lack of efficacy. The MOVe-OUT trial, however, had specified that patients with oxygen saturation lower than 93% should be excluded, so there were probably slightly sicker participants in the Indian trials, and it is not known at this time whether some were hospitalized. At this time, the two generic manufacturers are continuing Phase 3 trials of generic molnupiravir in patients with mild disease.
Accumulating evidence on real-world use of molnupiravir suggests a benefit when it is used in high-risk outpatients. A manufacturer-funded secondary partially post-hoc analysis of the MOVe-Out trial examined levels of C-reactive protein, oxygen saturations, and need for respiratory and medical services among the 1433 largely unvaccinated participants in the MOVe-OUT trial. There were more decreases in C-reactive protein and more and earlier improvement in oxygen saturations in the molnupiravir recipients than in the placebo recipients, particularly over the 5 days of treatment (Johnson, August 2022). There were fewer respiratory interventions needed among the participants who received molnupiravir than in participants who received placebo (42/709 [5.9%] as compared to 63/699 [9%]). This trend was recapitulated among the participants who went on to be hospitalized. (There was less overall need for respiratory interventions among the molnupiravir recipients than the placebo recipients.)
Some observational data on the effectiveness of molnupiravir in real-world settings is emerging. One retrospective cohort study from Hong Kong (Wong, July 2022 – preprint, not peer-reviewed) examined outcomes for 40,776 people hospitalized with COVID-19 between February and April of 2022 (a period in Hong Kong when the Omicron BA.2 variant was dominant in the community) but not requiring oxygen at baseline. (As oxygen requirement is one of the main indications for admission in the U.S. for people with COVID-19, it is strange that this large hospitalized cohort did not require supplemental oxygen at baseline, but it is possible that they were admitted to isolation wards primarily for the purposes of infection control.) The study included 1,856 people who took molnupiravir, 890 who took nirmatrelvir/ritonavir and 2,746 propensity-score-matched controls. The study reported a significantly lower all-cause mortality rate in the group who had received oral antivirals (molnupiravir: HR=0.48, 95%CI=0.40-0.59, p<0.0001 and nirmatrelvir/ritonavir: HR=0.34, 95%CI=0.23-0.50, p<0.0001). Similar significant reductions in disease progression and need for supplemental oxygen were also seen. Virologic outcomes were also investigated, and there was more of a drop in SARS-CoV-2 viral load (increase in Ct value) by day 7 among oral antiviral users than matched controls (molnupiravir users: diff=2.50, 95%CI=1.34-3.66, p<0.0001) and nirmatrelvir/ritonavir users: (diff=2.86, 95%CI=0.96-4.76, p=0.0034).
In addition, some real-world observational data from Poland has emerged (Flisiak, July 2022 – preprint, not peer-reviewed) on the use of molnupiravir among hospitalized people with COVID-19 in the era of Omicron. Out of a total of 590 patients, 203 were given a 5-day course of molnupiravir, and 387 were not given any antiviral treatment. Among people who received molnupiravir within 5 days from symptom onset, there were fewer deaths at day 7 (5.1 vs. 9.2%, p=0.05), lower supplemental oxygen requirement (42.4 vs. 50.4%, p=0.06) and higher proportions discharged from the hospital (12.1 vs. 5.7%, p=0.005). This effect enhanced with older age, and in those over age 80, deaths occurred in 7.3% of molnupiravir recipients vs. 16.5% of placebo recipients (p=0.03). Interestingly, however, there were similar rates of mechanical ventilation between the two groups (the group that received no antivirals was more likely to receive steroids and baricitinib, so that may have played a role). Length of hospitalization was not different across the groups (mean±SD 11.6±7.9 vs. 11.5±9.3 days; p=0.965). Across the 28 days of follow-up, molnupiravir recipients had lower need for oxygen supplementation compared to recipients of no antivirals (31.7 vs. 49.2%, p=0.00005).
There is accumulating human safety data for molnupiravir, though as yet no long-term safety data, which may be more relevant for genetic or reproductive toxicities.
FDA’s Fact Sheet for Health Care Providers states: “Based on findings from animal reproduction studies, molnupiravir may cause fetal harm when administered to pregnant individuals ... therefore, molnupiravir is not recommended for use during pregnancy.”
NIH’s COVID-19 Treatment Guidelines Panel states: “When other therapies are not available, pregnant people with COVID-19 who are at high risk of progressing to severe disease, particularly those who are beyond the time of embryogenesis (i.e., >10 weeks’ gestation), may reasonably choose molnupiravir therapy after being fully informed of the risks.”
FDA and NIH both recommend that prescribing clinicians should document that a discussion with the patient of the risks and benefits occurred, and that the patient chose this therapy after the discussion occurred.
Theoretical safety concerns have arisen from the drug’s mechanism. The prodrug molnupiravir is quickly converted into NHC. NHC in turn gets converted by intracellular kinases/phosphatases into the triphosphorylated active drug, NHC-TP (or EIDD-2061). NHC-TP is recognized by the RNA-dependent RNA polymerase of the coronavirus, which confuses it with cytidine, in a manner that is not detected and corrected by the proofreading exonuclease enzyme of coronavirus (an advantage in preventing the acquisition of drug resistance). NHC-monophosphate gets incorporated into the coronavirus genome and causes lethal mutagenesis (an accumulation of detrimental mutations resulting in viral error catastrophe) in the nascent strand of viral RNA, interfering further with viral functioning.
As the presumed mechanism of action of molnupiravir is to induce lethal mutagenesis in the nascent SARS-CoV-2 viral strand, questions have previously arisen about the potential for an NHC metabolite to be incorporated into human DNA and induce mutagenesis in human cells (Stuyver, January 2003). The basis for this concern is that a common ribonucleoside diphosphate form of NHC can be transformed into ribonucleoside triphosphates (causing damage to viral RNA) or be recognized by the host ribonucleotide reductase enzyme and transformed into 2′-deoxyribonucleoside triphosphates (which are potentially incorporated into and cause damage to host cell DNA in actively dividing cells). One study examined this potential using a hypoxanthine phosphoribosyltransferase gene mutation assay in cells derived from hamster ovaries and exposed the cells to high doses of molnupiravir for 32 days. The study found that 3 µM concentrations of NHC were associated with mutagenesis in cell culture (Zhou, August 2021). It is worth noting that the maximum course being studied in clinical trials is 5 days of twice daily molnupiravir, and that the positive control, 1 minute of UV light, caused a higher mutation rate than any of the drug concentrations.
As in vitro Ames testing for NHC did show positive results with mutagenicity for two of six bacterial strains, likely on the basis of the incorporation of the molecule into bacterial DNA, the manufacturer of molnupiravir has followed that with extensive in vivo preclinical toxicology studies to assess whether molnupiravir has toxicities in small mammals. This testing included the Big Blue assay, which uses transgenic rodents carrying a mutation (lacI) that allows for detection of small mutations and deletions in tissues, to test whether high doses of molnupiravir induced mutagenesis within the animals. It also included the PIG-a assay, which uses flow cytometry to detect mutations in a reporter gene to see whether a drug causes mutations in vivo. The totality of the mutational toxicology assays performed for molnupiravir was reportedly reassuring, as the drug was found to be neither mutagenic nor genotoxic in mammals (Painter, October 2021).
FDA’s Antimicrobial Drugs Advisory Committee held a hearing on molnupiravir on Nov. 30, 2021, to make further regulatory decisions regarding the drug. Other approved antivirals such as ribavirin and favipiravir have similar (less potently) mutagenic mechanisms (Crotty, June 2001), and favipiravir has restrictions placed on its use by Japan’s regulatory body for that reason (Nagata, February 2015).
No clinical drug-drug interaction studies of molnupiravir have been conducted, but no drug-drug interactions are expected based on available information.