56 ms·

Discovering Paxlovid

96 points by jjwiseman 5y ago

beebmam 5y ago
Paxlovid is one of the most incredible antiviral medications ever created. I can't wait to see COVID-19 become a virtual non-issue (for mortality) when this medication is available everywhere. As for COVID-19 morbidity, I am still quite concerned. We still don't know much about Long COVID-19, but a significant percent of people seem to be experiencing it with the Omicron variant. Not to mention other possible morbidities that may come from COVID-19: Diabetes, DVTs, kidney damage, and others edit: Please keep in mind that the animals which were bred for and tested upon in the studies that led to this medication being discovered had no choice in the matter, and I personally have a hard time justifying this practice ethically. Animal testing may lead to better discoveries, but the same exact argument could be made for forced human testing.
- kevinmchugh 5y ago
  The earliest omicron cases were ~2 months ago. How confident can we be about elevated long Covid from omicron at this point?
  - notatoad 5y ago
    Long covid is just the existence of symptoms after the infection subsides. 2 months is plenty of time to monitor that.
- kavalg 5y ago
  Got COVID around Christmas. I don't know which variant. It went as a regular flu for 3-4 days, then 2 days feeling better and thinking I am recovering. 6-th day getting fever again, lots of sweating, heart rate up to 90 from 65, feeling bad for 3-5 days. Apart from aspirin and vitamins I started taking Cefuroxime for 5 days (not sure if the latter was 100% necessary, some doctors prescribe it, some not). At day 9 got another examination. Chest x-ray and cardiogram normal, body temperature still high (38C / 100F), heart rate still high, blood pressure normal. Starting to feel much better around day 14, but still not feeling recovered and heart rate was around 80. At day 20 most symptoms were gone, but still got a bit higher heart rate than usual, and some residual coughing, esp when doing some light to moderate physical activity. Now that more than a month has passed since initial symptoms, I still feel that my heart and blood circulation is not back to normal and I am a bit afraid to exercise. I only do some walks on a moderately steep trail and some stretching. I don't know if this counts as a long covid, but definitely it feels a lot different than a regular flu. It looks like most of the damage is first done to your blood circulation system and then that harms some other organs. I hope that circulation system will fully recover, but I don't know how much time it would take. Other people told me that it took them 2-3 months to feel back to normal.
  - nicoburns 5y ago
    > Now that more than a month has passed since initial symptoms, I still feel that my heart and blood circulation is not back to normal and I am a bit afraid to exercise. I only do some walks on a moderately steep trail and some stretching. > Other people told me that it took them 2-3 months to feel back to normal. If you're lucky. I have similar symptoms, and I'm 18 months in and still not back to normal (I have improved, but intense exercise seems to cause a regression). > It looks like most of the damage is first done to your blood circulation system and then that harms some other organs. It seems to vary between people and infections, but that's certainly one of the ways it can go. EDIT: Not sure why this is being downvoted?
    - johnchristopher 5y ago
      > EDIT: Not sure why this is being downvoted? There's a strong vibe of long covid denial on HN and some people are quick to point to a study that stated long covid is mostly a psychological issue.
      - edmcnulty101 5y ago
        I don't think it's taken seriously from a scientific perspective. There's not too many papers on it compared to Covid as a whole.
  - pqs 5y ago
    Were you vaccinated? I'm 40, I got Covid-19 in Christmas, I got the second shot of Pfizer last July. I did not have a fever, I was just very tired for a few days. Then cough came. One month later I still feel something in my chest, I cough a little when I talk, and I collapse on Friday morning, instead of Friday evening, after a week of work (so I have a little less energy than before). I'm doing push-ups, pull-ups and one leg squats as before. No problem there.
    - kavalg 5y ago
      Yes, I had the single dose Jansen vaccine in May. I also had some residual coughing when exercising or talking emotionally (positive emotions, not shouting). Same thing with strength as with you. No problem with push and pull ups, squats or jumping. It is just that my heart rate goes up faster than usual. E.g. I had to carry a 50 lbs box upstairs and after the second floor I already felt my heart beating. Wouldn't have been an issue before, even if running upstairs with 50 lbs.
- throaway46546 5y ago
  I had covid in April of 2020 and I still can't do any strenuous exercise without getting out of breath. Shit sucks.
  - edmcnulty101 5y ago
    The vaccine carries risk of cardiovascular issues but then you increase that risk as well when you get covid. How is a fact being downvoted.
- ceejayoz 5y ago
  > Paxlovid is one of the most incredible antiviral medications ever created. I can't wait to see COVID-19 become a virtual non-issue (for mortality) when this medication is available everywhere. I hope we’re a little more judicious with it than we were with antibiotics.
  - rbanffy 5y ago
    In general, anti-virals kill viruses before they kill the patient (a bit like chemo kills everything, but it kills cancer faster than the really important body parts). Antibiotics are far safer.
    - ceejayoz 5y ago
      I'm speaking more to the resistance end of things. Antibiotics were similarly seen as a miracle drug; now we're struggling to keep them effective due to overuse.
      - rbanffy 5y ago
        Microorganisms have been using antibiotics against each other since life begun on Earth and have evolved ways to evolve around them and develop resistance. For a drug to become ineffective, its target needs a possible evolutionary path around its effect. Depending on what the drug effect, it's possible such path does not exist. Of course, as Jeff Goldblum wisely said, life always finds a way. We can only hope it takes a long time for that to happen.
        ceejayoz 5y ago
        > Microorganisms have been using antibiotics against each other since life begun on Earth and have evolved ways to evolve around them and develop resistance. The same is true with regards to viruses, is it not? I certainly hope they've found a pathway viruses can't evolve around, but that seems pretty unlikely. We've seen antiviral resistance evolve just like antibiotic resistance does. https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm https://www.cdc.gov/flu/professionals/antivirals/antiviral-d...
- rbanffy 5y ago
  > Animal testing may lead to better discoveries, but the same exact argument could be made for forced human testing. Morality is a human construct and, as such, it's completely arbitrary. We humans decide where we draw the line at which time. At what point of the "from annoyance to existential threat" should we draw lines for animal testing, voluntary human testing and forced human testing? There are no absolute answers for these and I hope we never need to find it out.
- inglor_cz 5y ago
  Synthesis of Paxlovid isn't easy, it uses a lot of reactants and we won't be producing it in volume necessary for the entire world anytime soon. https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/making-paxlovid
- ren_engineer 5y ago
  Covid might end up being kind of like WWII where a global emergency led to massive R&D spending that benefits humans in all sorts of other areas due to the tech being created. Would be nice if something good could be salvaged from the situation and these treatments can be generalized to treating other viruses
- skocznymroczny 5y ago
  Long Covid is problematic because it's hard to determine what symptoms exactly are caused by covid. A large chunk of long covid cases seem to be anxiety caused psychosomatic responses. I remember when the first batch of vaccines entered the market, there were many stories of people's "long covid" disappearing minutes after getting the vaccine injection.
  - kvgr 5y ago
    I think I had it back in the day when it was just appearing in Italy. I was on a skying trip and a week after we came back the first case was confirmed. I felt really bad for 2 weeks, breathless, tired, like bad flu but not much of a fever. For some time I felt off, tired, unfocused. And then it just slowly dissapeared I think... but I got the vaccine 1,5 year after the susspected infection so I didn't feel a difference much. If I had covid confirmed, I would think I had long covid.
    - nicoburns 5y ago
      > If I had covid confirmed, I would think I had long covid. Worth noting the post-viral fatigue and other post-viral symptoms are well established phenomena following other viral infections including influenza.
- WillPostForFood 5y ago
  >but a significant percent of people seem to be experiencing it with the Omicron variant How do we know if this is true? Omicron was only identified two months ago, the bulk the cases have been in the last 30 days. Not enough time has passed to qualify for long covid, so there is very little to even measure at this point. If you were sick two weeks ago and still feel bad, that's not unusual with a respiratory virus or flu.
- deleted 5y ago
  [deleted]
bvm 5y ago
Interesting claim (and subsequent debate) in the comments that Pfizer is rewriting history in order to cover up "stealing" the basis for the compound from Merck's Victrelis (boceprevir), a Hep C antiviral. https://www.science.org/content/blog-post/discovering-paxlovid#comment-5698641622 https://www.science.org/content/blog-post/discovering-paxlov...
- 323 5y ago
  Merck is not some random PHd with no power that you can steal from. If there is some merit to this claim, surely it will be tested in court.
deleted 5y ago
[deleted]
baybal2 5y ago
Bangladeshi pharmas are already popping generics of all covid antivirals: Paxlovid, Molnupiravir, and Remdesivir
- rbanffy 5y ago
  Looking at that Paxlovid molecule, I wonder how hard is it to make. There seems to be explosives safer to handle.
  - bradrn 5y ago
    See this article (by the same author as OP) for a synthetic scheme: https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/making-paxlovid
akkawwakka 5y ago
First, this proves that investment in drug discovery for all pandemic potential viruses, fueled by basic science research, needs to be a huge priority going forward. Imagine having antivirals on the shelf for the Coronas, Avian influenza, Nipah, Ebola, etc. to stop pandemics before they started. Secondly, I’m a little curious whether if we’d ideally administer Paxlovid in double- or triple-therapy, like we do for HIV and Hepatitis C, if we had the option. Will resistance arise to it in the next 12 - 24 months? Would love to be assuaged of my fear here.
- thehappypm 5y ago
  I don’t know if there’s much of a realistic evolutionary advantage to being Paxlovid resistant. By the time a person starts taking Paxlovid they’re a dead end for the virus anyway. They’ve been tested, told to isolate, and people around them know to stay away or use PPE. The virus at that point is going to either kill the host or be killed by the host.
  - ceejayoz 5y ago
    > They’ve been tested, told to isolate... If there's one thing we've learned in this pandemic, it's definitely that people will follow that sort of instruction perfectly. I know people who didn't disclose COVID symptoms to avoid missing work and gatherings, and people already stop taking antibiotics early in the course because they're already feeling a lot better.
    - thehappypm 5y ago
      Still, this is not the primary pathway the virus uses. A Paxlovid resistant virus won’t suddenly have a general evolutionary advantage for growth. It’ll just be more likely to kill people.
      - ceejayoz 5y ago
        Why would a virus that can survive Paxlovid and continue infecting people not have an evolutionary advantage in a society with widely available Paxlovid treatments?
RcouF1uZ4gsC 5y ago
> but this is the hands-down all-time champion example of accelerated drug development, and I know of nothing that even comes close. For all the flack that Big Pharma gets, when we really needed them, they came through with vaccines and anti-virals. Meanwhile, governments and government agencies largely covered themselves in shame and incompetence and poor communication. I am happy that Big Pharma makes big profits that keep very smart people employed. Society is much better off with all those smart people working on drugs or Han if they were working on optimizing click through rates for ads.
- rsfern 5y ago
  Since this seems to be generating some controversy (presumably because Big Pharma?) what alternative research and drug discovery, development, testing, and manufacturing ecosystem should we as a society strive for? There are some interesting startups in the space, but mostly they seem to be focused on ML-driven lead generation. I’m optimistic, but not aware of a grand slam demonstration of success on this front. Honestly some of Derek’s discussion makes me hesitant; are the data one would need to assess things like oral availability and manufacturability available enough to make the current ML approaches viable for creating the finish line? How critical is the role of all this tacit knowledge? Are there smaller more lab focused drug discovery outfits that would benefit from some policy change that gives unfair advantage to the BigCos with the scale advantage?
  - natechols 5y ago
    The regulatory overhead to getting a drug approved by the FDA is enormous and this places a huge burden on small companies. I have no magic ideas for fixing this but it's a classic problem of regulatory capture, in many other fields besides pharmaceuticals. I suspect there are ways that the government (and/or private funders) could effectively centralize just the testing and data collection, while keeping the R&D independent and flexible, but it would require a different mindset than we usually apply to public policy.
- axg11 5y ago
  Everything in society that can be criticized, will be criticized by a subgroup. Even still, I don't think Big Pharma gets enough credit for the multiple vaccines and treatments developed over the last two years.
vizzah 5y ago
Would be interested in a study how this compares to Tollovid, which claims to deliver 3CL protease inhibitor extracted from a natural plant and already received FDA approval as "immune support" dietary supplement.
- tcbawo 5y ago
  It sounds like you're comparing an over the counter supplement with a unique designer drug from a pharmaceutical company specifically targeting Covid-19. A brief search did not pull up much regarding the product you mentioned apart from the company itself.
- ceejayoz 5y ago
  > already received FDA approval as "immune support" dietary supplement Someone lied to you. https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements https://www.fda.gov/food/information-consumers-using-dietary... "By law (DSHEA), the manufacturer is responsible for ensuring that its dietary supplement products are safe before they are marketed. Unlike drug products that must be proven safe and effective for their intended use before marketing, there are no provisions in the law for FDA to "approve" dietary supplements for safety or effectiveness before they reach the consumer."
Jimmc414 5y ago
How similar is this to the protease inhibitor Ivermectin?
- 323 5y ago
  Ivermectin is not a protease inhibitor. From wikipedia: > Ivermectin and its related drugs act by interfering with the nerve and muscle functions of helminths and insects. The drug binds to glutamate-gated chloride channels common to invertebrate nerve and muscle cells. Cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853155/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853155/
  - greggeter 5y ago
    Protease binding is in fact a thing that Ivermctn does: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/
  - greggeter 5y ago
    From the article I cited: "Taken together, our data on the interaction between ivermectin and viral proteins indicated that ivermectin majorly acts by interfering with the viral entry through inhibiting the function of spike protein and protease. "
  - wrp 5y ago
    There does seem to be some protease inhibition involved. An in silico data analysis conducted by Choudhury et al. demonstrated that ivermectin efficiently utilizes viral spike protein, main protease, replicase, and human TMPRSS2 receptors as the most possible targets for executing its "antiviral efficiency" by disrupting binding.[1] [1] https://www.nature.com/articles/s41429-021-00491-6 https://www.nature.com/articles/s41429-021-00491-6
- shrubble 5y ago
  It's $700 USD per course of treatment vs. $10. Obviously very dissimilar.
- javagram 5y ago
ck2 5y ago
Derek Lowe is great (and so is paxlovid except the price) see his previously too: https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/pfizer-s-paxlovid-holds https://www.science.org/content/blog-post/pfizer-s-paxlovid-...
m0llusk 5y ago
Really interesting to take in all these details. Protease inhibitors have raised great hopes for many years, but actually making them work as expected has run into all kinds of problems and in general has been a colossal failure that used up enormous amounts of money and effort. To my knowledge this is the first strongly effective protease inhibitor be used in humans, but it would be nice to hear about any other successes.
- 323 5y ago
  Not an expert, but this 1996 paper talks about a highly effective HIV protease inhibitor: https://pubmed.ncbi.nlm.nih.gov/11363781/ https://pubmed.ncbi.nlm.nih.gov/11363781/
- shrubble 5y ago
  Pepcid AC, an over the counter drug, contains famotidine, which is also a 3CLpro protease inhibitor (but testing didn't seem to indicate it would work against covid). It's been used in humans for many many years...
solarkraft 5y ago
> it was only possible because of that earlier work on the closely related SARS protease - and remember, at the time (and for some years thereafter!) that work looked like wasted effort for the most part. After all, there was no SARS to treat, and there were no other related coronaviruses out there causing trouble. But that's science: once you discover something, it stays discovered (or it had better, anyway), and that knowledge is out there waiting to be put to a new use. This also somewhat applies to mRNA technology. It was initially being worked on for cancer treatments and (as far as I am aware) not seriously considered for vaccines.
axg11 5y ago
Are there any sources or predictions on how Paxlovid production and availability will scale? I'm specifically wondering when (if ever) Paxlovid will be widely available and begin to have an impact on COVID hospitalization.
disambiguation 5y ago
Kind of amazing that Pfizer beat everyone to the market twice, first with vaccines and again now with Paxlovid.
aylons 5y ago
I'm all for Pfizer getting recognition for their work, investment and success, but it is a bit frustrating that other people and institutions involved are not getting any at all. Specifically, I'm aware that Argonne National Laboratory[1] was involved in the discovery and development of this molecule, and I think we can safely assume there are other public institutions and universities involved as well. This is just one more reason why people get alienated from the importance of public institutions they fund, and the importance of universities and academia. [1] https://www.aps.anl.gov/APS-News/2021-11-06/aps-and-imca-cat-help-pfizer-create-covid-19-antiviral-treatment/2021-11-06/aps https://www.aps.anl.gov/APS-News/2021-11-06/aps-and-imca-cat...
- natechols 5y ago
  The ANL maintains a large research facility called the Advanced Photon Source, a giant X-ray machine that the government rents out to academics (for free) and pharma companies (for $$$). The APS is very important and has been involved in many major pharma discoveries as well as a few Nobel prizes, and they pay very smart people to run their facilities, but the relationship is much more contractual than your comment implies. I don't know what beamtime at APS costs but if it's anything like other such facilities, Pfizer paid thousands of dollars an hour for the privilege of keeping their data collections private from staff and other users. (And to give credit where it's due, pharma execs have testified before Congress about the importance of these facilities.)

96 points by jjwiseman 5y ago

Paxlovid is one of the most incredible antiviral medications ever created. I can't wait to see COVID-19 become a virtual non-issue (for mortality) when this medication is available everywhere. As for COVID-19 morbidity, I am still quite concerned. We still don't know much about Long COVID-19, but a significant percent of people seem to be experiencing it with the Omicron variant. Not to mention other possible morbidities that may come from COVID-19: Diabetes, DVTs, kidney damage, and others edit: Please keep in mind that the animals which were bred for and tested upon in the studies that led to this medication being discovered had no choice in the matter, and I personally have a hard time justifying this practice ethically. Animal testing may lead to better discoveries, but the same exact argument could be made for forced human testing.

kevinmchugh 5y ago
The earliest omicron cases were ~2 months ago. How confident can we be about elevated long Covid from omicron at this point?
- notatoad 5y ago
  Long covid is just the existence of symptoms after the infection subsides. 2 months is plenty of time to monitor that.
kavalg 5y ago
Got COVID around Christmas. I don't know which variant. It went as a regular flu for 3-4 days, then 2 days feeling better and thinking I am recovering. 6-th day getting fever again, lots of sweating, heart rate up to 90 from 65, feeling bad for 3-5 days. Apart from aspirin and vitamins I started taking Cefuroxime for 5 days (not sure if the latter was 100% necessary, some doctors prescribe it, some not). At day 9 got another examination. Chest x-ray and cardiogram normal, body temperature still high (38C / 100F), heart rate still high, blood pressure normal. Starting to feel much better around day 14, but still not feeling recovered and heart rate was around 80. At day 20 most symptoms were gone, but still got a bit higher heart rate than usual, and some residual coughing, esp when doing some light to moderate physical activity. Now that more than a month has passed since initial symptoms, I still feel that my heart and blood circulation is not back to normal and I am a bit afraid to exercise. I only do some walks on a moderately steep trail and some stretching. I don't know if this counts as a long covid, but definitely it feels a lot different than a regular flu. It looks like most of the damage is first done to your blood circulation system and then that harms some other organs. I hope that circulation system will fully recover, but I don't know how much time it would take. Other people told me that it took them 2-3 months to feel back to normal.
- nicoburns 5y ago
  > Now that more than a month has passed since initial symptoms, I still feel that my heart and blood circulation is not back to normal and I am a bit afraid to exercise. I only do some walks on a moderately steep trail and some stretching. > Other people told me that it took them 2-3 months to feel back to normal. If you're lucky. I have similar symptoms, and I'm 18 months in and still not back to normal (I have improved, but intense exercise seems to cause a regression). > It looks like most of the damage is first done to your blood circulation system and then that harms some other organs. It seems to vary between people and infections, but that's certainly one of the ways it can go. EDIT: Not sure why this is being downvoted?
  - johnchristopher 5y ago
    > EDIT: Not sure why this is being downvoted? There's a strong vibe of long covid denial on HN and some people are quick to point to a study that stated long covid is mostly a psychological issue.
    - edmcnulty101 5y ago
      I don't think it's taken seriously from a scientific perspective. There's not too many papers on it compared to Covid as a whole.
- pqs 5y ago
  Were you vaccinated? I'm 40, I got Covid-19 in Christmas, I got the second shot of Pfizer last July. I did not have a fever, I was just very tired for a few days. Then cough came. One month later I still feel something in my chest, I cough a little when I talk, and I collapse on Friday morning, instead of Friday evening, after a week of work (so I have a little less energy than before). I'm doing push-ups, pull-ups and one leg squats as before. No problem there.
  - kavalg 5y ago
    Yes, I had the single dose Jansen vaccine in May. I also had some residual coughing when exercising or talking emotionally (positive emotions, not shouting). Same thing with strength as with you. No problem with push and pull ups, squats or jumping. It is just that my heart rate goes up faster than usual. E.g. I had to carry a 50 lbs box upstairs and after the second floor I already felt my heart beating. Wouldn't have been an issue before, even if running upstairs with 50 lbs.
throaway46546 5y ago
I had covid in April of 2020 and I still can't do any strenuous exercise without getting out of breath. Shit sucks.
- edmcnulty101 5y ago
  The vaccine carries risk of cardiovascular issues but then you increase that risk as well when you get covid. How is a fact being downvoted.
ceejayoz 5y ago
> Paxlovid is one of the most incredible antiviral medications ever created. I can't wait to see COVID-19 become a virtual non-issue (for mortality) when this medication is available everywhere. I hope we’re a little more judicious with it than we were with antibiotics.
- rbanffy 5y ago
  In general, anti-virals kill viruses before they kill the patient (a bit like chemo kills everything, but it kills cancer faster than the really important body parts). Antibiotics are far safer.
  - ceejayoz 5y ago
    I'm speaking more to the resistance end of things. Antibiotics were similarly seen as a miracle drug; now we're struggling to keep them effective due to overuse.
    - rbanffy 5y ago
      Microorganisms have been using antibiotics against each other since life begun on Earth and have evolved ways to evolve around them and develop resistance. For a drug to become ineffective, its target needs a possible evolutionary path around its effect. Depending on what the drug effect, it's possible such path does not exist. Of course, as Jeff Goldblum wisely said, life always finds a way. We can only hope it takes a long time for that to happen.
      - ceejayoz 5y ago
        > Microorganisms have been using antibiotics against each other since life begun on Earth and have evolved ways to evolve around them and develop resistance. The same is true with regards to viruses, is it not? I certainly hope they've found a pathway viruses can't evolve around, but that seems pretty unlikely. We've seen antiviral resistance evolve just like antibiotic resistance does. https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm https://www.cdc.gov/flu/professionals/antivirals/antiviral-d...
rbanffy 5y ago
> Animal testing may lead to better discoveries, but the same exact argument could be made for forced human testing. Morality is a human construct and, as such, it's completely arbitrary. We humans decide where we draw the line at which time. At what point of the "from annoyance to existential threat" should we draw lines for animal testing, voluntary human testing and forced human testing? There are no absolute answers for these and I hope we never need to find it out.
inglor_cz 5y ago
Synthesis of Paxlovid isn't easy, it uses a lot of reactants and we won't be producing it in volume necessary for the entire world anytime soon. https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/making-paxlovid
ren_engineer 5y ago
Covid might end up being kind of like WWII where a global emergency led to massive R&D spending that benefits humans in all sorts of other areas due to the tech being created. Would be nice if something good could be salvaged from the situation and these treatments can be generalized to treating other viruses
skocznymroczny 5y ago
Long Covid is problematic because it's hard to determine what symptoms exactly are caused by covid. A large chunk of long covid cases seem to be anxiety caused psychosomatic responses. I remember when the first batch of vaccines entered the market, there were many stories of people's "long covid" disappearing minutes after getting the vaccine injection.
- kvgr 5y ago
  I think I had it back in the day when it was just appearing in Italy. I was on a skying trip and a week after we came back the first case was confirmed. I felt really bad for 2 weeks, breathless, tired, like bad flu but not much of a fever. For some time I felt off, tired, unfocused. And then it just slowly dissapeared I think... but I got the vaccine 1,5 year after the susspected infection so I didn't feel a difference much. If I had covid confirmed, I would think I had long covid.
  - nicoburns 5y ago
    > If I had covid confirmed, I would think I had long covid. Worth noting the post-viral fatigue and other post-viral symptoms are well established phenomena following other viral infections including influenza.
WillPostForFood 5y ago
>but a significant percent of people seem to be experiencing it with the Omicron variant How do we know if this is true? Omicron was only identified two months ago, the bulk the cases have been in the last 30 days. Not enough time has passed to qualify for long covid, so there is very little to even measure at this point. If you were sick two weeks ago and still feel bad, that's not unusual with a respiratory virus or flu.
deleted 5y ago
[deleted]

bvm 5y ago

Interesting claim (and subsequent debate) in the comments that Pfizer is rewriting history in order to cover up "stealing" the basis for the compound from Merck's Victrelis (boceprevir), a Hep C antiviral. https://www.science.org/content/blog-post/discovering-paxlovid#comment-5698641622 https://www.science.org/content/blog-post/discovering-paxlov...

323 5y ago
Merck is not some random PHd with no power that you can steal from. If there is some merit to this claim, surely it will be tested in court.

deleted 5y ago

[deleted]

baybal2 5y ago

Bangladeshi pharmas are already popping generics of all covid antivirals: Paxlovid, Molnupiravir, and Remdesivir

rbanffy 5y ago
Looking at that Paxlovid molecule, I wonder how hard is it to make. There seems to be explosives safer to handle.
- bradrn 5y ago
  See this article (by the same author as OP) for a synthetic scheme: https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/making-paxlovid

akkawwakka 5y ago

First, this proves that investment in drug discovery for all pandemic potential viruses, fueled by basic science research, needs to be a huge priority going forward. Imagine having antivirals on the shelf for the Coronas, Avian influenza, Nipah, Ebola, etc. to stop pandemics before they started. Secondly, I’m a little curious whether if we’d ideally administer Paxlovid in double- or triple-therapy, like we do for HIV and Hepatitis C, if we had the option. Will resistance arise to it in the next 12 - 24 months? Would love to be assuaged of my fear here.

thehappypm 5y ago
I don’t know if there’s much of a realistic evolutionary advantage to being Paxlovid resistant. By the time a person starts taking Paxlovid they’re a dead end for the virus anyway. They’ve been tested, told to isolate, and people around them know to stay away or use PPE. The virus at that point is going to either kill the host or be killed by the host.
- ceejayoz 5y ago
  > They’ve been tested, told to isolate... If there's one thing we've learned in this pandemic, it's definitely that people will follow that sort of instruction perfectly. I know people who didn't disclose COVID symptoms to avoid missing work and gatherings, and people already stop taking antibiotics early in the course because they're already feeling a lot better.
  - thehappypm 5y ago
    Still, this is not the primary pathway the virus uses. A Paxlovid resistant virus won’t suddenly have a general evolutionary advantage for growth. It’ll just be more likely to kill people.
    - ceejayoz 5y ago
      Why would a virus that can survive Paxlovid and continue infecting people not have an evolutionary advantage in a society with widely available Paxlovid treatments?

RcouF1uZ4gsC 5y ago

> but this is the hands-down all-time champion example of accelerated drug development, and I know of nothing that even comes close. For all the flack that Big Pharma gets, when we really needed them, they came through with vaccines and anti-virals. Meanwhile, governments and government agencies largely covered themselves in shame and incompetence and poor communication. I am happy that Big Pharma makes big profits that keep very smart people employed. Society is much better off with all those smart people working on drugs or Han if they were working on optimizing click through rates for ads.

rsfern 5y ago
Since this seems to be generating some controversy (presumably because Big Pharma?) what alternative research and drug discovery, development, testing, and manufacturing ecosystem should we as a society strive for? There are some interesting startups in the space, but mostly they seem to be focused on ML-driven lead generation. I’m optimistic, but not aware of a grand slam demonstration of success on this front. Honestly some of Derek’s discussion makes me hesitant; are the data one would need to assess things like oral availability and manufacturability available enough to make the current ML approaches viable for creating the finish line? How critical is the role of all this tacit knowledge? Are there smaller more lab focused drug discovery outfits that would benefit from some policy change that gives unfair advantage to the BigCos with the scale advantage?
- natechols 5y ago
  The regulatory overhead to getting a drug approved by the FDA is enormous and this places a huge burden on small companies. I have no magic ideas for fixing this but it's a classic problem of regulatory capture, in many other fields besides pharmaceuticals. I suspect there are ways that the government (and/or private funders) could effectively centralize just the testing and data collection, while keeping the R&D independent and flexible, but it would require a different mindset than we usually apply to public policy.
axg11 5y ago
Everything in society that can be criticized, will be criticized by a subgroup. Even still, I don't think Big Pharma gets enough credit for the multiple vaccines and treatments developed over the last two years.

vizzah 5y ago

Would be interested in a study how this compares to Tollovid, which claims to deliver 3CL protease inhibitor extracted from a natural plant and already received FDA approval as "immune support" dietary supplement.

tcbawo 5y ago
It sounds like you're comparing an over the counter supplement with a unique designer drug from a pharmaceutical company specifically targeting Covid-19. A brief search did not pull up much regarding the product you mentioned apart from the company itself.
ceejayoz 5y ago
> already received FDA approval as "immune support" dietary supplement Someone lied to you. https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements https://www.fda.gov/food/information-consumers-using-dietary... "By law (DSHEA), the manufacturer is responsible for ensuring that its dietary supplement products are safe before they are marketed. Unlike drug products that must be proven safe and effective for their intended use before marketing, there are no provisions in the law for FDA to "approve" dietary supplements for safety or effectiveness before they reach the consumer."

Jimmc414 5y ago

How similar is this to the protease inhibitor Ivermectin?

323 5y ago
Ivermectin is not a protease inhibitor. From wikipedia: > Ivermectin and its related drugs act by interfering with the nerve and muscle functions of helminths and insects. The drug binds to glutamate-gated chloride channels common to invertebrate nerve and muscle cells. Cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853155/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853155/
- greggeter 5y ago
  Protease binding is in fact a thing that Ivermctn does: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/
- greggeter 5y ago
  From the article I cited: "Taken together, our data on the interaction between ivermectin and viral proteins indicated that ivermectin majorly acts by interfering with the viral entry through inhibiting the function of spike protein and protease. "
- wrp 5y ago
  There does seem to be some protease inhibition involved. An in silico data analysis conducted by Choudhury et al. demonstrated that ivermectin efficiently utilizes viral spike protein, main protease, replicase, and human TMPRSS2 receptors as the most possible targets for executing its "antiviral efficiency" by disrupting binding.[1] [1] https://www.nature.com/articles/s41429-021-00491-6 https://www.nature.com/articles/s41429-021-00491-6
shrubble 5y ago
It's $700 USD per course of treatment vs. $10. Obviously very dissimilar.
javagram 5y ago

ck2 5y ago

Derek Lowe is great (and so is paxlovid except the price) see his previously too: https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/making-paxlovid https://www.science.org/content/blog-post/pfizer-s-paxlovid-holds https://www.science.org/content/blog-post/pfizer-s-paxlovid-...

m0llusk 5y ago

Really interesting to take in all these details. Protease inhibitors have raised great hopes for many years, but actually making them work as expected has run into all kinds of problems and in general has been a colossal failure that used up enormous amounts of money and effort. To my knowledge this is the first strongly effective protease inhibitor be used in humans, but it would be nice to hear about any other successes.

323 5y ago
Not an expert, but this 1996 paper talks about a highly effective HIV protease inhibitor: https://pubmed.ncbi.nlm.nih.gov/11363781/ https://pubmed.ncbi.nlm.nih.gov/11363781/
shrubble 5y ago
Pepcid AC, an over the counter drug, contains famotidine, which is also a 3CLpro protease inhibitor (but testing didn't seem to indicate it would work against covid). It's been used in humans for many many years...

solarkraft 5y ago

> it was only possible because of that earlier work on the closely related SARS protease - and remember, at the time (and for some years thereafter!) that work looked like wasted effort for the most part. After all, there was no SARS to treat, and there were no other related coronaviruses out there causing trouble. But that's science: once you discover something, it stays discovered (or it had better, anyway), and that knowledge is out there waiting to be put to a new use. This also somewhat applies to mRNA technology. It was initially being worked on for cancer treatments and (as far as I am aware) not seriously considered for vaccines.

axg11 5y ago

Are there any sources or predictions on how Paxlovid production and availability will scale? I'm specifically wondering when (if ever) Paxlovid will be widely available and begin to have an impact on COVID hospitalization.

disambiguation 5y ago

Kind of amazing that Pfizer beat everyone to the market twice, first with vaccines and again now with Paxlovid.

aylons 5y ago

I'm all for Pfizer getting recognition for their work, investment and success, but it is a bit frustrating that other people and institutions involved are not getting any at all. Specifically, I'm aware that Argonne National Laboratory[1] was involved in the discovery and development of this molecule, and I think we can safely assume there are other public institutions and universities involved as well. This is just one more reason why people get alienated from the importance of public institutions they fund, and the importance of universities and academia. [1] https://www.aps.anl.gov/APS-News/2021-11-06/aps-and-imca-cat-help-pfizer-create-covid-19-antiviral-treatment/2021-11-06/aps https://www.aps.anl.gov/APS-News/2021-11-06/aps-and-imca-cat...

natechols 5y ago
The ANL maintains a large research facility called the Advanced Photon Source, a giant X-ray machine that the government rents out to academics (for free) and pharma companies (for $$$). The APS is very important and has been involved in many major pharma discoveries as well as a few Nobel prizes, and they pay very smart people to run their facilities, but the relationship is much more contractual than your comment implies. I don't know what beamtime at APS costs but if it's anything like other such facilities, Pfizer paid thousands of dollars an hour for the privilege of keeping their data collections private from staff and other users. (And to give credit where it's due, pharma execs have testified before Congress about the importance of these facilities.)