> Pfizer’s phase 2/3 trial randomized non-hospitalized adult COVID-19 patients who were at high risk of progressing to severe illness to receive placebo or Paxlovid, a combination of the protease inhibitors PF-07321332 and ritonavir. The efficacy analysis is based on 1,219 patients.
One noteworthy feature is the newness of this drug:
> PF-07321332 was developed from scratch during the current pandemic. It’s a reversible covalent inhibitor that reacts with one of the main protease’s cysteine residues. Owen [director of medicinal chemistry at Pfizer] also discussed the chemistry involved in scaling up the compound. The first 7 mg of the compound were synthesized in late July 2020. Encouraged by the early biological data, the Pfizer team aimed to scale up the synthesis. By late October, they’d made 100 g of the compound. Just two weeks later, the chemists had scaled up the synthesis to more than 1 kg. Owen said 210 researchers had worked on the project.
Less than two years from lab to clinic is highly unusual. If approved, I believe this would be the fastest lab-to-approval for a small molecule drug in the history of the FDA.
>Less than two years from lab to clinic is highly unusual.
I assume like most other COVID vaccines/treatments, the timeline is shrunk by going straight to more expensive phases of the trial instead of having preliminary ones of escalating cost and confidence. Or at least prepping for them.
For instance, all the vaccines started setting up commercial production around the same time they started trials, because it's not worth the months delay of setting up a production line to determine if it worked first.
It's not uncommon for human tragedies to serve as a backdrop for significant scientific progress.
Wars and pandemics seem to be the testbeds for medicine, where people are desperate enough to try anything, and legislation is relaxed accordingly. The biotech companies know this all too well, and take advantage when the opportunity arises.
Development tools help accelerate software development. Better tools help you go faster. This is happening in biotech as well - they're getting some very good development tools.
Is anyone familiar how this scaling up process works? To what point can it be scaled up using lab methods, and at which point does it make sense to start making it large-scale?
I think it’s hard to overstate what a big deal this is for science. This is a completely novel molecule that appears effective as an antiviral. This would a huge achievement for the field of drug design, and will hopefully lead to all kinds of great medicine.
I am thinking: if and when this is approved, we have to think about distribution.
This drug is fantastically effective at preventing hospitalisation and death, if administered within three days of symptom onset.
That gives quite a long time! But we still need to make it easy to take. Do pharmacies give it out? ER rooms? We don't want to wait until people are hospitalised; we are trying to avoid that.
So when you test positive, does the government send you out a pill with the "sorry, you have to isolate" SMS?
> As a protease inhibitor, Paxlovid is free from the theoretical DNA-alteration risk tied to the mechanism of action of Merck’s molnupiravir.
This is the line I was looking for. Not that I know how protease inhibitor works, but looks more like a traditional anti-viral approach v.s. the potentially DNA altering molnupiravir.
> [...] patients who received Paxlovid within five days of symptom onset [...]
I wonder how well it will do on people who are farther along in their COVID infection?
There are a lot of people who don't get vaccinated, don't take precautions to avoid COVID, dismiss their early symptoms either because they believe COVID isn't worse than a typical cold or flu or because they think that is probably what they have, just treat it at home with vitamins and ivermectin if they do anything at all about it, and don't end up going to a doctor or hospital until they are having so much trouble breathing they have to go to the emergency room.
I wonder if having an effective oral antiviral readily available will result in someone who would have acted in the manner you suggest seeking this treatment instead.
So no we have the Pfizer vaccine (which I got) who cuts the risk of both catching the virus and the risk of severe complication by a lot (forgot the number but it's big) and in addition to that we now have Pfizer oral medication that can be given to positive cases and which reduces both hospitalization and death risk by 85%.
> Pfizer used data on patients who were treated within three days of symptom onset as the headline finding in its press release
> There were six hospitalizations and no deaths among the 607 patients who received Paxlovid within five days of symptom onset, compared to 41 hospitalizations and 10 deaths in the placebo cohort.
> Like Merck, Pfizer excluded people vaccinated against COVID-19 from its late-phase study.
No pricing information. I'm worried that "3 days after symptoms onset" is too short to be usable in real-life, but I could be wrong.
Yahoo news[0] and other news sources report significant efficacy even at the 5 day mark.
"Rates were similar for patients treated within five days of symptoms - 1% of the treatment group was hospitalized, compared with 6.7% for the placebo group, which included 10 deaths."
"The U.S. government has been in negotiations with Pfizer for enough pills for 1.7 million courses of treatment, with an additional option for 3.3 million, according to a senior administration official. That is about the same quantity that the United States has ordered from Merck. The government expects to pay about $700 per treatment course for both drugs, the official said."
Monoclonal antibody treatments are also commonly administered about 3 days after symptoms onset. They have proven to be somewhat effective in real life, although they still aren't being given to some patients who could potentially benefit.
If the cost is low enough and the side effects are mild enough it could work. People would take it before a test is positive so would end up taking it when they didn’t really need it.
It’s similar to the antivirals for flu where you need to take it early on so it becomes habit to test early and start early.
Home labs will help with this too. Where someone could take a test, get a prescription and pickup within a few hours.
If you take an antiviral like this, do you still develop a good immune response to reinfection?
I wonder because almost everyone who might end up needing this isn't vaccinated (based on hospitalization rates) so I hope that at the end they also end up having some immunity to catching it again at least.
In the moment of course it is better to use than not.
While this looks like potentially great news, Pfizer really needs a new Head of Making Up Drug Names. Paxlovid! Between this and ‘Comirnaty’ (the vaccine) it is clearly not their strong point.
trifluoroacetyl is a pretty stable substituent, as far as the fluorines go. trifluoromethyl as a substituent is a classic "medicinal chemist's favorite" and will not be labile. for example: efavirenz, fluoxetine, celecoxib all have a TFM. It's true fluorine chemistry is generally tricky, including some organofluorine chemistry, on the other hand in this case trifluoroacetic acid, trifluoroacetyl chloride etc are commercially available, affordable and common so no issue to make the trifluoroacetyl amide at some point.
anyway for me this is a really nice "medchem" friendly compound.. i like the little oddball bicyclo[3.1.0]hexane ringsystem in there (the part that looks like a pentagon fused with a triangle).
Exactly what I was thinking, especially for an entirely novel molecule. I wonder how novel the scaffold is. Whichever med chemist led this initiative is an artist -- amazing job.
I hope this proves to be real going forward. The vaccination route seems to be hitting a deadend as a way to end the pandemic. The pill will have to be cheap and available over the counter, it makes no sense not to subsidize this.
> compared to 41 hospitalizations and 10 deaths in the placebo cohort
This makes me weirdly sad. Can you imagine entering the trial for a long sought drug against a deadly disease that turn out to be working, and end up in the control group? I know that there's more to it (it's necessary, they knew, it could have not worked, plainly be nocive, etc.) but it's like being unlucky twice in a row and die out of that while having received the real thing would have saved you
This is Pfizer’s antiviral drug. Merck’s drug might be effective as well, but if seems like to be also a drug with many side affects interfering with your genome.
Getting vaccinated looks like a better option to me. Anyone know if the Pfizer one works similarly?
Note that to make the overall risk of adverse effects from covid19 lower, any treatment that is taken after the onset of symptoms must be much more effective at preventing adverse effects in symptomatic patients compared to a vaccine. This is because the vaccine greatly reduces the probabilty of symptomatic infections, while the other treatments do not.
To mention it, not necessarily directed at you. Larger test groups are required when trying to distinguish between less effective treatments.
If rabies has a 99% death rate and you try your rabies treatment on 10 people, 9 of whom live, that's much stronger evidence than a situation where 50% of people died without treatment versus 48% with treatment (sample size 100). To be confident it's not just random chance, you'll need a really large sample size for the 2nd situation.
This is a randomized clinical trial; participants are recruited into the study using methods that eliminate the biases associated with self-selected participation, like internet or TV polls. You can get statistically valid results from small samples, that apply to very broad populations, using this methodology.
[+] [-] pezzana|4 years ago|reply
One noteworthy feature is the newness of this drug:
> PF-07321332 was developed from scratch during the current pandemic. It’s a reversible covalent inhibitor that reacts with one of the main protease’s cysteine residues. Owen [director of medicinal chemistry at Pfizer] also discussed the chemistry involved in scaling up the compound. The first 7 mg of the compound were synthesized in late July 2020. Encouraged by the early biological data, the Pfizer team aimed to scale up the synthesis. By late October, they’d made 100 g of the compound. Just two weeks later, the chemists had scaled up the synthesis to more than 1 kg. Owen said 210 researchers had worked on the project.
https://cen.acs.org/acs-news/acs-meeting-news/Pfizer-unveils...
Less than two years from lab to clinic is highly unusual. If approved, I believe this would be the fastest lab-to-approval for a small molecule drug in the history of the FDA.
[+] [-] HWR_14|4 years ago|reply
I assume like most other COVID vaccines/treatments, the timeline is shrunk by going straight to more expensive phases of the trial instead of having preliminary ones of escalating cost and confidence. Or at least prepping for them.
For instance, all the vaccines started setting up commercial production around the same time they started trials, because it's not worth the months delay of setting up a production line to determine if it worked first.
[+] [-] osrec|4 years ago|reply
Wars and pandemics seem to be the testbeds for medicine, where people are desperate enough to try anything, and legislation is relaxed accordingly. The biotech companies know this all too well, and take advantage when the opportunity arises.
[+] [-] UncleOxidant|4 years ago|reply
[+] [-] ricardobayes|4 years ago|reply
[+] [-] snarf21|4 years ago|reply
[+] [-] catlikesshrimp|4 years ago|reply
"reversible covalent"
A chemical covalent bond. Maybe it means something else in this article?
[+] [-] deanCommie|4 years ago|reply
[deleted]
[+] [-] shusaku|4 years ago|reply
[+] [-] orra|4 years ago|reply
This drug is fantastically effective at preventing hospitalisation and death, if administered within three days of symptom onset.
That gives quite a long time! But we still need to make it easy to take. Do pharmacies give it out? ER rooms? We don't want to wait until people are hospitalised; we are trying to avoid that.
So when you test positive, does the government send you out a pill with the "sorry, you have to isolate" SMS?
[+] [-] fredliu|4 years ago|reply
This is the line I was looking for. Not that I know how protease inhibitor works, but looks more like a traditional anti-viral approach v.s. the potentially DNA altering molnupiravir.
[+] [-] tzs|4 years ago|reply
I wonder how well it will do on people who are farther along in their COVID infection?
There are a lot of people who don't get vaccinated, don't take precautions to avoid COVID, dismiss their early symptoms either because they believe COVID isn't worse than a typical cold or flu or because they think that is probably what they have, just treat it at home with vitamins and ivermectin if they do anything at all about it, and don't end up going to a doctor or hospital until they are having so much trouble breathing they have to go to the emergency room.
[+] [-] jaywalk|4 years ago|reply
[+] [-] grey413|4 years ago|reply
[+] [-] swader999|4 years ago|reply
[+] [-] TacticalCoder|4 years ago|reply
When can life go back to normal?
[+] [-] phh|4 years ago|reply
> There were six hospitalizations and no deaths among the 607 patients who received Paxlovid within five days of symptom onset, compared to 41 hospitalizations and 10 deaths in the placebo cohort.
> Like Merck, Pfizer excluded people vaccinated against COVID-19 from its late-phase study.
No pricing information. I'm worried that "3 days after symptoms onset" is too short to be usable in real-life, but I could be wrong.
[+] [-] exogenousdata|4 years ago|reply
"Rates were similar for patients treated within five days of symptoms - 1% of the treatment group was hospitalized, compared with 6.7% for the placebo group, which included 10 deaths."
[0] - https://finance.yahoo.com/news/pfizer-says-antiviral-pill-cu...
[+] [-] adventured|4 years ago|reply
"The U.S. government has been in negotiations with Pfizer for enough pills for 1.7 million courses of treatment, with an additional option for 3.3 million, according to a senior administration official. That is about the same quantity that the United States has ordered from Merck. The government expects to pay about $700 per treatment course for both drugs, the official said."
https://www.nytimes.com/2021/11/05/health/pfizer-covid-pill....
[+] [-] nradov|4 years ago|reply
[+] [-] prepend|4 years ago|reply
It’s similar to the antivirals for flu where you need to take it early on so it becomes habit to test early and start early.
Home labs will help with this too. Where someone could take a test, get a prescription and pickup within a few hours.
[+] [-] ganzuul|4 years ago|reply
Medical ethics are confusing. Maybe this field needs more oversight. Especially on the corporate level.
[+] [-] loceng|4 years ago|reply
[+] [-] neltnerb|4 years ago|reply
I wonder because almost everyone who might end up needing this isn't vaccinated (based on hospitalization rates) so I hope that at the end they also end up having some immunity to catching it again at least.
In the moment of course it is better to use than not.
[+] [-] rsynnott|4 years ago|reply
[+] [-] dopa42365|4 years ago|reply
There goes the "company A has better names than company B" theory?
[+] [-] RicoElectrico|4 years ago|reply
https://www.nytimes.com/2020/02/11/style/amazon-trademark-co...
Bonus: search for OOTDTY and you'll find all sorts of unrelated items.
[+] [-] oblio|4 years ago|reply
[+] [-] dekhn|4 years ago|reply
Obligatory classic: https://www.science.org/content/blog-post/things-i-won-t-wor...
[+] [-] gpcr1949|4 years ago|reply
[+] [-] comicjk|4 years ago|reply
[+] [-] whymauri|4 years ago|reply
[+] [-] cblconfederate|4 years ago|reply
[+] [-] jdlyga|4 years ago|reply
[+] [-] gonational|4 years ago|reply
[deleted]
[+] [-] charles_f|4 years ago|reply
This makes me weirdly sad. Can you imagine entering the trial for a long sought drug against a deadly disease that turn out to be working, and end up in the control group? I know that there's more to it (it's necessary, they knew, it could have not worked, plainly be nocive, etc.) but it's like being unlucky twice in a row and die out of that while having received the real thing would have saved you
[+] [-] ImaCake|4 years ago|reply
https://www.pfizer.com/news/press-release/press-release-deta...
[+] [-] hungryforcodes|4 years ago|reply
[+] [-] shoto_io|4 years ago|reply
Getting vaccinated looks like a better option to me. Anyone know if the Pfizer one works similarly?
https://www.forbes.com/sites/williamhaseltine/2021/11/02/har...
[+] [-] blackbear_|4 years ago|reply
[+] [-] charbull|4 years ago|reply
[+] [-] roywiggins|4 years ago|reply
https://www.pfizer.com/news/press-release/press-release-deta...
[+] [-] DavidPeiffer|4 years ago|reply
If rabies has a 99% death rate and you try your rabies treatment on 10 people, 9 of whom live, that's much stronger evidence than a situation where 50% of people died without treatment versus 48% with treatment (sample size 100). To be confident it's not just random chance, you'll need a really large sample size for the 2nd situation.
[+] [-] tpxl|4 years ago|reply
[+] [-] spywaregorilla|4 years ago|reply
[+] [-] nonfamous|4 years ago|reply
[+] [-] dragontamer|4 years ago|reply
[+] [-] unknown|4 years ago|reply
[deleted]
[+] [-] anonuser123456|4 years ago|reply
[+] [-] Someone1234|4 years ago|reply
https://en.wikipedia.org/wiki/Molnupiravir#Mechanism_of_acti...