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Paxlovid Update

May 04, 2022 7:20 AM ETMRK, PFE5 Comments
Derek Lowe profile picture
Derek Lowe
3.75K Followers

Summary

  • Let’s catch up with what’s going on with Paxlovid, the Pfizer drug that inhibits the Main Protease (MPro) of the coronavirus.
  • Since Merck’s molnupiravir has shown disappointing clinical trial results, Paxlovid is also the main small molecule drug that’s being used to treat the infection.
  • In its initial clinical trials, Paxlovid showed efficacy in preventing hospitalization or death in unvaccinated patients, both high-risk ones and standard-risk ones.

Medical syringes with inscription Paxlovid for Covid-19 treatment

Evgeny Lonskov/iStock via Getty Images

Let’s catch up with what’s going on with Paxlovid, the Pfizer (PFE) drug that inhibits the Main Protease (MPro) of the coronavirus. Since Merck’s (MRK) molnupiravir has shown

This article was written by

Derek Lowe profile picture
3.75K Followers
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek, email him directly: derekb.lowe@gmail.com (mailto:derekb.lowe@gmail.com)

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Comments (5)

j
As always, an enlightening post!
edaskew profile picture
I don't think Paxlovid will be given to a big enough segment of the population for there to be any worry about mutations developing in the dominant strain. I would not use it in any patient who wasn't at high risk of a bad outcome, and now with what we saw this winter, that's a pretty slim slice of the population. I pray that we have seen the last of Delta, and that from now on, SARS CoV2 is an Omicron descendant. It will be bad for my PFE investment but good for everything else in my life. If all we have is Omicron, I don't know if we'll need very much Paxlovid. Then I think this just goes to show you: the problem with Covid is that it was a new pathogen, adapting to it's host, half of whom had no immunity to it. Now, 95% of the population has immunity, and the virus has adapted to us, so, it may be a done deal. I sure hope so.
m
Again you are muddying the waters with respect to the potential emergence of viral resistance mutations to Paxlovid.

Only in very specific cases: HIV, HCV do we see the frequent emergence of antiviral drug resistance necessitating combination therapy. Both viruses have very high rates of mutation and both cause chronic / life long infection requiring life long therapy.

HIV and HCV are the exception not the rule.

Gangciclovir and acyclovir have remained highly efficacious against all manner of herpes virus infections since introduction in the 1980’s. We’re out 40 years now and no meaningful resistance.

Relenza and Tamiflu have remained mostly useful as monotherapy for influenza A virus since introduction in 2006 and 1999.

Transient viral infections are not treated with combination small molecule antiviral therapy. There is literally not a single approved product in that category.

The MPro of SARS-CoV-2 is so highly conserved that Paxlovid has in vitro activity against 2003 SARS, and MERS. For highly conserved targets usually the cost of antiviral drug resistance is so high we never see such strains spread in the community in the absence of constant selective pressure.

Paxlovid is so potent at the prescribed dose that the patient’s viral load falls into the non-infectious range within 24-48h. Even if there are a handful of resistant viruses kicking around there’s not enough of them to be transmissible to the next person. And the immune system tends to do a good job of clearing the last few viruses by itself. Though granted there do seem to be immune suppressed people whose viral load rebounds after the course of Paxlovid is finished. These individuals would perhaps benefit from a 10d course rather than a 5d course.

Ultimate influenza A is a far more variable virus than SARS-CoV-2, with frequent recombination with an endless animal reservoir, and yet tamiflu still works well after 23 years
on the market, despite targeting a highly variable protein - neuraminidase.

We’ll be just fine with single agent Paxlovid
K
Small molecule/DNA/RNA research always amazes me.
navyair profile picture
@Derek Lowe Good article, thanks. The vaccine market is rapidly changing given the m-RNA advances.

Curious as to your thoughts on the Alzheimer's market effects now that Biogen is abandoning Aduhelm and the CEO is leaving? I've had a small position in AVXL for about 18 months. (Wife's mother and maternal grandmother died of Alzheimers, so obviously we're interested.) Naturally, a big setback for one developer in the market could affect others.

Just intersted if you've developed an opinion on this yet. Keep up the good work. JC
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