Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients

Standing et al., Nature Communications, doi:10.1038/s41467-024-45641-0, ISRCTN30448031

Feb 2024

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PANORAMIC virology-sub-study showing increased viral persistence with molnupiravir treatment. Molnupiravir 800mg twice daily for 5 days led to faster initial viral decline but 86% still had detectable virus by day 5. By day 14, molnupiravir was associated with significantly higher proportions with detectable virus and lower anti-spike antibodies compared to usual care. Serial genome sequencing revealed substantially increased mutagenesis with molnupiravir. Viable virus was cultured from samples up to 9 days post-treatment.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-14. Multiple analyses have identified variants potentially created by molnupiravir15-19.

Standard of Care (SOC) for COVID-19 in the study country, the United Kingdom, is very poor with very low average efficacy for approved treatments20. The United Kingdom focused on expensive high-profit treatments, approving only one low-cost treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of treatment—especially early—due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.

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viral culture+, 103.4% higher, RR 2.03, p = 0.33, treatment 6 of 117 (5.1%), control 3 of 119 (2.5%), days 6-20.

viral culture+, 31.1% lower, RR 0.69, p = 0.11, treatment 26 of 249 (10.4%), control 52 of 343 (15.2%), NNT 21, days 2-5.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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13. Standing et al., Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients, Nature Communications, doi:10.1038/s41467-024-45641-0.nature.com, doi.org.

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Standing et al., 23 Feb 2024, Randomized Controlled Trial, United Kingdom, peer-reviewed, 54 authors, study period March 2022 - April 2022, trial ISRCTN30448031. Contact: j.standing@ucl.ac.uk.

This Paper Molnupiravir All

Abstract: Article https://doi.org/10.1038/s41467-024-45641-0 Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients Received: 4 August 2023 A list of authors and their afﬁliations appears at the end of the paper 1234567890():,; 1234567890():,; Accepted: 26 January 2024 Check for updates Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with signiﬁcantly higher viral persistence and signiﬁcantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031 Treatment of SARS-CoV-2 with the nucleoside analogue molnupiravir (MK4482, EIDD2801) was reported to reduce viral load, hospitalisation and mortality in unvaccinated participants with early COVID-19 in the MOVeOUT trial1,2. Based on these data, molnupiravir received emergency use authorisation in the UK in November 2021 for early treatment of SARS-CoV-2 in individuals deemed to be at higher risk of complications due to age or underlying comorbidities. Molnupiravir is metabolised intracellularly to NHC-triphosphate, which competes with natural cytidine and uridine for incorporation by the viral RNA-dependent RNA polymerase (RdRp) into the nascent viral RNA. This leads to abnormal, non-Watson-Crick pairing with guanosine and uridine in further rounds of replication, increasing the substitution of adenosine for guanosine and cytosine for uridine, so-called transition mutations, within the SARS-CoV-2 genome. Lethal mutagenesis resulting from treatment with RdRp inhibitors eventually leads to viral extinction3,4. A distinctive pattern of transition mutagenesis is evident in viral genomes recovered from animals and humans who have received molnupiravir3–5. The risk that, following molnupiravir treatment, some highly mutated viruses might remain viable and capable of onward transmission has been postulated6,7. To measure the impact of molnupiravir in a largely vaccinated population, the Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community (PANORAMIC) was established. The ﬁrst drug tested in PANORAMIC was molnupiravir, and amongst 25,783 mostly vaccinated individuals, found that molnupiravir did not reduce hospitalisation or death8 (primary endpoint). Secondary outcomes showed those receiving molnupiravir experienced signiﬁcantly reduced viral load during treatment and reported faster symptom recovery and fewer general..

DOI record: { "DOI": "10.1038/s41467-024-45641-0", "ISSN": [ "2041-1723" ], "URL": "http://dx.doi.org/10.1038/s41467-024-45641-0", "abstract": "AbstractViral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031", "alternative-id": [ "45641" ], "article-number": "1652", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "4 August 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "26 January 2024" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "23 February 2024" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "J.F.S. has participated on a data safety monitoring board for GlaxoSmithKline (Sotrovimab) with fees paid to his institution. JSN-V-T was seconded to the Department of Health and Social Care, England (DHSC) from October 2017–March 2022. The views and opinions expressed in this paper are not necessarily those of DHSC or any of its arms-length bodies. JSN-V-T performed one-off paid consultancy for Merck Sharp and Dohme in June 2023, unrelated to the subject of the manuscript. K.H. was a member of the Health Technology Assessment General Committee and Funding Strategy Group until November 2022, and Research Professors Funding Committee at the UK National Institute for Health and Care Research (NIHR), received a grant from AstraZeneca (paid to their institution) to support a trial of Evusheld for the prevention of COVID-19 in high-risk individuals (RAPID-Protection), and was an independent member of the independent data monitoring committee for the OCTAVE-DUO trial of vaccines in individuals at high risk of COVID-19. D.M.L. has received grants or contracts from LifeArc, the UK Medical Research Council, Bristol Myers Squibb, GlaxoSmithKline, the British Society for Antimicrobial Chemotherapy, and Blood Cancer UK, personal fees or honoraria from Biotest UK, Gilead, and Merck, consulting fees from GlaxoSmithKline (paid to their institution), and conference support from Octapharma. DBR has received consulting fees from OMASS Therapeutics, GSK, and Sosei-Heptares and has a leadership and fiduciary role in the Heal-COVID trial TMG. M.L. is a member of the data monitoring and ethics committee of RAPIS-TEST (NIHR efficacy and mechanism evaluation). S.K. reports grants from GlaxoSmithKline, ViiV, Ridgeback Biotherapeutics, Vir, Merck, the UK Medical Research Council, and the Wellcome Trust (all paid to his institution), speaker’s honoraria from ViiV, and donations of drugs for clinical studies from ViiV Healthcare, Toyama, and GlaxoSmithKline. M.A. has received grants from the Blood and Transplant Research Unit, Janssen, Pfizer, Prenetics, Dunhill Medical Trust, the BMA Trust (Kathleen Harper Fund), and Antibiotic Research UK (all of which were paid to their institution), and consultancy fees from Prenetics and OxDx. M.A. reports a planned patent for Ramanomics, has participated on data safety monitoring boards or advisory boards for Prenetics, and has an unpaid leadership or fiduciary role in the E3 Initiative. NPBT has received payment for participation on an advisory board from MSD (before any knowledge or planning of this trial). O.v.H. has received consulting fees from MindGap (fees paid to Oxford University lnnovation), has participated on data safety monitoring boards or advisory boards for the CHICO trial, and has an unpaid leadership or fiduciary role in the British Society of Antimicrobial Chemotherapy. J.B. has received consulting fees from GlaxoSmithKline (paid to her institution). 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