Molnupiravir, an Oral Antiviral Treatment for COVID-19

Fischer et al., medRxiv, doi:10.1101/2021.06.17.21258639, NCT04405570, Jun 2021

https://c19early.org/fischer.html

RCT 202 outpatients in the USA showing significantly faster viral clearance, but no significant differences in symptom duration or severity. NCT04405570 (history).

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 USA, is very poor with very low average efficacy for approved treatments20. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

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risk of death, 76.5% lower, RR 0.23, p = 0.31, treatment 0 of 140 (0.0%), control 1 of 62 (1.6%), NNT 62, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), all.

risk of death, 65.4% lower, RR 0.35, p = 1.00, treatment 0 of 55 (0.0%), control 1 of 62 (1.6%), NNT 62, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), 800mg.

risk of death, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 62 (0.0%), control 1 of 62 (1.6%), NNT 62, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), 400mg.

risk of death, 57.8% lower, RR 0.42, p = 1.00, treatment 0 of 23 (0.0%), control 1 of 62 (1.6%), NNT 62, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), 200mg.

risk of hospitalization, 32.9% higher, RR 1.33, p = 1.00, treatment 3 of 140 (2.1%), control 1 of 62 (1.6%), all.

risk of hospitalization, 12.7% higher, RR 1.13, p = 1.00, treatment 1 of 55 (1.8%), control 1 of 62 (1.6%), 800mg.

risk of hospitalization, 100% higher, RR 2.00, p = 1.00, treatment 2 of 62 (3.2%), control 1 of 62 (1.6%), 400mg.

risk of hospitalization, 57.8% lower, RR 0.42, p = 1.00, treatment 0 of 23 (0.0%), control 1 of 62 (1.6%), NNT 62, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), 200mg.

risk of no viral clearance, 49.2% lower, RR 0.51, p = 0.12, treatment 10 of 118 (8.5%), control 9 of 54 (16.7%), NNT 12, infectious, day 3, all.

risk of no viral clearance, 88.7% lower, RR 0.11, p = 0.02, treatment 1 of 53 (1.9%), control 9 of 54 (16.7%), NNT 6.8, infectious, day 3, 800mg.

risk of no viral clearance, 30.2% lower, RR 0.70, p = 0.57, treatment 5 of 43 (11.6%), control 9 of 54 (16.7%), NNT 20, infectious, day 3, 400mg.

risk of no viral clearance, 9.1% higher, RR 1.09, p = 1.00, treatment 4 of 22 (18.2%), control 9 of 54 (16.7%), infectious, day 3, 200mg.

risk of no viral clearance, 92.3% lower, RR 0.08, p = 0.004, treatment 1 of 117 (0.9%), control 6 of 54 (11.1%), NNT 9.8, infectious, day 5, all.

risk of no viral clearance, 92.2% lower, RR 0.08, p = 0.03, treatment 0 of 53 (0.0%), control 6 of 54 (11.1%), NNT 9.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), infectious, day 5, 800mg.

risk of no viral clearance, 91.4% lower, RR 0.09, p = 0.03, treatment 0 of 42 (0.0%), control 6 of 54 (11.1%), NNT 9.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), infectious, day 5, 400mg.

risk of no viral clearance, 59.1% lower, RR 0.41, p = 0.67, treatment 1 of 22 (4.5%), control 6 of 54 (11.1%), NNT 15, infectious, day 5, 200mg.

risk of no viral clearance, 29.5% lower, RR 0.70, p = 0.30, treatment 19 of 137 (13.9%), control 12 of 61 (19.7%), NNT 17, all.

risk of no viral clearance, 61.6% lower, RR 0.38, p = 0.10, treatment 4 of 53 (7.5%), control 12 of 61 (19.7%), NNT 8.2, 800mg.

risk of no viral clearance, 8.3% higher, RR 1.08, p = 1.00, treatment 13 of 61 (21.3%), control 12 of 61 (19.7%), 400mg.

risk of no viral clearance, 55.8% lower, RR 0.44, p = 0.33, treatment 2 of 23 (8.7%), control 12 of 61 (19.7%), NNT 9.1, 200mg.

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

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Fischer et al., 18 Jun 2021, Randomized Controlled Trial, USA, preprint, 18 authors, study period 19 June, 2020 - 25 January, 2021, average treatment delay 4.6 days, trial NCT04405570 (history).

This Paper Molnupiravir All

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..

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DOI record: { "DOI": "10.1101/2021.06.17.21258639", "URL": "http://dx.doi.org/10.1101/2021.06.17.21258639", "abstract": "AbstractBackgroundEasily 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 (ClinicalTrials.govNCT04405570).MethodsEligible 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.ResultsAmong 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.ConclusionsMolnupiravir 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.", "accepted": { "date-parts": [ [ 2021, 6, 17 ] ] }, "author": [ { "affiliation": [], "family": "Fischer", "given": "William", "sequence": "first" }, { "affiliation": [], "family": "Eron", "given": "Joseph J.", "sequence": "additional", "suffix": "Jr" }, { "affiliation": [], "family": "Holman", "given": "Wayne", "sequence": "additional" }, { "affiliation": [], "family": "Cohen", "given": "Myron S.", "sequence": "additional" }, { "affiliation": [], "family": "Fang", "given": "Lei", "sequence": "additional" }, { "affiliation": [], "family": "Szewczyk", "given": "Laura J.", "sequence": "additional" }, { "affiliation": [], "family": "Sheahan", "given": "Timothy P", "sequence": "additional" }, { "affiliation": [], "family": "Baric", "given": "Ralph", "sequence": "additional" }, { "affiliation": [], "family": "Mollan", "given": "Katie R.", "sequence": "additional" }, { "affiliation": [], "family": "Wolfe", "given": "Cameron R.", "sequence": "additional" }, { "affiliation": [], "family": "Duke", "given": "Elizabeth R.", "sequence": "additional" }, { "affiliation": [], "family": "Azizad", "given": "Masoud M.", "sequence": "additional" }, { "affiliation": [], "family": "Borroto-Esoda", "given": "Katyna", "sequence": "additional" }, { "affiliation": [], "family": "Wohl", "given": "David A.", "sequence": "additional" }, { "affiliation": [], "family": "Loftis", "given": "Amy James", "sequence": "additional" }, { "affiliation": [], "family": "Alabanza", "given": "Paul", "sequence": "additional" }, { "affiliation": [], "family": "Lipansky", "given": "Felicia", "sequence": "additional" }, { "affiliation": [], "family": "Painter", "given": "Wendy P.", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2021, 6, 18 ] ], "date-time": "2021-06-18T05:30:17Z", "timestamp": 1623994217000 }, "deposited": { "date-parts": [ [ 2022, 12, 31 ] ], "date-time": "2022-12-31T15:29:53Z", "timestamp": 1672500593000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2024, 3, 26 ] ], "date-time": "2024-03-26T23:10:51Z", "timestamp": 1711494651280 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 122, "issued": { "date-parts": [ [ 2021, 6, 17 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2021.06.17.21258639", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2021, 6, 17 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2021, 6, 17 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2021061908100663000_2021.06.17.21258639v1.1", "unstructured": "World Health Organisation. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

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