I think I figured out why Xocova is much more effective as a COVID-19 prophylactic compared to Paxlovid. The drug, approved in Japan, has many other benefits too!
When I was evaluating antivirals for a long covid startup a couple years back, I used the ratio of [unbound Cmin: IC50], which takes into account pharmacokinetics including plasma protein binding. I already liked XOCOva back then because of it!
Xocova: 12.8 (low) - 26.7 (high)
Paxlovid: 4.3 (low) - 30.0 (high)
Higher is better. And these used substantially worse IC50 values than yours, 300-500nMfor xocova vs. 16-74nM for nirmatrelvir.
Personally in a pandemic I think this ratio would be a very acceptable surrogate endpoint, and we would just need to prove safety.
I can share the spreadsheet I made back then if you like
That makes a lot of sense, and I have heard of that ratio, it is used when considering what dose to give. There are IC50 and Ki values reported all over the map for the two compounds, although typically all in the 10-500 nM range, which is considered a very strong binder. High variance in IC50 is common due to differences in assay design. The numbers I quote (IC50=49 nM for Ensitrelvir vs IC50=44 nM for Nirmatrelvir) come from the same lab, exact same assay, so they are a true head-to-head comparison.
It would be nice to feel better faster, but my #1 concern with SARS-CoV-2 is minimizing the risk of long covid. I'm especially interested in keeping all my IQ points. For my purposes, the headline finding is that Xocova definitely reduces the risk of long covid (including neurological symptoms) and Paxlovid definitely doesn't:
The FDA is causing vast amounts of human misery with this ridiculous foot-dragging on the so-called "Fast Track." What we need is new law forcing the FDA to recognize convincing trials conducted in other countries - and to stop them from citing arbitrary "diversity" variables or other irrelevant trial minutiae when they choose to unilaterally withhold effective medicines from the American people. It's like we learned nothing from the Tuskegee Study:
Yes Chris, after I published I lamented not mentioning that. But, I was reluctant to mention it since the I was not very convinced by what I read in the company's press release. The studies on Paxlovid for preventing long covid are mixed. So I was a bit reluctant to stake a claim about Long Covid. However, after publishing, I realized the company has published their full results (https://www.sciencedirect.com/science/article/pii/S0166354224001670)
The data is a bit messy, but overall there's a definite effect, I would say maybe a 20% risk reduction. One of the perplexing things however, is that taking 2x the normal dose didn't result in further risk reduction, in fact, the risk reduction decreased in many cases.
The biggest effect was seen in reducing neurological symptoms at 337 days (neurological symptoms were defined as "difficulty with concentration and thinking, difficulty in reasoning and solving problems, memory loss, or insomnia."
Point taken that the long covid results aren't quite as open and shut as I make them out to be. And also point taken that the data, taken as a whole, are still plenty good enough to tell us which of the two drugs is the better bet for maintaining IQ points. Also, I share your view that early treatment is of paramount importance - so my bet would be that if were allowed to have Xocova on hand to take the same day I test positive it would give me a strong chance of even better IQ-maintenance effects than observed in the trial.
Coming from the world of academic publishing, it has taken me a long time to get used to the idea that I can go back and make major edits to my Substack posts. Sometimes I'm still shy and all I do is add a dated update at the bottom of the post. But other times I order a copy at the Wayback Machine for posterity, and then I proceed to make major overhauls. Although in this case we've now got a nice comment thread that obviates overhaul.
Nice!
When I was evaluating antivirals for a long covid startup a couple years back, I used the ratio of [unbound Cmin: IC50], which takes into account pharmacokinetics including plasma protein binding. I already liked XOCOva back then because of it!
Xocova: 12.8 (low) - 26.7 (high)
Paxlovid: 4.3 (low) - 30.0 (high)
Higher is better. And these used substantially worse IC50 values than yours, 300-500nMfor xocova vs. 16-74nM for nirmatrelvir.
Personally in a pandemic I think this ratio would be a very acceptable surrogate endpoint, and we would just need to prove safety.
I can share the spreadsheet I made back then if you like
That makes a lot of sense, and I have heard of that ratio, it is used when considering what dose to give. There are IC50 and Ki values reported all over the map for the two compounds, although typically all in the 10-500 nM range, which is considered a very strong binder. High variance in IC50 is common due to differences in assay design. The numbers I quote (IC50=49 nM for Ensitrelvir vs IC50=44 nM for Nirmatrelvir) come from the same lab, exact same assay, so they are a true head-to-head comparison.
It would be nice to feel better faster, but my #1 concern with SARS-CoV-2 is minimizing the risk of long covid. I'm especially interested in keeping all my IQ points. For my purposes, the headline finding is that Xocova definitely reduces the risk of long covid (including neurological symptoms) and Paxlovid definitely doesn't:
https://www.eatg.org/hiv-news/shionogi-presents-pivotal-ensitrelvir-fumaric-acid-phase-3-data-and-exploratory-long-covid-data
https://www.cidrap.umn.edu/covid-19/studies-show-mostly-poor-long-covid-protection-paxlovid
The FDA is causing vast amounts of human misery with this ridiculous foot-dragging on the so-called "Fast Track." What we need is new law forcing the FDA to recognize convincing trials conducted in other countries - and to stop them from citing arbitrary "diversity" variables or other irrelevant trial minutiae when they choose to unilaterally withhold effective medicines from the American people. It's like we learned nothing from the Tuskegee Study:
https://christharrington.substack.com/p/the-lost-lesson-of-tuskegee
Yes Chris, after I published I lamented not mentioning that. But, I was reluctant to mention it since the I was not very convinced by what I read in the company's press release. The studies on Paxlovid for preventing long covid are mixed. So I was a bit reluctant to stake a claim about Long Covid. However, after publishing, I realized the company has published their full results (https://www.sciencedirect.com/science/article/pii/S0166354224001670)
The data is a bit messy, but overall there's a definite effect, I would say maybe a 20% risk reduction. One of the perplexing things however, is that taking 2x the normal dose didn't result in further risk reduction, in fact, the risk reduction decreased in many cases.
The biggest effect was seen in reducing neurological symptoms at 337 days (neurological symptoms were defined as "difficulty with concentration and thinking, difficulty in reasoning and solving problems, memory loss, or insomnia."
Also, absolutely, we should have reciprocity with Japan's regulatory agency (PMDA) and the EMA. That's high on my list of FDA reforms: https://moreisdifferent.blog/p/a-laundry-list-of-possible-fda-reforms
It would save pharma companies and taxpayers an enormous amount of money also.
Point taken that the long covid results aren't quite as open and shut as I make them out to be. And also point taken that the data, taken as a whole, are still plenty good enough to tell us which of the two drugs is the better bet for maintaining IQ points. Also, I share your view that early treatment is of paramount importance - so my bet would be that if were allowed to have Xocova on hand to take the same day I test positive it would give me a strong chance of even better IQ-maintenance effects than observed in the trial.
Coming from the world of academic publishing, it has taken me a long time to get used to the idea that I can go back and make major edits to my Substack posts. Sometimes I'm still shy and all I do is add a dated update at the bottom of the post. But other times I order a copy at the Wayback Machine for posterity, and then I proceed to make major overhauls. Although in this case we've now got a nice comment thread that obviates overhaul.
Signed petition and reposted your explanation :)