Pfizer's oral Covid-19 antiviral cuts hospitalization, death by 85%
fiercebiotech.com
fiercebiotech.com
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?
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...
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.
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.
When I first read about molnupiravir's mode of action, my gut reaction was "cancer in a pill, no thanks"
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.
> 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.
There goes the "company A has better names than company B" theory?
https://www.nytimes.com/2020/02/11/style/amazon-trademark-co...
Bonus: search for OOTDTY and you'll find all sorts of unrelated items.
Obligatory classic: https://www.science.org/content/blog-post/things-i-won-t-wor...
The molecule I worked with in grad school, 5FU, contains a fluorine, it's a very effective anticancer drug which ultimately came from fluroacetyl which is highly toxic. In fact most of the molecules I worked with in grad school that had fluorine were toxic specifically because of fluorine. Not because they were unstable bonds, but because F is very effective in nucleoside analogs. So you can imagine why I am a bit wary of F and just in general don't think of F as being particularly compatible with life.
When I wrote my comment I knew somebody was going to come along and think I was implying CF3 was explosive.
There are other methods, graph substructure similarity is common. More to your actual question, it was derived from a previous attempt (https://en.wikipedia.org/wiki/Lufotrelvir) which has a very similar structure, and I wasn't able to find prior information by doing a little literature searching to see if there are other similar compounds.
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
It is difficult to overstate just how much thought and argument has gone into clinical trial design in the last half century. It may seem detached and unfeeling, but basically every step is carefully considered compassion, ethics, and a desire for unambiguous causal truth of drug effectiveness.
It would be unethical if this placebo was given in place of a known working alternative treatment.
From what little I know of cancer treatment, that isn't how studies are generally run. When you're part of a trial, you're either given the experimental treatment, or the "standard of care", not a placebo.
So for cancer at least, you're either getting a novel treatment, or standard chemo.
https://www.pfizer.com/news/press-release/press-release-deta...
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...
> As a protease inhibitor, Paxlovid is free from the theoretical DNA-alteration risk tied to the mechanism of action of Merck’s molnupiravir.
https://www.pfizer.com/news/press-release/press-release-deta...
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.
https://en.wikipedia.org/wiki/Molnupiravir#Mechanism_of_acti...
Here's something to read on this (note the three criteria for a TL;DR): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024796/
Let’s say you have a randomized clinical trial with a control arm (placebo) and test arm (drug). If the vast majority of the test cases do significantly better (like 90% of the test cases), at some point it becomes unethical to continue. Why? Because you already have the evidence that the treatment works, so having the control arm becomes meaningless. You already know that the drug works, so there is no longer a point to collect more data AND you know that the control arm isn’t going to help half the patients. So, you stop the trial early so that you can get started with the approval process so that the drug can get to all patients faster.
I am curious though: do they ever continue with the trial, with the patients on the actual drug? Might that be useful for monitoring rare-ish side effects, even if the drug is highly effective?
I can't imagine wanting to keep people in the control group when the experimental treatment is so dramatically effective.
> 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.
Intuitively you would expect that the treatment also lowers the rate of spread.
I know it shouldn't be shocking but it just hit me that being in the control group here is very close to getting a death sentence. I couldn't find it in the article OP shared or the press release, but did the control group get any other treatment?
When trials are extremely effective, they are sometimes halted and rolled out early. That sounds like exactly what Pfizer is attempting to do here. The company thinks that they have a clear-enough signal to be worth going to the press and preparing FDA for the EUA.
Pfizer will have made an embarrassing error if the final trial-results turn out to differ with their claims, but if they don't, then Pfizer has given a several-week head start to rolling the drug out to all patients.
How does this work? You sign up for the program when you're sick and you might get meds that help you? That would really suck if a loved one was in the program and died because they happened to get the placebo.
Trials like this are performed in desperate situations, and you only ever hear about the success stories. Most such trials probably result in no measurable benefit, and run the risk of an even worse outcome than the placebo.
When to Stop a Clinical Trial Early for Benefit: Lessons Learned and Future Approaches:
https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.111...
If it does conclusively show effectiveness quite quickly, often they will cut the phase of the trial short and put everybody on the actual drug I think.
Real science does have a price.
Part of that price is honesty on what's truly known, indicated, suggested, hypothesized, or unknown. What is "blathering" to you is intellectual integrity to others.
I'm not following. Are you under the impression that the COVID-19 vaccine trials weren't similarly double blinded?
But what do I know. We have survived for 2m years without this. I'm sure we can be fine without it.
I just feel people are too quick to accept a for-profit mega-corporation as the defacto source of all things covid cure.
https://www.nature.com/articles/d41586-021-02689-y
https://www.businessinsider.com/delta-variant-made-herd-immu...
https://theexpose.uk/wp-content/uploads/2021/09/Pierpont-Why...
https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7031e2-H.pdf
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3897733
So, how could the outcome at the societal level be worse?
Serious disease? - The same/similar (though studies have shown this declines within 6 months). Op is correct.
Catching/Transmission? - The current vaccines are systemic and not mucosal, so they don't stop it infecting the upper respiratory tract. - A recent study shows fully-vaccinated households can spread at similar rates to unvaccinated households [1]
[1] https://www.thelancet.com/journals/laninf/article/PIIS1473-3...
Next door in Kansas City Missouri I stopped at a gas station and an employee was shouting at a woman to put on a mask, then was yelling at the same woman to leave because she refused to comply. I’m glad she didn’t see me because I literally didn’t think to bring a mask with me and needed to run to the restroom.
I guess 5 miles difference magically makes COVID much more contagious.
No, 5 miles means you have a different government with a different policy response. (The difference itself doesn't justify either side.)
That's just inherent in the existence of political borders.
In my nearest town (in the UK) there are two supermarkets. In the budget one (Aldi) nobody wears a mask, in the upmarket one (Waitrose) everybody does.
Well, based on case and death counts between the two states, this is true. Kansas has significantly higher case and death rates than Missouri.
Of all the problems in your story, the employee shouting is the least 'wrong'. You've got a woman who won't wear a mask, yourself who sneaked in without a mask, and that's just in that moment of time, but somehow the employee who has to deal with that behavior all day every day is the bad person because they lost their cool.
It's one of those 'everyone sucks here' stories.
Thus, COVID precautions are necessary to reduce the rate of infection to levels that do not overwhelm the healthcare system.
And all those areas that have "returned to normal" are sending their COVID patients to regions that are still masking because they've exhausted their local ICU capacity.
This has been my experience as well. My state is pretty strict overall, but my area of my state is not.
Our hospital has been operating at capacity for 6 months or so, but nobody is talking about it. Because we can just ship to where they have stricter COVID control measures.
We're causing problems for other people because we can't be bothered to be part of society.
It's a joke all around. The entire world. Nihilism is almost impossible to escape right now.
I live in South Carolina & their Department of health website has great data. As of today, there are currently 551 Covid patients hospitalized statewide. 1280 ICU beds are occupied for a 76% utilization rate. Of those beds, 150 are Covid patients. That means 88% of folks in ICU are non-covid related.
https://scdhec.gov/covid19/covid-19-data/acute-hospital-bed-...
This data doesn’t exactly corroborate what your saying. The way you tell it, the ICUs are still overflowing with Covid, and they just aren’t. Not in SC at least. And we’re not exactly known for our stringent Covid restrictions.
https://www.npr.org/sections/health-shots/2020/12/09/9443799...
2021 is already "mostly normal", for me. I hope sometime in 2022 we will be back to "100% normal", but I'm not confident.
This tracks with Dr. Vanden Bossche's assessment [2] from March of this year that mass vaccination with prophylactic vaccines will actually prolong and worsen the pandemic due to shedding of infectious variants.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481107/ [2] https://www.geertvandenbossche.org/
https://www.theatlantic.com/health/archive/2021/11/what-amer...
been going to packed bars, house parties, restaurants, music festivals, concerts all with no masks
Children are now eligible for a vaccine. It'll take a few weeks for this to trickle through the population, but we're pretty close to the point where everyone who wants a vaccination will have one.
At that point, I expect restrictions to swiftly ease up. In Massachusetts, things are already mostly back to normal. With children protected, there's definitely a light at the end of the tunnel.
When hospitalization and community transmission is "low" based on the CDC definition of low, and when 80% of the total population is vaccinated or eight weeks from yesterday, whichever comes first. They also publish a dashboard with the information so anyone can see how we are progressing: https://covid19.sccgov.org/dashboards
We were at almost 80% vax rate for 12+ already and hospitalizations are currently low and have been for a while, however community transmission remains high.
So at least in our county they have specific standards as to when the restrictions leave. Other than a mask mandate, there are no other restrictions anymore, except for school kids.
Some businesses require their employees to all be vaccinated. Governor appears to be fighting against that, would not be surprised if those same businesses just don't hire unvaccinated people going forward and the situation is resolved via attrition.
Now we're JUST starting to talk about relaxing again. If this is any barometer, not to mention the rate of which we are seeing pills/vaccines/what have you, I imagine 2022. Outside of work, things are largely "normal".
For what it's worth - I live in a dense Northern state not seeing a surge of cases.
Some places will do that earlier than others, and quite a few practically already have.
> This will go on forever without exit criteria.
It will go on without an exit decision, but the exit criteria that have been issued have frequently been adjusted anyway, because understanding of how current metrics project the future have evolved. Which is probably why their are fewer announced criteria and more reliance on periodic, holistic review.
You wouldn't believe it, but no one wanted to make a good hip broach to fix grandma. It took athlete injury repair R&D money to make that happen.
Then do we understand the risk profile of this thing? That sounds like the sort of innovation that people would want to be at the back of the queue for.
Side effects don't have to happen in the next 6 months.
If this is a molecule with a short half-life that is broken down and expelled by the body, it isn't going to have random side effects that show up months in the future.
That being said, one of the reasons that protease inhibitors are considered the way to go is that “no human proteases with a similar cleavage specificity are known, such inhibitors are unlikely to be toxic.” [1]
"We can do proper code review, unit testing, integration testing and full test cycle later on, when the pressure fades away."
We engineers all understand the risk of pushing untested code to production, but when it comes to medicine and other fields, we forget everything and rush it out. We basically act based on fear and hope.
If you're willing to go that route, the same could be said for COVID itself.
“The only way they are alike is that they are both pills,” Petri said.
Dr. Kevin J. Downes, assistant professor of pediatrics at the Perelman School of Medicine of the University of Pennsylvania, agreed, “They are dramatically different molecules. The drugs are different in their structure and their molecular size.”
[...]
Ivermectin binds to glutamate-gated chloride channels and is used to treat parasite infections, said Joseph Glajch, a consultant in pharmaceutical and analytical chemistry.
“These two are so far apart,” he said. “If you look at how they interact with the body..., they don’t even go to the same pathways or receptors.”'
In related news, Merck's molnupiravir has been approved in the UK as well.
And vaccinated people can get infected and suffer from serious symptoms. If the entire world were vaccinated and 0.1% of people would have serious symptoms, that would still be more than 8 million people looking for a cure.
also if this can help impact the rate of hospitalization and death among unvaccinated than it also alleviates the need for actual vaccinations to do the lift of ending the overall pandemic.
Why just assume this and post it as if your opinion on what it COULD be without even reading a little bit about it has any value?
Read it carefully. Pfizer falsifies clinical data and covers up significant adverse effects. FDA knows about all of that and covers their asses. Whatever comes from Pfizer will be authorized without any questions being asked. It's not even a legislation, but a straight up internal arrangements between FDA and Pfizer executives.
Whatever you see in media about Pfizer is a complete crap.
I also want to remind you that Pfizer is responsible for the largest health care fraud in history. They had to pay $2.3B fine in 2009.
https://www.cbs17.com/news/north-carolina-news/fact-check-re...
> The Pfizer Phase III trial involved 44,000 people and 153 locations. From August 2020 through Sept. 17, 2020 — when she was fired — Jackson told CBS 17 that Ventavia accounted for at least 1,200 of those people and accounted for three sites.
The author of the BMJ piece is quoted as saying “people are going to use this to push a political position because that’s what they’re interested in”, so congrats on demonstrating that.
Found a recap via google @ https://www.jpands.org/hacienda/blevins1.html
Burzynski: Cancer Is Serious Business @ https://www.youtube.com/watch?v=F_7LZ8GLerI
I can't find that in the article you linked, can you cite the relevant parts of the text?
- Should we choose the moderna vaccine instead ?
- Should we avoid the oral vaccine, and opt for the injection instead ?
- Should we merely be skeptical and wait ?
https://ebm.bmj.com/content/early/2021/05/26/bmjebm-2021-111...
https://www.cochranelibrary.com/content?templateType=full&ur...
Fuck off with this fud.
> The rates of hospitalization or death in the Paxlovid and control arms were 1% and 6.7%, respectively, resulting in a risk reduction of 85%. Most people that get COVID don’t go to the hospital nor do they die. How much is from a null hypothesis; people who wouldn’t have complications anyway? It’s barely significant if you use 5% as the minimum, and it can still be noise. Vaccinated people are not going to have complications like this anyway. People care about not getting infected, this treatment is inferior to monoclonal antibodies and not barely significantly different from control.
> The rates of hospitalization or death in the Paxlovid and control arms were 1% and 6.7%, respectively, resulting in a risk reduction of 85%.
> Pfizer used data on patients who were treated within three days of symptom onset as the headline finding in its press release. In that subpopulation, the rates of hospitalization or death in the Paxlovid and control groups were 0.8% and 7%, respectively, resulting in a risk reduction of 89%. Merck’s 50% reduction was seen in patients who were randomized within five days of symptom onset.
Oh, a protease inhibitor you say? I was told those were horse dewormers by the media.
This whole thing is bullshit. With this much money at stake we were never going to learn the truth.
“The only way they are alike is that they are both pills,” Petri said.
Dr. Kevin J. Downes, assistant professor of pediatrics at the Perelman School of Medicine of the University of Pennsylvania, agreed, “They are dramatically different molecules. The drugs are different in their structure and their molecular size.”
[...]
Ivermectin binds to glutamate-gated chloride channels and is used to treat parasite infections, said Joseph Glajch, a consultant in pharmaceutical and analytical chemistry.
“These two are so far apart,” he said. “If you look at how they interact with the body..., they don’t even go to the same pathways or receptors.”'