> 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.
Also one factor slowing some studies has been the need to wait for test cases: you can't infect people with, say, Ebola so you need to wait for enough people in your study cohort to contract it naturally to get enough data to say whether a vaccine candidate is having an impact. During a pandemic, it's sadly easy to hit a statistically-significant number of infections.
And that was due to the wisdom of operation warpspeed. Trump is under credited for this (whether his idea or not, he could claim it as such). What’s shocking to me is that he hasn’t been more pro-vax given we have the vaccines we do because of his administration.
The Latest article in BMJ about the failures in scientific integrity in the pfizer trials are a likely consequence of your last paragraph I would guess.
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?
Aren't we? I thought that until SARS the scientific consensus was that coronaviruses are not interesting. And SARS died out too quickly to achieve much. But I might have not paid enough attention.
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.
> 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.
According to the Pfizer press release [0] Paxlovid uses Ritonavir [1], which is a known HIV antiviral, originally patented in 1989.
At the start of the covid pandemic, chinese scientists even tried Kaletra, a generic that combines Ritonavir with another HIV antiviral, and found it to not improve outcomes [2], but this might have been due to them not giving the drug early enough in the infection, but only to hospitalized patients, while Pfizer gave it to non-hospitalized patients with a risk of later hospitalization.
Yeah, as parent mentioned in another reply below, ritonavir is an antiviral, but has no effect on SARS-CoV-2 (https://pubmed.ncbi.nlm.nih.gov/34048671/). Ritonavir is just used to inhibit CYP and therefore reducing clearance of the drug.
> PF-07321332 is designed to block the activity of [a specific] enzyme that the coronavirus needs to replicate. Co-administration with a low dose of ritonavir helps slow [the breakdown] of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.
It's a two-part drug. PF-07321332 is the new and shiny thing that impairs a crucial enzyme for the virus, while the pre-existing drug ritonavir lets PF-07321332 last longer, making it more clinically useful.
They can copyright it and make tons of money off of it is what it means. All of the other things that already work can't make them insane profits so, bought and paid for the news that you are fed tells you this is one of few valid ways to fight a virus you can dodge by staying in the sun for an hour each day and exercising your body.
If unvaccinated people all died or went to the hospital it would be impressive, the title is misleading or lying about it’s effectiveness. The null hypothesis would probably neutralize it’s effectiveness. They don’t use infection prevention which would be much higher for unvaccinated because in reality it’s probably not very effective against COVID. The control we also don’t know any statistics about.
This is a placebo-controlled trial. The statistical comparison shown (85% fewer hospitalizations & deaths in the treatment group) already takes into account the non-hospitalized cases in the control group.
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?
I highly recommend Derek Lowe's post on it for some of the details. It links to the press release which contains this information showing it was very effective still starting at 5 days from symptoms onset:
> Similar reductions in COVID-19-related hospitalization or death were observed in patients treated within five days of symptom onset; 1.0% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (6/607 hospitalized, with no deaths), compared to 6.7% of patients who received a placebo (41/612 hospitalized with 10 subsequent deaths), with high statistical significance (p<0.0001). In the overall study population through Day 28, no deaths were reported in patients who received PAXLOVID™ as compared to 10 (1.6%) deaths in patients who received placebo.
Those extra two days (three versus five) could make a huge difference.
Who is the market for this? The assumption is that you give it ASAP and people want to take it. If people aren’t interested in vaccinations they may not want it either, and the vaccines are already very effective at preventing these issues.
I think skepticism of vaccines largely doesn't transfer to the broader medical field. The ineffective fad treatments (ivermectin and hydroxychloroquine) are still medicine, but are still "popular" with vaccine skeptics. It's not rational, but I think vaccine skepticism is largely not rational to begin with.
I'd say that this will appeal to people who are covid vaccine skeptical. If you're skeptical of the mRNA vaccines, you'd probably be in favor of this treatment than the vaccines.
And unfortunately the window for this closes before a skeptic will get desperate. Once people go on a vent they appear to become open minded to other treatment options.
> 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.
In brief, coronaviruses make all their proteins as one long chain and then cut it up into the appropriate pieces to form the proteins (spike etc). 3CL protease is the cutting machine and Paxlovid inhibits that.
It's interesting to learn about. Other molecules are also found to inhibit replication of 3CL protease in SARS cov-2 [1].
The UK scientific advisory group SAGE published a few months ago that combination therapy might be useful to avoid 'antiviral resistant' strains of SARS cov-2 evolving. Perhaps these 3cl protease inhibitors may be used in combination.
> [...] 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.
Because theres no reason to believe it does. Firstly the study that Ivermectin-for-covid is based on in vitro(cell-in-petri-dish) studies of rhesus monkey liver cells[1]. Additionally. Rhesus monkeys have differing bodies sizes and in order to get an equivalent dose in humans would require overdosing on ivermectin, which can and has lead to death. Ivermectin targets the host nuclear transport importin α/β1 heterodimer in host tissue, exerting effects directly on cells of the human body.[2]
On top of this you refer to 'long covid' which has nothing to do with the covid virus itself. Long covid is the syndrome after a person gets over a covid infection. They're not entirely sure what causes it, but damage to internal organs and the venous system have been observed[3]. At this point there is no active viral infection in your system, inhibiting viral replication is basically irrelevant. There is absolutely zero reason, even according to the logic of ivermectin-for-covid, that ivermectin would treat that damage.
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%.
Old normal is gone and will never come back - instead we are building a new normal, but it will take at least another year or two to solidify. It probably will be similar to what we had before. It's kind of like after 9/11 - we wanted things back to normal, too, but that old normal never returned.
It's impossible to plan anything further than 2 weeks ahead with a relative certainty that things will go through. How is that 99% normal? The uncertainties around things considered "normal" is extremely high. Wearing a mask is not normal, yet still very common (and mandated again as of today in The Netherlands).
Going through extensive testing and requiring proof of vaccinations for a thing as simple as going to the zoo is also not 99% normal. I have two trips abroad planned in the next 3 months, yet chances are high that I won't go to either due to external circumstances.
People with potentially life threatening health issues such as brain tumors are seeing their treatments postponed. Excess deaths are still very high in many countries, even with high vaccination rates.
Have you tried travelling abroad? It’s still much more complicated than it was, you have to check both countries requirements, spend money on tests, fill additional forms
I feel sorry for those in the US. You have made a miserable new normal for yourselves (and, as you say, despite everyone dutifully wearing masks and getting vaccinated, and now having the option of an effective treatment).
> 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.
The monoclonal therapies are also administered by IV in a clinical setting, whereas this can be taken at home and could probably even be delivered. It should be even easier to make it within the three-day window with this treatment.
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.
A useful comparison. I have never taken Tamiflu because I know I’d need to haul my weak, shivering, flu-infected self through public to see a doctor to get the Rx, go to the pharmacy… all for the personally-uncertain benefit of Tamiflu.
Nowadays, this should be easier with so many virtual appointment options and delivery services. It should be, but is it?
There should be an app that does all of it for you.
1. Scan your insurance card.
2. You get notified when a doctor is ready for your virtual visit.
3. If appropriate you get the Rx written.
4. That day, some delivery service will bring you the Rx. 5. Maybe a testing service stops by as well.
Insurance companies should want to participate if it decreases Flu or Covid hospitalization for a reasonable cost.
Anyone want to make this happen? My fall classes are nearly all finished.
Edit: Pharmaceutical companies may wish to partner as well. Lots of avenues for this kind of service to find revenue.
> 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.
Are you actually able to get tests? I've brought my kid into urgent care and they won't test for flu, so it doesn't matter that there's a drug available, because they won't test.
Patients enrolling in a clinical trial know they may get the placebo control. It wouldnt be more ethical to give it to all patients as in the case the medication does have a side effects you are only guaranteeing everyone gets hurt.
As House put it--
>Just to shortcut this discussion.. People should not be testing drugs because they're desperate. But, people won't test drugs unless they're desperate. We need drugs to save children and puppies, ergo we need desperate people, ergo welfare kills sick children.
It's almost as if we could just let people make and live by their own medical decisions. We've got one case in recent history of an argument about "you're making decisions that affect me", and it turns out that this entire argument is bunk because the "vaccines" do not prevent the spread. So it's purely a personal decision about your own health.
And pertaining to clinical trials, if I want to sign up for a clinical trial for a what might be a placebo for a great white shark bite in the midriff, that's my own choice. If I die because of this choice, that's my fault.
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.
You should -- protease inhibitors inhibit replication, but existing viruses should be more than enough to generate a durable response in most individuals.
Anyone taking this should still develop an immune memory to covid. As I recall, even people who took monoclonal antibodies (that is to say, an antiviral where they literally inject functional anti-covid antibodies into your veins) developed some degree of natural immunity.
No. There's a big difference between drugs and vaccines. The drug doesn't generally illicit an immune response, but the vaccine is designed to do exactly that.
Readit News
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.
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.
I frequently hear/read complaints of "that's outrageous [that this medicine costs $X]!"
Well, maybe it is; maybe it isn't, but if you make sure it costs $X/100, I can be pretty sure you'll get less drug R&D.
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.
Here's a scholarly article on the evolution of synthesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340098/
"reversible covalent"
A chemical covalent bond. Maybe it means something else in this article?
Dead Comment
According to the Pfizer press release [0] Paxlovid uses Ritonavir [1], which is a known HIV antiviral, originally patented in 1989.
At the start of the covid pandemic, chinese scientists even tried Kaletra, a generic that combines Ritonavir with another HIV antiviral, and found it to not improve outcomes [2], but this might have been due to them not giving the drug early enough in the infection, but only to hospitalized patients, while Pfizer gave it to non-hospitalized patients with a risk of later hospitalization.
[0]: https://investors.pfizer.com/investor-news/press-release-det...
[1]: https://en.wikipedia.org/wiki/Ritonavir
[2]: https://doi.org/10.1056/NEJMoa2001282
Both are protease inhibitors.
On the other side: what are you folks not curing, with your magic powers, just because you know you won't be able to make a buck from it...?
Can someone please ELI5 what makes this unique from others?
> PF-07321332 is designed to block the activity of [a specific] enzyme that the coronavirus needs to replicate. Co-administration with a low dose of ritonavir helps slow [the breakdown] of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.
It's a two-part drug. PF-07321332 is the new and shiny thing that impairs a crucial enzyme for the virus, while the pre-existing drug ritonavir lets PF-07321332 last longer, making it more clinically useful.
That's my take on it.
Deleted Comment
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?
> Similar reductions in COVID-19-related hospitalization or death were observed in patients treated within five days of symptom onset; 1.0% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (6/607 hospitalized, with no deaths), compared to 6.7% of patients who received a placebo (41/612 hospitalized with 10 subsequent deaths), with high statistical significance (p<0.0001). In the overall study population through Day 28, no deaths were reported in patients who received PAXLOVID™ as compared to 10 (1.6%) deaths in patients who received placebo.
Those extra two days (three versus five) could make a huge difference.
However, that means something like this is still very useful because of that 5–8%, especially for the elderly and the immunosuppressed, etc.
(I share your skepticism anti vaxxers would be interested in an effective treatment.)
Anti-Vaxx people seem to absolutely love non-vax treatments.
I don't know if the rationalization is sound, but I'm not sure it's really that.
The anti-vaxx stigma pre-COVID I think has had it's toll.
The notion of 'government pushing you to take something' as well.
Whereas, 'you get sick, you take a pill' is an easy concept.
My fear is that a lot of people won't bother with a vax if they think there's a 'cure'.
Wealthy people.
If this drug is safe and can be made sufficiently cheap, it could be a great treatment for most kinds of common cold.
Why suffer for weeks with cold symptoms if you can simply spray this up your nose and feel better?
It could (potentially) be used similarly to Tamiflu.
The majority of the common cold cases is caused by rhinoviruses. But yes, like 20% (ballpark) are caused by coronaviruses.
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.
The UK scientific advisory group SAGE published a few months ago that combination therapy might be useful to avoid 'antiviral resistant' strains of SARS cov-2 evolving. Perhaps these 3cl protease inhibitors may be used in combination.
[1] https://www.nature.com/articles/s42003-020-01577-x
When I first read about molnupiravir's mode of action, my gut reaction was "cancer in a pill, no thanks"
https://www.bbc.com/news/health-59163899
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.
On top of this you refer to 'long covid' which has nothing to do with the covid virus itself. Long covid is the syndrome after a person gets over a covid infection. They're not entirely sure what causes it, but damage to internal organs and the venous system have been observed[3]. At this point there is no active viral infection in your system, inhibiting viral replication is basically irrelevant. There is absolutely zero reason, even according to the logic of ivermectin-for-covid, that ivermectin would treat that damage.
1- https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7129059/
2- http://dicyt.uto.edu.bo/observatorio/wp-content/uploads/2020...
3- https://www.mayoclinic.org/diseases-conditions/coronavirus/i...
When can life go back to normal?
I gotta wear a mask indoors to some degree, so I guess we're at like 99% normal.
Going through extensive testing and requiring proof of vaccinations for a thing as simple as going to the zoo is also not 99% normal. I have two trips abroad planned in the next 3 months, yet chances are high that I won't go to either due to external circumstances.
People with potentially life threatening health issues such as brain tumors are seeing their treatments postponed. Excess deaths are still very high in many countries, even with high vaccination rates.
Things are 1% normal, not 99% normal.
Dead Comment
> 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.
"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...
"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....
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.
Nowadays, this should be easier with so many virtual appointment options and delivery services. It should be, but is it?
There should be an app that does all of it for you. 1. Scan your insurance card. 2. You get notified when a doctor is ready for your virtual visit. 3. If appropriate you get the Rx written. 4. That day, some delivery service will bring you the Rx. 5. Maybe a testing service stops by as well.
Insurance companies should want to participate if it decreases Flu or Covid hospitalization for a reasonable cost.
Anyone want to make this happen? My fall classes are nearly all finished.
Edit: Pharmaceutical companies may wish to partner as well. Lots of avenues for this kind of service to find revenue.
Are you actually able to get tests? I've brought my kid into urgent care and they won't test for flu, so it doesn't matter that there's a drug available, because they won't test.
Medical ethics are confusing. Maybe this field needs more oversight. Especially on the corporate level.
As House put it--
>Just to shortcut this discussion.. People should not be testing drugs because they're desperate. But, people won't test drugs unless they're desperate. We need drugs to save children and puppies, ergo we need desperate people, ergo welfare kills sick children.
And pertaining to clinical trials, if I want to sign up for a clinical trial for a what might be a placebo for a great white shark bite in the midriff, that's my own choice. If I die because of this choice, that's my fault.
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.