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Today, November 26, Merck and Ridgeback have issued a press release¹ providing the sum of the numbers for its Molnupiravir trials. The putative results of the Part 1 Trial (patients recruited through August 5) were announced in their October 1 press release². The Part 2 Trial comprises patients recruited after August 5.

In the Part 2 Trial (patients recruited after August 5), Merck’s Molnupiravir has shown inferior results compared with placebo: 6.2% (20/324) bad outcomes in the Molnupiravir group compared to 4.7% (15/322) bad outcomes in the placebo group. The bad outcome is defined as hospitalization or death. In each group, one patient died. Thus, Molnupiravir has increased chances of bad outcome by ~25%.

This result might be possibly explained by bone marrow toxicity of Molnupiravir ^{3 4}, hypothetically causing temporary immunosuppression in patients.

Also of note is the prevalence of the Delta variant in the Part 2 Trial. Delta variant exhibits faster growth and shorter incubation period compared with the wild type and earlier variants ⁵.

The Part 1 and Part 2 cannot be combined and treated as one trial, even as only one trial was registered. The sponsor decided to break it into parts, and to present and analyze the first part as a separate complete trial². Thus, the second part should be also treated as a separate trial. The Part 2 Trial is more representative because it better corresponds to the current conditions, when almost all cases are Delta.

If one wants to combine its results with those from the Part 1 Trial, the only rigorous way to do so is a meta-analysis, discounting the Part 1 Trial because it is obsolete and has many other defects, and then accounting for the heterogeneity⁶ between these trials.

The results of the Part 2 Trial are also more in agreement with the theory and experience of the lethal mutagenesis, the mechanism of Molnupiravir action. Lethal mutagenesis  works slowly⁷ (if at all^{8 9}) and cannot be effective for an acute disease like COVID-19 ¹⁰. 

Table 1. Calculation of the numbers in the Part 2 Trial from Merck’s press release ¹

References

1. Merck. Merck and Ridgeback Biotherapeutics Provide Update on Results from MOVe-OUT Study of Molnupiravir, an Investigational Oral Antiviral Medicine, in At Risk Adults With Mild-to-Moderate COVID-19. Published November 26, 2021. https://www.businesswire.com/news/home/20211126005279/en/Merck-and-Ridgeback-Biotherapeutics-Provide-Update-on-Results-from-MOVe-OUT-Study-of-Molnupiravir-an-Investigational-Oral-Antiviral-Medicine-in-At-Risk-Adults-With-Mild-to-Moderate-COVID-19
2. Merck. Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study. Merck.com. Published October 1, 2021. https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
3. MHRA. Summary of Product Characteristics for Lagevrio. GOV.UK. Published November 4, 2021. https://www.gov.uk/government/publications/regulatory-approval-of-lagevrio-molnupiravir/summary-of-product-characteristics-for-lagevrio
4. Goldstein L. Molnupiravir: mutagenic, carcinogenic, authorized in the UK. TrialSite News. Published online November 6, 2021. https://trialsitenews.com/molnupiravir-mutagenic-carcinogenic-authorized-in-the-uk/
5. Wang Y, Chen R, Hu F, et al. Transmission, viral kinetics and clinical characteristics of the emergent SARS-CoV-2 Delta VOC in Guangzhou, China. EClinicalMedicine. 2021;40:101129. doi:10.1016/j.eclinm.2021.101129
6. Veroniki AA, Jackson D, Viechtbauer W, et al. Methods to estimate the between-study variance and its uncertainty in meta-analysis. Res Synth Methods. 2016;7(1):55-79. doi:10.1002/jrsm.1164
7. Belshaw R, Gardner A, Rambaut A, Pybus OG. Pacing a small cage: mutation and RNA viruses. Trends Ecol Evol. 2008;23(4):188-193. doi:10.1016/j.tree.2007.11.010
8. Elena SF, Sanjuán R. Virus Evolution: Insights from an Experimental Approach. Annu Rev Ecol Evol Syst. 2007;38(1):27-52. doi:10.1146/annurev.ecolsys.38.091206.095637
9. Anciaux Y, et al. Evolutionary Rescue over a Fitness Landscape. Oxf Acad. Published online March 13, 2018. https://academic.oup.com/genetics/article/209/1/265/5931020
10. Goldstein L. Molnupiravir: ineffective, carcinogenic, and a global threat. Published online November 15, 2021. https://downloads.regulations.gov/FDA-2021-N-0758-0021/attachment_1.pdf

Leo Goldstein^[1]                                                          PREPRINT                                     November 26, 2021

[1] Contact ah@defyccc.com

Can be cited as: Goldstein L., Merck’s Part 2 Trial Shows Molnupiravir is Inferior to Placebo, defyccc.com, PREPRINT, https://defyccc.com/molnupiravir-inferior-to-placebo, 2021

PDF version: Molnupiravir-Inferior-to-Placebo.pdf

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November 26, 2021 at 01:41PM