Molnupiravir for COVID-19: real-time analysis of all 10 studies

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

Arribas et al., NEJM Evidence, doi:10.1056/EVIDoa2100044 (Peer Reviewed)

RCT 304 hospitalized patients, 218 treated with molnupiravir, showing no significant differences. MOVe-IN MK-4482-001. NCT04575584.

risk of death, 281.9% higher, RR 3.82, p = 0.31, treatment 11 of 216 (5.1%), control 1 of 75 (1.3%), combined, excluding imputed deaths.

risk of death, 216.9% higher, RR 3.17, p = 0.36, treatment 3 of 71 (4.2%), control 1 of 75 (1.3%), 800mg, excluding imputed death.

risk of death, 316.7% higher, RR 4.17, p = 0.20, treatment 4 of 72 (5.6%), control 1 of 75 (1.3%), 400mg, excluding imputed death.

risk of death, 311.0% higher, RR 4.11, p = 0.21, treatment 4 of 73 (5.5%), control 1 of 75 (1.3%), 200mg.

risk of no recovery, 1.0% lower, RR 0.99, p = 0.96, treatment 72, control 75, 800mg.

risk of no recovery, 11.5% lower, RR 0.88, p = 0.53, treatment 73, control 75, 400mg.

risk of no recovery, 1.0% higher, RR 1.01, p = 0.96, treatment 73, control 75, 200mg.

recovery time, no change, relative time 1.00, treatment 72, control 75, 800mg.

recovery time, no change, relative time 1.00, treatment 73, control 75, 400mg.

recovery time, no change, relative time 1.00, treatment 73, control 75, 200mg.

risk of no virological cure, 11.8% lower, RR 0.88, p = 0.57, treatment 26 of 52 (50.0%), control 34 of 60 (56.7%), NNT 15, 800mg, Table S16, day 15 mid-recovery.

risk of no virological cure, 2.4% higher, RR 1.02, p = 1.00, treatment 29 of 50 (58.0%), control 34 of 60 (56.7%), 400mg, Table S16, day 15 mid-recovery.

risk of no virological cure, 20.6% lower, RR 0.79, p = 0.27, treatment 27 of 60 (45.0%), control 34 of 60 (56.7%), NNT 8.6, 200mg, Table S16, day 15 mid-recovery.

risk of no virological cure, 8.3% lower, RR 0.92, p = 1.00, treatment 9 of 53 (17.0%), control 10 of 54 (18.5%), NNT 65, 800mg, Table S16, day 29.

risk of no virological cure, 48.2% higher, RR 1.48, p = 0.35, treatment 14 of 51 (27.5%), control 10 of 54 (18.5%), 400mg, Table S16, day 29.

risk of no virological cure, 21.5% lower, RR 0.79, p = 0.61, treatment 8 of 55 (14.5%), control 10 of 54 (18.5%), NNT 25, 200mg, Table S16, day 29.

Arribas et al., 12/16/2021, Double Blind Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 21 authors.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Jayk Bernal et al., New England Journal of Medicine, doi:10.1056/NEJMoa2116044 (Peer Reviewed)

MOVe-OUT RCT, showing significantly lower risk of hospitalization or death. In subgroup analysis efficacy was much lower with the delta variant. NCT04575597.

Discussion of concerns with this trial can be found at [1, 2]. See also: [3, 4].

[1] trialsitenews.com/molnupiravir-mutagenic-carcinogenic-authorized-in-the-uk/

[2] defyccc.com/wp-content/uploads/Molnupiravir-Mutagenic-Carcinogenic-TSN.pdf

[3] twitter.com/Covid19Crusher/status/1464249681446420485

[4] twitter.com/Covid19Crusher/status/1464269071818661893

risk of death, 89.0% lower, RR 0.11, p = 0.01, treatment 1 of 709 (0.1%), control 9 of 699 (1.3%), NNT 87.

risk of death/hospitalization, 30.4% lower, RR 0.70, p = 0.05, treatment 48 of 709 (6.8%), control 68 of 699 (9.7%), NNT 34.

risk of death/hosp. (gamma variant), 94.1% lower, RR 0.06, p = 0.004, treatment 0 of 37 (0.0%), control 9 of 47 (19.1%), NNT 5.2, relative risk is not 0 because of continuity correction due to zero events.

risk of death/hosp. (mu variant), 49.5% lower, RR 0.50, p = 0.15, treatment 6 of 75 (8.0%), control 13 of 82 (15.9%), NNT 13.

risk of death/hosp. (delta variant), 23.7% lower, RR 0.76, p = 0.41, treatment 18 of 237 (7.6%), control 22 of 221 (10.0%), NNT 42.

risk of death/hosp. (other variants), 42.2% lower, RR 0.58, p = 0.36, treatment 5 of 47 (10.6%), control 7 of 38 (18.4%), NNT 13.

Jayk Bernal et al., 12/16/2021, Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, 22 authors.

Treating a Pandemic Respiratory Disease with a Mutagen is a Doomsday Scenario

Anonymous, Authorea, doi:10.22541/au.163854323.34557301/v1 (Review) (Preprint)

Review of molnupiravir's mutagenic mechanism of action, and analysis of the increased probability of creating dangerous variants.

Anonymous et al., 12/3/2021, preprint, 1 author.

Molnupiravir: mutagenic, carcinogenic, authorized in the UK

Goldstein, L., TrialSite News (Review) (News)

Discussion of concerns with molnupiravir and the MOVe-OUT trial. Author notes that results showing bone marrow toxicity in dogs were mentioned in this preprint [1], but removed from the journal version [2]. Some additional details were provided by the UK regulator:

“Reversible, dose-related bone marrow toxicity affecting all haematopoietic cell lines was observed in dogs at ≥17 mg/kg/day (0.4 times the human NHC exposure at the recommended human dose (RHD)).” [3]

For those without TrialSite News access, this article can also be found at [4].

[1] medrxiv.org/content/10.1101/2020.12.10.20235747v1

[2] journals.asm.org/doi/full/10.1128/AAC.02428-20

[3] gov.uk/government/publications/regulatory-approval-of-lagevrio-molnupiravir/summary-of-product-cha..

[4] defyccc.com/wp-content/uploads/Molnupiravir-Mutagenic-Carcinogenic-TSN.pdf

Goldstein et al., 11/6/2021, preprint, 1 author.

Molnupiravir: coding for catastrophe

Malone et al., Nature Structural & Molecular Biology, doi:10.1038/s41594-021-00657-8 (Review) (Peer Reviewed)

Review of recent studies on molnupiravir's mechanism of lethal mutagenesis. Authors note that potential off-target effects require further investigation, because molnupiravir may be mutagenic to host DNA during host DNA replication.

Malone et al., 9/13/2021, peer-reviewed, 2 authors.

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 (Peer Reviewed)

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.

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.

Khoo et al., 8/27/2021, Randomized Controlled Trial, United Kingdom, Europe, peer-reviewed, 38 authors.

Optimus announces Interim Clinical Results from Phase III Clinical Trials of Molnupiravir conducted in India

Optimus Press Release (News)

Interim report on CTRI/2021/06/033992, showing faster viral clearance. Event counts are approximate, the press release only provides percentages.

risk of no virological cure, 58.0% lower, RR 0.42, p < 0.001, treatment 38 of 175 (21.7%), control 93 of 180 (51.7%), NNT 3.3, day 5.

Optimus et al., 7/21/2021, Randomized Controlled Trial, India, South Asia, preprint, 1 author.

Hetero Announces Interim Clinical Results from Phase III Clinical Trials of Molnupiravir conducted in India

Hetero Press Release (Peer Reviewed)

Interim results for CTRI/2021/05/033739, showing lower mortality and faster recovery.

risk of hospitalization, 69.6% lower, RR 0.30, p = 0.003, treatment 7 of 371 (1.9%), control 23 of 370 (6.2%), NNT 23.

recovery time, 33.3% lower, relative time 0.67, p < 0.001, treatment 371, control 370.

Hetero et al., 7/9/2021, Randomized Controlled Trial, India, South Asia, peer-reviewed, 1 author.

Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model

Abdelnabi et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiab361 (Peer Reviewed)

Hamster study showing molnupiravir effective against the original, B.1.1.7, and B.1.351 variants.

Abdelnabi et al., 7/9/2021, peer-reviewed, 6 authors.

Molnupiravir, an Oral Antiviral Treatment for COVID-19

Fischer et al., medRxiv, doi:10.1101/2021.06.17.21258639 (Preprint)

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

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, 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, 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, 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, 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, 200mg.

risk of no virological cure, 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 virological cure, 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 virological cure, 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 virological cure, 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 virological cure, 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 virological cure, 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, infectious, day 5, 800mg.

risk of no virological cure, 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, infectious, day 5, 400mg.

risk of no virological cure, 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 virological cure, 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 virological cure, 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 virological cure, 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 virological cure, 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.

Fischer et al., 6/18/2021, Randomized Controlled Trial, USA, North America, preprint, 18 authors.

β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells

Zhou et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247 (Peer Reviewed) (In Vitro)

In Vitro study showing that NHC (initial metabolite of molnupiravir) has high antiviral activity against SARS-CoV-2, but also shows host mutational activity in an animal cell culture assay. Authors note the concern that mutations in host DNA could contribute to the development of cancer, or cause birth defects either in a developing fetus or through incorporation into sperm precursor cells. Response from Merck: [1].

[1] academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab362/6319402

Zhou et al., 5/7/2021, peer-reviewed, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Merck and Ridgeback Biotherapeutics Provide Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19

Merck, News Release (Preprint)

News release reporting that the trial of molnupiravir with hospitalized patients (NCT04575584) has been discontinued because data indicates it is unlikely to demonstrate a clinical benefit in hospitalized patients. Results are not available yet. Interim results for the trial with outpatients show positive dose-dependent results for viral clearance.

Merck et al., 4/15/2021, preprint, 1 author.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption