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Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial

Zou et al., Frontiers in Pharmacology, doi:10.3389/fphar.2022.939573, ChiCTR2200056817

Jun 2022

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RCT 116 mild/moderate COVID-19 patients in China, showing improved viral clearance with treatment.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-15.

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recovery time, 28.6% lower, relative time 0.71, p = 0.50, treatment 77, control 31.

time to viral-, 10.0% lower, relative time 0.90, p = 0.009, treatment 76, control 31.

risk of no viral clearance, 51.1% lower, RR 0.49, p = 0.02, treatment 18 of 76 (23.7%), control 15 of 31 (48.4%), NNT 4.0, day 10.

risk of no viral clearance, 36.7% lower, RR 0.63, p < 0.001, treatment 45 of 76 (59.2%), control 29 of 31 (93.5%), NNT 2.9, day 7.

risk of no viral clearance, 18.4% lower, RR 0.82, p = 0.009, treatment 62 of 76 (81.6%), control 31 of 31 (100.0%), NNT 5.4, day 5.

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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. Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.sciencedirect.com, doi.org.

7. 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.

8. 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.

9. 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.

10. 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.

11. Focosi et al., The fitness of molnupiravir-signed SARS-CoV-2 variants: imputation analysis based on prescription counts and GISAID analyses by country, Intervirology, doi:10.1159/000540282.karger.com, doi.org.

12. 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.

13. 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.

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

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

Zou et al., 15 Jun 2022, Randomized Controlled Trial, China, peer-reviewed, 16 authors, study period 3 March, 2022 - 21 March, 2022, trial ChiCTR2200056817. Contact: lis.lisong@gmail.com, luhongzhou@szsy.sustech.edu.cn, zhongwu@bmi.ac.cn, szsy_lyx@szsy.sustech.edu.cn.

This Paper Molnupiravir All

Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial

Rongrong Zou, Ling Peng, Dan Shu, Lei Zhao, Jianfeng Lan, Guoyu Tan, Jinghan Peng, Xiangyi Yang, Miaona Liu, Chenhui Zhang, Jing Yuan, Huxiang Wang, Song Li, Hongzhou Lu, Wu Zhong, Yingxia Liu

Frontiers in Pharmacology, doi:10.3389/fphar.2022.939573

Background: The rapid worldwide spread of the Omicron variant of SARS-CoV-2 has unleashed a new wave of COVID-19 outbreaks. The efficacy of molnupiravir, an approved drug, is still unknown in patients infected with the Omicron variant. Objective: Evaluated the antiviral efficacy and safety of molnupiravir in patients infected with SARS-CoV-2 Omicron variant, with symptom duration within 5 days. Methods: We conducted a randomized, controlled trial involving patients with mild or moderate COVID-19. Patients were randomized to orally receive molnupiravir (800 mg) plus basic treatment or only basic treatment for 5 days (BID). The antiviral efficacy of the drug was evaluated using reverse transcriptase polymerase chain reaction. Results: Results showed that the time of viral RNA clearance (primary endpoint) was significantly decreased in the molnupiravir group (median, 9 days) compared to the control group (median, 10 days) (Log-Rank p = 0.0092). Of patients receiving molnupiravir, 18.42% achieved viral RNA clearance on day 5 of treatment, compared to the control group (0%) (p = 0.0092). On day 7, 40.79%, and 6.45% of patients in the molnupiravir and control groups, respectively, achieved viral RNA clearance (p = 0.0004). In addition, molnupiravir has a good safety profile, and no serious adverse events were reported. Conclusion: Molnupiravir significantly accelerated the SARS-CoV-2 Omicron RNA clearance in patients with COVID-19.

ETHICS STATEMENT The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Third People's Hospital of Shenzhen (No. 2022-034-02) . The patients/ participants provided their written informed consent to participate in this study. AUTHOR CONTRIBUTIONS SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2022.939573/ full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Arora, Zhang, Rocha, Sidarovich, Kempf et al., Comparable Neutralisation Evasion of SARS-CoV-2 Omicron Subvariants BA.1, BA.2, and BA.3, Lancet. Infect. Dis, doi:10.1016/s1473-3099(22)00224-9

Bernal, Gomes Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients, N. Engl. J. Med, doi:10.1056/NEJMoa2116044

Chen, Wang, Gilby, Wei, Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance, J. Chem. Inf. Model, doi:10.1021/acs.jcim.1c01451

Cheng, Ip, Chu, Tam, Chan et al., Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron Subvariant BA.2 in a Single-Source Community Outbreak, Clin. Infect. Dis, doi:10.1093/cid/ciac203

Fischer, Eron, Jr, Holman, Cohen et al., A Phase 2a Clinical Trial of Molnupiravir in Patients with COVID-19 Shows Accelerated SARS-CoV-2 RNA Clearance and Elimination of Infectious Virus, doi:10.1126/scitranslmed.abl7430

He, Hong, Pan, Lu, Wei, SARS-CoV-2 Omicron Variant: Characteristics and Prevention, MedComm, doi:10.1002/mco2.110

Merck, Merck and Ridgeback's Molnupiravir, an Oral COVID-19 Antiviral Medicine

Rosenke, Okumura, Lewis, Feldmann, Meade-White et al., Molnupiravir Inhibits SARS-CoV-2 Variants Including Omicron in the Hamster Model, JCI Insight, doi:10.1172/jci.insight.160108

Saxena, Kumar, Ansari, Paweska, Maurya et al., Characterization of the Novel SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern and its Global Perspective, J. Med. Virol, doi:10.1002/jmv.27524

Shuai, Chan, Hu, Chai, Yuen et al., Attenuated Replication and Pathogenicity of SARS-CoV-2 B.1.1.529 Omicron, Nature, doi:10.1038/s41586-022-04442-5

Takashita, Kinoshita, Yamayoshi, Sakai-Tagawa, Fujisaki et al., Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant, N. Engl. J. Med, doi:10.1056/NEJMc2119407

Uraki, Kiso, Iida, Imai, Takashita et al., Characterization and Antiviral Susceptibility of SARS-CoV-2 Omicron/BA.2, Nature, doi:10.1038/s41586-022-04856-1

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