Molnupiravir, an Oral Antiviral Treatment for COVID-19
MD William Fischer, MD Joseph J Eron Jr, MD Wayne Holman, MD Myron S Cohen, Lei Fang, Laura J Szewczyk, PhD Timothy P Sheahan, Ralph Baric, MS Katie R Mollan, MBBS MPH Cameron R Wolfe, MD Elizabeth R Duke, MD Masoud M Azizad, Katyna Borroto-Esoda, MD David A Wohl, BSc Amy James Loftis, BSc Paul Alabanza, Felicia Lipansky, MD, MPH Wendy P Painter
doi:10.1101/2021.06.17.21258639
Background: Easily distributed oral antivirals are urgently needed to treat coronavirus disease-2019 (COVID-19), prevent progression to severe illness, and block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the results of a All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Change from Baseline in SARS-CoV-2 Viral Load The decrease in viral RNA from baseline to Days 3 to 28 was greater for the 800 mg molnupiravir group than any other group (Table 2 and Figure 2c ). For participants administered 400 or 800 mg molnupiravir, the least squares mean viral load change from baseline was significantly greater on Day 5 when compared to placebo, with differences in least squares means of -0.434 and -0.547 log 10 copies/mL (p = 0.03 and 0.006), respectively. Additionally, for participants administered 800 mg molnupiravir, the least squares mean viral load change from baseline was also significantly greater on Day 7 compared to placebo, with a least squares mean difference of -0.534 log 10 copies/mL (p = 0.006). The reduction in viral load from baseline to Day 5 between 800 mg molnupiravir and placebo remained significant during sensitivity analyses of participants who were negative for antibodies at baseline (least squares mean difference of -0.613 log 10 copies/mL; p = 0.002; Supplementary Table 6 ) and when compared to concurrent placebo (least squares mean difference of -0.376 log 10 copies/mL; p = 0.045; Supplementary Table 8 ).
SARS-CoV-2 Antibody Detection Participants were tested for SARS-CoV-2-specific immunoglobulin (Ig) A, IgM, and IgG at baseline and on Days 7 and 28. The proportions of participants with any antibody to SARS-CoV-2 at baseline varied between the groups, with 15.0%, 30.0%, 35.3%, and 18.2% in the 200, 400, 800 mg..
References
Agostini, Pruijssers, Chappell, Small-molecule antiviral β-D-N4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance, J Virol
Aydillo, Gonzalez-Reiche, Aslam, Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer, N Engl J Med
Bullard, Dust, Funk, Predicting Infectious Severe Acute Respiratory Syndrome Coronavirus 2 From Diagnostic Samples, Clin Infect Dis Off Publ Infect Dis Soc Am
Chen, Nirula, Heller, SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19, N Engl J Med
Chen, Qi, Liu, Clinical progression of patients with COVID-19 in Shanghai, China, J Infect
Cox, Wolf, Plemper, Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nat Microbiol
Folgueira, Luczkowiak, Lasala, Pérez-Rivilla, Delgado, Prolonged SARS-CoV-2 cell culture replication in respiratory samples from patients with severe COVID-19, Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis
González, Vielot, Sciaudone, Seroepidemiology of SARS-CoV-2 infections in an urban Nicaraguan population, MedRxiv Prepr Serv Health Sci
Gottlieb, Nirula, Chen, Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA
Liu, Yan, Wan, Viral dynamics in mild and severe cases of COVID-19, Lancet Infect Dis
Markmann, Giallourou, Bhowmik, Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals, MedRxiv Prepr Serv Health Sci
Menachery, Yount, Debbink, A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence, Nat Med
Painter, Bowen, Bluemling, The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection, Antiviral Res
Painter, Holman, Bush, Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2, Antimicrob Agents Chemother
Premkumar, Segovia-Chumbez, Jadi, The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients, Sci Immunol
Pruijssers, George, Schäfer, Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice, Cell Rep
Sheahan, Sims, Zhou, An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus, Sci Transl Med
Singanayagam, Patel, Charlett, Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020, Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull
Van Kampen, Van De Vijver, Fraaij, Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19), Nat Commun
Wahl, Gralinski, Johnson, SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801, Nature
Weinreich, Sivapalasingam, Norton, REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19, N Engl J Med
Wölfel, Corman, Guggemos, Author Correction: Virological assessment of hospitalized patients with COVID-2019, Nature
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Easily '
'distributed oral antivirals are urgently needed to treat coronavirus disease-2019 (COVID-19), '
'prevent progression to severe illness, and block transmission of severe acute respiratory '
'syndrome coronavirus 2 (SARS-CoV-2). We report the results of a Phase 2a trial evaluating the '
'safety, tolerability, and antiviral efficacy of molnupiravir in the treatment of COVID-19 '
'(<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" '
'xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</jats:ext-link><jats:ext-link '
'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" '
'xlink:href="NCT04405570">NCT04405570</jats:ext-link>).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Eligible '
'participants included outpatients with confirmed SARS-CoV-2 infection and symptom onset '
'within 7 days. Participants were randomized 1:1 to 200 mg molnupiravir or placebo, or 3:1 to '
'molnupiravir (400 or 800 mg) or placebo, twice-daily for 5 days. Antiviral activity was '
'assessed as time to undetectable levels of viral RNA by reverse transcriptase polymerase '
'chain reaction and time to elimination of infectious virus isolation from nasopharyngeal '
'swabs.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Among 202 treated '
'participants, virus isolation was significantly lower in participants receiving 800 mg '
'molnupiravir (1.9%) versus placebo (16.7%) at Day 3 (p = 0.02). At Day 5, virus was not '
'isolated from any participants receiving 400 or 800 mg molnupiravir, versus 11.1% of those '
'receiving placebo (p = 0.03). Time to viral RNA clearance was decreased and a greater '
'proportion overall achieved clearance in participants administered 800 mg molnupiravir versus '
'placebo (p = 0.01). Molnupiravir was generally well tolerated, with similar numbers of '
'adverse events across all '
'groups.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Molnupiravir '
'is the first oral, direct-acting antiviral shown to be highly effective at reducing '
'nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and '
'tolerability profile.</jats:p></jats:sec>',
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'Administration of REGEN-COV™(casirivimab with imdevimab) [Internet]. '
'Cision PR Newswire. 2021 [cited 2021 May 12];Available from: '
'https://www.prnewswire.com/news-releases/phase-3-prevention-trial-showed-81-reduced-risk-of-symptomatic-sars-cov-2-infections-with-subcutaneous-administration-of-regen-cov-casirivimab-with-imdevimab-301266366.html'}],
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