Molnupiravir COVID-19 studies. Potential risks of the mechanism of action include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity [Hadj Hassine, Swanstrom, Waters]. See [Fountain-Jones, Sanderson, twitter.com] for analysis of variants potentially created by molnupiravir. There is substantial publication bias. Two trials (CTRI/2021/05/033864 and CTRI/2021/08/0354242) reported no significant efficacy, however the results have not been published. Multiple trials have not reported results and did not respond to requests [Lawrence].
Recent:Goodwin European Medicines Agency Wan Merck Service Sanderson Evans.
Molnupiravir has been officially adopted
in 14 countries.
Submit updates/corrections .
Mar 15 |
et al., PLOS ONE, doi:10.1371/journal.pone.0281915 | Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK |
| 110% higher mortality [p=0.47] and 58% lower hospitalization [p=0.7]. Retrospective 604 outpatients in the UK, showing lower risk of hospitalization with molnupiravir treatment, without statistical significance due to the small number of hospitalizations. | ||
Feb 24 |
(News) | Refusal of the marketing authorisation for Lagevrio (molnupiravir) |
| The European Medicines Agency has recommended the refusal of the marketing authorisation of molnupiravir. | ||
Feb 22 |
et al., Journal of Infection, doi:10.1016/j.jinf.2023.02.029 | Molnupiravir and nirmatrelvir-ritonavir reduce mortality risk during post-acute COVID-19 phase |
| 11% lower mortality [p=0.02], 1% lower hospitalization [p=0.76], and 4% higher progression [p=0.18]. Retrospective 30,040 hospitalized patients in Hong Kong, showing lower mortality with molnupiravir treatment. | ||
Feb 21 |
, Press Release (Preprint) | Merck Provides Update on Phase 3 MOVe-AHEAD Trial Evaluating LAGEVRIO™ (molnupiravir) for Post-exposure Prophylaxis for Prevention of COVID-19 |
| MOVe-AHEAD PEP RCT reporting no significant difference in cases. Limited information is available. There were 23.6% fewer cases with treatment, but the number of cases and confidence interval are not provided. | ||
Feb 1 |
, R., Science, doi:10.1126/science.adg9677 (News) | Could a popular COVID-19 antiviral supercharge the pandemic? |
| Coverage of [Fountain-Jones, Sanderson] which show evidence for molnupiravir creating new variants. The quote "Right now, it’s much ado about nothing" is from Emory University, where Molnupiravir was invented.. | ||
Jan 27 |
et al., medRxiv, doi:10.1101/2023.01.26.23284998 (Preprint) | Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases |
| Identification of SARS-CoV-2 variants likely to have been created by molnupiravir treatment. Authors find a class of long phylogenetic branches almost exclusively matching the time period, location, and age groups of widespread molnupirav.. | ||
Jan 25 |
et al., Journal of Infection, doi:10.1016/j.jinf.2023.02.012 | Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: A retrospective cohort study |
| 51% lower combined mortality/hospitalization [p=0.008]. Retrospective high risk outpatients in the UK, showing lower hospitalization/death with molnupiravir treatment. Residual confounding is likely with adjustments having no detail on specific comorbidities. | ||
Jan 22 |
et al., medRxiv, doi:10.1101/2023.01.20.23284849 (Preprint) | Comparative effectiveness of Paxlovid versus sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in non-hospitalised patients: observational cohort study using the OpenSAFELY platform |
| 285% higher combined mortality/hospitalization [p=0.004]. OpenSAFELY retrospective 5,638 outpatients in the UK, showing significantly higher hospitalization/death for molnupiravir compared with paxlovid. | ||
Jan 15 |
et al., Research Square, doi:10.21203/rs.3.rs-2451986/v1 (Preprint) | Real-world data concerning the efficacy of molnupiravir in patients vaccinated against COVID-19 during the Omicron surge in Japan |
| 127% higher combined mortality/hospitalization [p=0.22] and 127% higher hospitalization [p=0.22]. Retrospective 294 consecutive patients in Japan, showing higher risk of hospitalization/death with molnupiravir, without statistical significance. | ||
Dec 22 |
et al., medRxiv, doi:10.1101/2022.12.21.22283811 (Preprint) | Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients |
| Analysis of immunocompromised patients showing rapid creation of new variants with molnupiravir. All patients treated with molnupiravir accrued new mutations in the spike protein of the virus, including non-synonymous mutations that alter.. | ||
Dec 21 |
et al., Journal of Clinical Medicine, doi:10.3390/jcm12010034 | Safety Profile of Molnupiravir in the Treatment of COVID-19: A Descriptive Study Based on FAERS Data |
| Safety analysis of molnupiravir reporting an unexpectedly high rate of serious adverse reactions. | ||
Dec 6 |
et al., medRxiv, doi:10.1101/2022.12.05.22283134 (Preprint) | Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes |
| 18% lower mortality [p=0.4], 1% lower ICU admission [p=1], and 30% higher hospitalization [p=0.04]. Retrospective 112,380 high-risk patients in the USA, showing significantly higher acute or long-term care admission at 180 days with molnupiravir treatment, and no significant difference for other outcomes. The title and headers of Table .. | ||
Nov 16 |
et al., BMJ, doi:10.1136/bmj-2022-071932 | Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe covid-19 outcomes in patients in the community: observational cohort study with the OpenSAFELY platform |
| 100% higher combined mortality/hospitalization [p=0.005]. Retrospective 3,331 sotrovimab and 2,689 molnupiravir patients in the UK, showing higher risk of combined hospitalization/death with molnupiravir. | ||
Nov 14 |
et al., Cureus, doi:10.7759/cureus.31508 | Efficacy and Safety of Molnupiravir in Mild COVID-19 Patients in India |
| 65% lower hospitalization [p=0.005], 53% greater improvement [p=0.01], and 48% improved viral clearance [p<0.0001]. RCT 1,218 outpatients in India, showing lower hospitalization, better clinical improvement, and improved viral clearance with molnupiravir. | ||
Oct 30 |
et al., Infectious Diseases and Therapy, doi:10.1007/s40121-022-00716-7 | Disease Progression of Hospitalized Elderly Patients with Omicron BA.2 Treated with Molnupiravir |
| 18% shorter hospitalization [p=0.14] and 21% faster viral clearance [p=0.1]. Retrospective 42 elderly patients in China showing faster viral clearance with molnupiravir. | ||
Oct 8 |
et al., The Lancet, doi:10.1016/S0140-6736(22)01586-0 | Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study |
| 24% lower mortality [p=0.01], 60% lower ventilation [p=0.02], 26% lower ICU admission [p=0.24], and 2% lower hospitalization [p=0.58]. PSM retrospective 1,074,856 outpatients in Hong Kong, showing lower mortality with molnupiravir. | ||
Oct 6 |
et al., The Lancet, doi:10.1016/S0140-6736(22)02597-1 (date from earlier preprint) | Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial |
| 6% higher combined mortality/hospitalization [p=0.69], 7% higher hospitalization [p=0.67], 2% lower transmission [p=0.88], and 22% improved recovery [p<0.0001]. 26,411 patient RCT in the UK, showing faster recovery but no significant difference in hospitalization/death or transmission. Improved recovery may be in part due to the open label design with self-reported symptomatic data. Viral load in.. | ||
Oct 6 |
et al., Research Square, doi:10.21203/rs.3.rs-2105569/v1 (Preprint) | Genomic Evolution of Sars-Cov-2 in Molnupiravir-Treated Patients Compared to Paxlovid-Treated and Drug-Naïve Patients: A Proof-of-Concept Study |
| Mutation analysis showing over 5x greater within-host genetic diversity with molnupiravir compared to paxlovid or no treatment. | ||
Oct 6 |
et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofac527 | Demographics and outcomes of initial phase of COVID-19 Medicines Delivery Units across 4 UK centres during peak B1.1.529 omicron epidemic: a service evaluation |
| 101% higher hospitalization [p=0.51]. Retrospective 442 patients in the UK treated with molnupiravir, and 222 eligible but declining treatment, showing no significant difference in hospitalization. No group details are provided and the results are subject to confounding by in.. | ||
Oct 5 |
et al., Clinical and Experimental Medicine, doi:10.1007/s10238-022-00949-3 (date from earlier preprint) | Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic |
| 53% lower progression [p=0.04]. Retrospective 1,921 patients in Japan, showing lower progression with molnupiravir use. | ||
Oct 1 |
et al., Environmental and Molecular Mutagenesis, doi:10.1002/em.22510 (In Vitro) | Evaluation of the mutagenic effects of Molnupiravir and N4-hydroxycytidine in bacterial and mammalian cells by HiFi sequencing |
| In Vitro genotoxocity study of molnupiravir showing dose dependent increased genome-wide mutation frequencies with mouse lymphoma L5178Y and human lymphoblastoid TK6 cells. | ||
Sep 29 |
et al., New England Journal of Medicine, doi:10.1056/NEJMoa2204919 (date from earlier preprint) (Preprint) | Molnupiravir Use and Severe Covid-19 Outcomes During the Omicron Surge |
| 74% lower mortality [p=0.008] and 45% lower hospitalization [p=0.01]. Retrospective 19,868 patients eligible for molnupiravir treatment in Israel with 1,069 treated, showing lower mortality and hospitalization with treatment for the subgroup of patients ≥65, and higher mortality for patients 40-64. Authors .. | ||
Sep 20 |
et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac781 | Effectiveness of Molnupiravir in High Risk Patients: a Propensity Score Matched Analysis |
| 19% lower mortality [p=0.48], 17% lower progression [p=0.34], and 25% lower severe cases [p=0.15]. PSM retrospective 2,661 molnupiravir patients in Israel, showing lower mortality and severe COVID-19, without statistical significance. Significant benefit was seen in some subgroups, and significant harm was seen in the <75 subgroup. | ||
Sep 9 |
et al., Infection, doi:10.1007/s15010-022-01914-8 | Outcome of lung transplant recipients infected with SARS-CoV-2/Omicron/B.1.1.529: a Nationwide German study |
| 15% higher severe cases [p=0.71]. Retrospective 218 COVID+ lung transplant patients in Germany, showing no significant difference in severe cases with early molnupiravir use. | ||
Aug 2 |
et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkac440 (date from earlier preprint) (meta analysis) | Evaluation of publication bias for 12 clinical trials of molnupiravir to treat SARS-CoV-2 infection in 13,694 patients with meta-analysis |
| Meta analysis of molnupiravir trials showing 12 registered RCTs in India with only one presented at a conference, and two issuing press releases suggesting failure. Authors find that ~90% of the global data on molnupiravir has not been pu.. | ||
Jul 29 |
et al., Nature Communications, doi:10.1038/s41467-022-32045-1 | SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model |
| Roborovski dwarf hamster and in vitro study finding molnupiravir efficacy varied significantly by SARS-CoV-2 variant in the hamster model, in contrast to no significant difference seen in cultured cells and human organoids. Efficacy for o.. | ||
Jul 24 |
et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(22)00644-2 (date from earlier preprint) | Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial |
| 89% lower hospitalization [p=0.12], 12% worse recovery [p=0.74], and 23% improved viral clearance [p=0.07]. RCT 90 molnupiravir and 90 placebo patients, showing faster viral clearance with treatment, not reaching the pre-defined threshold for superiority and recommendation as a candidate for large scale evaluation. | ||
Jul 6 |
et al., Pharmacological Reports, doi:10.1007/s43440-022-00408-6 (date from earlier preprint) | Real-world experience with molnupiravir during the period of SARS-CoV-2 Omicron variant dominance |
| 39% lower mortality [p=0.03], 5% lower ventilation [p=1], and 1% longer hospitalization [p=0.97]. Retrospective 590 patients in Poland, 203 treated with mulnupiravir, showing lower mortality with treatment. | ||
May 24 |
et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac687 (date from earlier preprint) | Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients |
| 12% higher combined mortality/ICU admission [p=0.66] and 17% higher hospitalization [p=0.06]. Propensity score weighted retrospective of 93,883 outpatients in Hong Kong, 5,808 treated with molnupiravir and 4,921 treated with paxlovid, showing higher hospitalization and higher combined mortality/mechanical ventilation/ICU admission.. | ||
May 20 |
et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(22)00507-2 (date from earlier preprint) | Real-world effectiveness of early molnupiravir or nirmatrelvir–ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study |
| 52% lower mortality [p<0.0001], 58% lower ventilation [p=0.06], 40% lower progression [p<0.0001], and 6% shorter hospitalization [p=0.03]. PSM retrospective 40,776 patients in Hong Kong, showing lower mortality and lower combined mortality, ventilation, ICU, and oxygen therapy with molnupiravir treatment. | ||
May 17 |
et al., JCI Insight, doi:10.1172/jci.insight.160108 | Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model |
| Syrian hamster study showing efficacy of molnupiravir for multiple variants including omicron. | ||
Apr 18 |
et al., Viruses, doi:10.3390/v14040841 (Review) | Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity |
| Review of lethal mutagenesis for RNA viruses, as used by molnupiravir, favipiravir, and ribavirin. Authors note the potential for permanently modifying the genomes of patients while causing teratogenicity or embryotoxicity, and the potent.. | ||
Apr 8 |
, T. (News) | PANORAMIC recruitment analysis |
| Analysis of the PANORAMIC trial recuitment suggesting that if the trial shows efficacy, the NNT will be >200. | ||
Mar 11 |
et al., The American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.21-1339 (Review) | Making Statistical Sense of the Molnupiravir MOVe-OUT Clinical Trial |
| Discussion of concerns with the MOVe-OUT trial, including the reversal of the treatment effect post-interim analysis. | ||
Feb 24 |
et al., SSRN Electronic Journal, doi:10.2139/ssrn.4042673 | Efficacy and Safety of Molnupiravir for the Treatment of Non-Hospitalized Adults With Mild COVID-19: A Randomized, Open-Label, Parallel-Group Phase 3 Trial |
| 46% lower hospitalization [p=0.26], 46% greater improvement [p<0.0001], and 59% improved viral clearance [p<0.0001]. RCT 1,220 patients in India, showing lower risk of hospitalization and improved recovery with treatment. CTRI/2021/07/034588. | ||
Feb 3 |
et al., Science, doi:10.1126/science.abn0048 (Review) | Lethal mutagenesis as an antiviral strategy |
| Review of the unknown long-term cancer, reproductive, and escape variant creation risks of molnupiravir. For more discussion see [twitter.com, twitter.com, twitter.com]. | ||
Jan 28 |
et al., Environmental and Molecular Mutagenesis, doi:10.1002/em.22471 (Review) | Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir |
| Review of antiviral nucleoside analog drugs that induce lethal mutagenesis, including molnupiravir and favipiravir, and the potential mutagenic risks to human DNA and human mitochondrial DNA. Author recommends monitoring for mutagenicity,.. | ||
Dec 16 2021 |
et al., NEJM Evidence, doi:10.1056/EVIDoa2100044 | Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19 |
| 282% higher mortality [p=0.31], 1% improved recovery [p=0.96], and 12% improved viral clearance [p=0.57]. RCT 304 hospitalized patients, 218 treated with molnupiravir, showing no significant differences. MOVe-IN MK-4482-001. NCT04575584. | ||
Dec 16 2021 |
et al., New England Journal of Medicine, doi:10.1056/NEJMoa2116044 | Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients |
| 89% lower mortality [p=0.01] and 30% lower combined mortality/hospitalization [p=0.05]. MOVe-OUT RCT, showing significantly lower risk of hospitalization or death. In subgroup analysis efficacy was much lower with the delta variant. NCT04575597. Discussion of concerns with this trial can be found at [defyccc.com, trialsitene.. | ||
Dec 3 2021 |
, Authorea, doi:10.22541/au.163854323.34557301/v1 (Review) (Preprint) | Treating a Pandemic Respiratory Disease with a Mutagen is a Doomsday Scenario |
| Review of molnupiravir's mutagenic mechanism of action, and analysis of the increased probability of creating dangerous variants. | ||
Nov 6 2021 |
, L., TrialSite News (Review) (News) | Molnupiravir: mutagenic, carcinogenic, authorized in the UK |
| Discussion of concerns with molnupiravir and the MOVe-OUT trial. Author notes that results showing bone marrow toxicity in dogs were mentioned in this preprint [medrxiv.org], but removed from the journal version [journals.asm.org]. Some a.. | ||
Oct 9 2021 |
(News) | Two Indian drugmakers to end trials of generic Merck pill for moderate COVID-19 |
| no change in recovery [p=1]. Trial CTRI/2021/08/035424 for moderate condition patients has been reported as terminated for futility. Results are not available yet [trialsearch.who.int]. | ||
Oct 9 2021 |
(News) | Two Indian drugmakers to end trials of generic Merck pill for moderate COVID-19 |
| no change in recovery [p=1]. Trial CTRI/2021/05/033864 for moderate condition patients has been reported as terminated for futility. Results are not available yet [trialsearch.who.int]. | ||
Sep 13 2021 |
et al., Nature Structural & Molecular Biology, doi:10.1038/s41594-021-00657-8 (Review) | Molnupiravir: coding for catastrophe |
| Review of recent studies on molnupiravir's mechanism of lethal mutagenesis. Authors note that potential off-target effects require further investigation, because molnupiravir may be mutagenic to host DNA during host DNA replication. | ||
Aug 27 2021 |
et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkab318 | Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study |
| 33% worse recovery [p=0.63]. Dose and safety study of molnupiravir with 18 participants, finding no serious adverse events in short-term followup. There was no significant difference in clinical outcomes. NCT04746183. | ||
Jul 21 2021 |
Press Release (News) | Optimus announces Interim Clinical Results from Phase III Clinical Trials of Molnupiravir conducted in India |
| 58% improved viral clearance [p<0.0001]. Interim report on CTRI/2021/06/033992, showing faster viral clearance. Event counts are approximate, the press release only provides percentages. | ||
Jul 9 2021 |
Press Release | Hetero Announces Interim Clinical Results from Phase III Clinical Trials of Molnupiravir conducted in India |
| 70% lower hospitalization [p=0.003] and 33% faster recovery [p=0.0001]. Interim results for CTRI/2021/05/033739, showing lower mortality and faster recovery. | ||
Jul 9 2021 |
et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiab361 | Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model |
| Hamster study showing molnupiravir effective against the original, B.1.1.7, and B.1.351 variants. | ||
Jun 18 2021 |
et al., medRxiv, doi:10.1101/2021.06.17.21258639 (Preprint) | Molnupiravir, an Oral Antiviral Treatment for COVID-19 |
| 77% lower mortality [p=0.31] and 49% improved viral clearance [p=0.12]. RCT 202 outpatients in the USA showing significantly faster viral clearance, but no significant differences in symptom duration or severity. NCT04405570. | ||
May 7 2021 |
et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247 (In Vitro) | β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells |
| In Vitro study showing that NHC (initial metabolite of molnupiravir) has high antiviral activity against SARS-CoV-2, but also shows host mutational activity in an animal cell culture assay. Authors note the concern that mutations in host .. | ||
Apr 15 2021 |
, News Release (Preprint) | Merck and Ridgeback Biotherapeutics Provide Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19 |
| News release reporting that the trial of molnupiravir with hospitalized patients (NCT04575584) has been discontinued because data indicates it is unlikely to demonstrate a clinical benefit in hospitalized patients. Results are not availab.. | ||
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