Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study

Khoo et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkab318, NCT04746183

Aug 2021

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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 (history).

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.

Important missing comments or errors? Let us know.

risk of no recovery, 33.3% higher, RR 1.33, p = 0.63, treatment 8 of 12 (66.7%), control 3 of 6 (50.0%), all dosages, symptomatic at day 15.

risk of no recovery, 100% higher, RR 2.00, p = 0.61, treatment 4 of 12 (33.3%), control 1 of 6 (16.7%), all dosages, symptomatic at day 29.

risk of no recovery, 100% higher, RR 2.00, p = 0.20, treatment 4 of 4 (100.0%), control 3 of 6 (50.0%), 800mg, symptomatic at day 15.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 2 of 4 (50.0%), control 3 of 6 (50.0%), 600mg, symptomatic at day 15.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 2 of 4 (50.0%), control 3 of 6 (50.0%), 300mg, symptomatic at day 15.

risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 1 of 4 (25.0%), control 1 of 6 (16.7%), 800mg, symptomatic at day 29.

risk of no recovery, 200.0% higher, RR 3.00, p = 0.50, treatment 2 of 4 (50.0%), control 1 of 6 (16.7%), 600mg, symptomatic at day 29.

risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 1 of 4 (25.0%), control 1 of 6 (16.7%), 300mg, symptomatic at day 29.

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

1. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

3. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

4. Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.hawaii.edu.

5. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

6. Gruber et al., Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study, Journal of Medical Virology, doi:10.1002/jmv.29642.wiley.com, doi.org.

7. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

8. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

9. Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.asianmedjam.com.

10. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

11. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

12. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

13. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Khoo et al., 27 Aug 2021, Randomized Controlled Trial, United Kingdom, peer-reviewed, 38 authors, study period 17 July, 2020 - 30 October, 2020, average treatment delay 4.0 days, trial NCT04746183 (history).

This Paper Molnupiravir All

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study

Saye H Khoo, Richard Fitzgerald, Thomas Fletcher, Sean Ewings, Thomas Jaki, Rebecca Lyon, Nichola Downs, Lauren Walker, Olana Tansley-Hancock, William Greenhalf, Christie Woods, Helen Reynolds, Ellice Marwood, Pavel Mozgunov, Emily Adams, Katie Bullock, Wayne Holman, Marcin D Bula, Jennifer L Gibney, Geoffrey Saunders, Andrea Corkhill, Colin Hale, Kerensa Thorne, Justin Chiong, Susannah Condie, Henry Pertinez, Wendy Painter, Emma Wrixon, Lucy Johnson, Sara Yeats, Kim Mallard, Mike Radford, Keira Fines, Victoria Shaw, Andrew Owen, David G Lalloo, Michael Jacobs, Gareth Griffiths

Objectives: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild ( grade 2). The probability of !30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

Author contributions S.H.K., G.G., T.J., S.E., R.F. and P.M. contributed to study design. S.H.K., G.G., T.J., S.E., G.S., K.T., P.M. and H.P. contributed to data analysis and interpretation. R.F. led clinical conduct as the principal investigator of the clinical site. T.F., L.W., R.L. and M.D.B. participated in clinical assessment and data collection. K.F. participated in the management of pharmacovigilance. S.C., E.W., M.R. and L.J. contributed to the digital data collection and data management of the trial. M.R. led set-up of the randomization system. W.G., T.F., V.S., E.A., K.B. and C.H. contributed to study bioanalysis. A.C., N.D., E.M., O.T.-H., S.Y., H.R., J.C., R.L., C.W., J.L.G., A.O., M.J. and D.G.L. contributed to study management and execution. K.M. contributed to monitoring activities. W.P. and W.H. contributed preclinical and safety data on molnupiravir. S.H.K., G.G., M.J., A.O. and D.G.L. were involved in primary manuscript writing. All authors contributed to the final version of the manuscript. The statisticians S.E., G.S. and K.T. had full access to all the data in the study and S.H.K. and G.G. had final responsibility for the decision to submit for publication. Disclaimer The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Supplementary data Supplement S1 and Supplement S2 are available as Supplementary data at JAC Online.

References

Cevik, Tate, Lloyd, SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis, Lancet Microbe

Cox, Wolf, Plemper, Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nat Microbiol

Griffiths, Fitzgerald, Jaki, AGILE-ACCORD: a randomized, multicentre, seamless, adaptive phase I/II platform study to determine the optimal dose, safety and efficacy of multiple candidate agents for the treatment of COVID-19: a structured summary of a study protocol for a randomised platform trial, Trials

Mozgunov, Jaki, Paoletti, Randomized dose-escalation designs for drug combination cancer trials with immunotherapy, J Biopharm Stat

Painter, Holman, Bush, Human safety, tolerability, and pharmacokinetics of a novel broad-spectrum oral antiviral compound, molnupiravir, with activity against SARS-CoV-2, Antimicrob Agents Chemother

Painter, Sheahan, Baric, Reduction in infectious SARS-CoV-2 in treatment study of COVID-19 with molnupiravir

Rosenke, Hansen, Schwarz, Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model, Nat Commun

Wahl, Gralinski, Johnson, SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801, Nature

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