Sharing a few threads on whether molnupiravir (new antiviral on the cusp of approval) risks generating new variants because the mutations it induces may, rarely but possibly, not kill the virus but generate viable variants instead. Many on the FDA panel who voted no raised this.https://twitter.com/CT_Bergstrom/status/1467611446053851145 …
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zeynep tufekci Retweeted Michael Lin, MD PhD 🧬
Another thread on the risk of sublethal mutagenesis (on the virus, not the human!) from molnupiravir:https://twitter.com/michaelzlin/status/1464424333246447620 …
zeynep tufekci added,
Michael Lin, MD PhD 🧬 @michaelzlinIn conclusion, it would be highly irresponsible to approve molnupiravir unless the possibility of sublethal accelerated viral mutagenesis is thoroughly addressed and satisfactorily rejected, especially within the target population of patients at risk of hospitalization.Show this thread4 replies 11 retweets 88 likesShow this thread -
zeynep tufekci Retweeted Chase W. Nelson 倪誠志
Another, also with a letter in virological. "Mutagenic antivirals: the evolutionary risk of low doses".https://twitter.com/chasewnelson/status/1465219400064122882 …
zeynep tufekci added,
Chase W. Nelson 倪誠志 @chasewnelsonTODAY at#Virological: throughout the#COVID19 pandemic, there has been a tendency to underestimate the potential of#SARSCoV2 to mutate and adapt. As the@US_FDA meets Tuesday to discuss#molnupiravir,@sarperotto and I fear another oversight.
1/15
https://virological.org/t/mutagenic-antivirals-the-evolutionary-risk-of-low-doses/768 …Show this thread1 reply 5 retweets 72 likesShow this thread -
zeynep tufekci Retweeted James E.K. Hildreth
This is Dr. Hildreth on the FDA advisory phrased it after the vote. (He wasn't the only one on the panel to raise the issue).https://twitter.com/JamesEKHildreth/status/1465806607909064705 …
zeynep tufekci added,
James E.K. Hildreth @JamesEKHildrethFDA AMDAC has voted 13 yes, 10 no for EUA for Merck's molnupiravir COVID-19 drug. I voted no. Inclusive data on mutagenic potential and concerns over generating troublesome SARS-CoV2 variants were not addressed to my satisfaction. Drug has modest 30% reduction in COVID-19 risk.2 replies 6 retweets 68 likesShow this thread -
One question I have is what happen with patience non-compliance? The pill is supposed to be taken over five days, every 12 hours at home (I think 40 pills total). There's going to be a lot of incomplete regimens in this scenario. How does this affect this risk?
2 replies 10 retweets 163 likesShow this thread -
(Also, the trial had two phases and the drug had *zero* efficacy in the second phase which is really weird. It suggests regression to the mean so perhaps there is little to no benefit after all. Seems worth a longer study, but that's a separate question).
3 replies 8 retweets 122 likesShow this thread -
Overall, we have multiple scientists raising the alarm that a new drug may end up generating new variants, many on the FDA panel voting no citing that very concern, and real questions on whether there's any benefit—already on the low side as claimed. Seems worth taking seriously.
6 replies 33 retweets 179 likesShow this thread -
Replying to @zeynep
This seems like as classic a case of Pascal's wager as I've ever seen in drug development. Theoretical arguments from smart people in either direction, no way to be sure… but Omicron moved the window for me on how I think about error tolerance of spike, at least.
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Replying to @roby_bhatt
I'm just trying to imagine a post-approval withdrawal because of this, and the damage it would do. Seems prudent to get some clarity, especially given the benefit itself is low to potentially non-existent. (I couldn't parse the trial data progression. Looks like noise at times).
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Replying to @zeynep
Right. Though it's not easy to imagine how to get "clarity" on the viral mutagenesis issue: it'll happen (that's how the drug works!), but will it drive functional mutants? Is mutation rate limiting in evolution, or not? ¯\_(ツ)_/¯ More clarity on efficacy would be welcome.
1 reply 0 retweets 2 likes
Yeah, clearly need more info on efficacy. On the other clarity part: I'm hoping someone will tell us! But the assumption has to be that many people will not complete the course as prescribed, will not quarantine, some will be immunocompromised (especially if it expands globally).
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Replying to @zeynep @roby_bhatt
With so many on the FDA panel raising this, specifically, as a significant enough concern, I'd like someone to tell us more about all this before approval, including how we'd get that kind of data/clarity.
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Replying to @zeynep
And while Omicron has affected my thinking on flexibility of ACE2 interface (bad for mutagenesis hypothesis), it's also prob compromised our best antivirals: mAb's. Therapies that mimic vaccines = not ideal. Orthogonal targets (protease, polymerase) = better. Nothing's easy.
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