Merck's COVID-19 pill significantly less effective in new analysis

[Emily]

https://www.reuters.com/business/he...-hospitalization-death-risk-by-30-2021-11-26/
November 26, 20212:50 PM CSTLast Updated 3 days ago
Healthcare & Pharmaceuticals Merck's COVID-19 pill significantly less effective in new analysis

By Manas Mishra and Michael Erman
Nov 26 (Reuters) - Merck & Co (MRK.N) said on Friday updated data from its study of its experimental COVID-19 pill showed the drug was significantly less effective in cutting hospitalizations and deaths than previously reported.

The drugmaker said its pill showed a 30% reduction in hospitalizations and deaths, based on data from 1,433 patients. In October, its data showed a roughly 50% efficacy, based on data from 775 patients. The drug, molnupiravir, was developed with partner Ridgeback Biotherapeutics.

The lower efficacy of Merck's drug could have big implications in terms of whether countries continue to buy the pill. Interim data from 1,200 participants in Pfizer Inc's (PFE.N) trial for its experimental pill, Paxlovid, showed an 89% reduction in hopsitalizations and deaths...

 

[Emily]

https://downloads.regulations.gov/FDA-2021-N-0758-0021/attachment_1.pdf
Molnupiravir: ineffective, carcinogenic, and a global threat
Leo Goldstein i November 15, 2021

 

[sharon sanders]

bump this

 

[Emily]

I think the FDA's drug approval branch doesn't know how to read anything but $$$'s these days.

https://virological.org/t/mutagenic-antivirals-the-evolutionary-risk-of-low-doses/768

SARS-CoV-2 coronavirus
chasewnelson November 29, 2021, 6:00am #1
Mutagenic antivirals: the evolutionary risk of low doses

Chase W. Nelson[SUP]1[/SUP], Sarah P. Otto[SUP]2[/SUP]

1. Institute for Comparative Genomics, American Museum of Natural History, New York, NY 10024, USA; cnelson@amnh.org
2. Department of Zoology, University of British Columbia, Vancouver BC Canada V6T 1Z4; otto@zoology.ubc.ca

Vaccines and antiviral drugs both have critical parts to play in the fight against COVID-19. Oral antivirals are of particular interest given their potential for equitable distribution, the occurrence of vaccine-breakthrough infections, and increasingly transmissible variants of concern.
Merck recently announced the mutagenic (mutation-inducing) antiviral molnupiravir, which improves COVID-19 outcomes when administered twice a day for five days (Merck & Co., Inc. 2021a; Merck & Co., Inc. 2021b). The drug is already authorized for emergency use in the U.K., and the U.S. Food and Drug Administration will meet to discuss emergency use authorization on Tuesday, November 30.
Antivirals can work via several mechanisms. Protease inhibitors, like masitinib (Drayman et al. 2021) and paxlovid (PF-07321332; ritonavir; Pfizer, Inc. 2021), prevent the production of mature viral proteins. Mutagens, like molnupiravir, instead increase the viral mutation rate beyond a tolerable limit. Specifically, molnupiravir is a nucleoside analog that incorporates into replicating RNA, preferentially inducing C→U mutations (Gordon et al. 2021). At the recommended doses, it is proposed to cause lethal mutagenesis (Loeb et al. 1999): newly replicated viral genomes accumulate so many errors as to become nonviable, an endpoint known as error catastrophe (Eigen and Schuster 1977) or mutational meltdown (Lynch and Gabriel 1990).
One drawback of self-administered oral medications is the risk of low drug concentrations due to missed doses, incomplete courses, or low initial drug penetrance at the site of action (e.g., mucosal membranes in the nasal passages or lungs). Critically, in the case of mutagenic antivirals like molnupiravir, low drug concentrations might increase the mutation rate without reaching the level required for error catastrophe, instead inducing only sublethal mutagenesis (Sadler et al. 2010). This could accelerate within-host evolution of the virus, potentiating new variants of concern that enhance transmissibility or immune escape (Pillai et al. 2008). Indeed, another antiviral, ribavirin, has mutagenic properties and induces adaptive mutations in other RNA viruses (Beaucourt and Vignuzzi 2014; Mejer et al. 2020). Moreover, previous SARS-CoV-2 variants of concern likely acquired adaptive combinations of mutations during single chronic infections (Kemp et al. 2021; Otto et al. 2021).
Given the potential for sublethal mutagenesis of SARS-CoV-2, steps should be taken to understand the evolutionary consequences of both drug concentration and improper administration for pathogen evolution. Among the issues to consider are:...