Gilead should ditch remdesivir and focus on its simpler and safer ancestor
statnews.com
statnews.com
And as others have mentioned, the only data for the alternative molecule is animal data versus remdesivir which already has phase 3 data. Sure, the other drug might be better, but it might not work at all.
Ben Goldacre (a Senior Clinical Research Fellow at the Centre for Evidence Based Medicine in the Department of Primary Care in the University of Oxford{0}), wrote in his book Bad Pharma, about an instance where a specific subset of SSRIs were given to eight(?) year olds for clinical depression. What the GPs prescribing them didn't know, however, was that the suicide rate for those children would go up after prescription. The pharmaceutical company knew about this. It was a negative result, and was unpublished.
This is just a single example I've pulled from the book, and the book covers only a smidgen of the hundreds of thousands of cases of incompetence and malice perpetrated by pharmaceutical companies over the last 20 years. You can find more information about this by him here ( https://www.theguardian.com/commentisfree/2008/jan/26/badsci... ), here ( https://blog.ted.com/5-prescription-drugs-doctors-had-no-ide... ), and more information in general here ( https://www.bmj.com/open-data ), and here ( https://www.livescience.com/8365-dark-side-medical-research-... )
Pharmaceutical companies' only duty is to turn a profit to their shareholders. If they spend five or ten years developing a drug that they find has either no or negative use, then in the eyes of the shareholders, they have wasted that money. The duty of the company is to find a use for the drug regardless of whether it is useful or not, regardless of whether there is a more beneficial alternative.
{0} - I copied this line, sue me :)
This is a pretty good paper that covers the issue. It wasn't that straightforward to actually get reliable data and the author here is arguing that the pendulum swung too far - adolescents weren't get antidepressants because doctors were so scared of the boxed warning the FDA added.[1]
And there is likely a bit of 20/20 hindsight going on here. Clinical trial is never black and white. You can get “signals” in the data that aren’t real, especially if the trial wasn’t powered well enough.
If we pulled drugs from the market every time someone found a signal, we’d probably have 10% of the drugs we do now, and people would be denied any benefit.
Drug development is all about risk versus benefit, and yes, the FDA is willing to approve a drug with significant risks if the drug is treating a serious disease.
[1]https://www.psychiatrictimes.com/special-reports/relationshi...
Disclaimer: the book mentions the institute where I'm currently employed, although the views and opinions I'm expressing are my own.
This book discusses the supply line of generic drugs on US shelves today.
If ever there has been a business decision to illustrate the whole “putting profits over people” this is it. And sunk costs, too.
When GS-441524 was used to treat cats with feline infectious peritonitis, a progressive and usually fatal disease caused by a coronavirus, it displayed remarkable safety and therapeutic efficacy, with 96% of cats recovering after treatment.
This argument actually threw me for a loop. Now I'm concerned about all the other drugs that the cats didn't use first. It must be the one major missing protocol from our vastly successful drug regulation system. /s
There is not good correlation of side effects between different animals and failures in phase 1 studies often show that safety data in animals did not predict side effects in humans that became apparent in very small human populations.
So, widespread use in animals can actually harm humans by bubbling up side effects that are not relevant to humans.
Among some safety people, there is even a question of whether there are drugs shelved for animal side effects that would be 100% safe in humans. But if a drug killed half your rats, you cannot ethically start dosing humans with it.
And at any rate, if Gilead choses not to develop it, then someone else can try to license it if they want to gamble on it being a good product.
Which is a neverending scandal that should outrage everyone.
It is only an appeal to authority.
Sounds like a good reason never to take either.
So even if they can get it manufactured, it's is a short term boon and long term, questionable.
It's critical to find drugs that target other parts of the virus' life cycle to include in a combination therapy.
Source: conversation with Sean Whelan https://en.wikipedia.org/wiki/Sean_Whelan_(scientist)
That said, it makes plenty of sense why you would begin with your drug that has already passed clinical trials. I'm a bit disappointed that the article didn't emphasis this point. I'm certain the authors know about it, and even if they aren't out writing a hachet job, it can make this piece seem like one.
And yes, remdesivir is a beast to make, but I don't think supply is an issue at all. They just packaged up and distributed 150 kg of it.
That is exactly how the manhattan project ran: Thermal Diffusion, Gaseous Diffusion, Centrifuge and Calutron were all followed up, and it wound up that Thermal fed Calutron to increase yield but gaseous diffusion and centrifuges are what we use now. The point here is that they didn't penny-pinch "which one is better" they did them ALL
So if we are in operations research linear programming mode, it may be less efficacious in some ways but its simpler to make and more of the active principle is liberated into the body.
Would you rather have more drug to use on more people with more of it in the body, or a better drug but in shorter supply which needs a higher dose?
That would give a good chance of being actually upstream for most relevant purposes.
> In multiple studies testing remdesivir in coronavirus-infected mice or rhesus macaques, it was rapidly converted to GS-441524 in the bloodstream.
The active agent in the bloodstream from both drugs is GS-441524 triphosphate. The 3-step pro-drug GS-441524 releases more into the bloodstream than remdesivir.
remdesivir takes 5 steps to make. GS-441524 takes 3 steps. Upstream means closer to the source. Something which takes 3 steps is upstream of something which takes 5 steps, because it is closer to the source.
You have completely inverted the sense of the article. Remdesivir is downstream (5 not 3 steps) of GS-441524 and remdesivir releases less not more of the triphosphate.
If so, then in what way is remdesivir better?
At least assuming people get vaccinated.
"On 12 May 2020, Gilead announced that it had granted non-exclusive voluntary licenses to five generic drug companies to manufacture remdesivir for distribution to 127 countries. The agreements were structured so that the licensees can set their own prices and will not have to pay royalties to Gilead until the WHO declares an end to the COVID-19 emergency or another medicine or vaccine is approved for COVID-19, whichever comes first"
https://www.gilead.com/stories/articles/an-update-on-covid-1...
Even if they made zero profit it's a questionable move.
"until the WHO declares an end to the COVID-19 emergency or another medicine or vaccine is approved for COVID-19, whichever comes first" could easily be very soon, after which who knows what they'll demand.
If they put their patent on GS-441524 in the public domain, on the other hand, it'd be quite clear that they're not creating a situation where the second the WHO changes the status they won't suddenly demand price increases to whatever level they want or punishing royalties to keep producing the drug that the generics company already constructed a manufacturing line for.
Maybe an analogy is suitable here -- I see this as like Apple telling everyone that they won't demand royalties on rounded corners for six months. Would you tool up a manufacturing line to make rounded corners if given that proposition? Because setting up a chemical manufacturing line takes even longer than reconfiguring a machining operation.
Also, sure it was patented earlier than remdesivir, but patent term is 20 years - GS-441524 has 9 more years on patent. Plenty of exclusive value that Gilead can extract.
Remdesivir is a prodrug, meaning it must be metabolized (chemically processed) in the body to the active form. Think of it like this:
R-OPX -> R-OH -> R-OPPP
where OPPP is the triphosphate and X is the thing the body hacks off. R-OPPP is the active form of Remdesivir. Your body must perform the net reaction R-OPX -> R-OPPP before it can use the drug.
GS-441524 is R-OH in the above equation.
X is non-trivial to build and install, and it looks like it required a lot of work.
But as these things often happen, nature doesn't give e hoot about the medicinal chemist's net-o hypothesis (R-OPX is better) and does what it will do. It turns out the fancy targeting component PX isn't necessary for efficacy in animals. You get even better results using plain old R-OH.
Even better, R-OH is the starting material for R-OPX, so you save yourself some reactions to boot.
At this point a lesson pops up that gets forgotten time and again in drug discovery programs:
ALWAYS RUN THE CONTROL IN ANIMALS - RUN IT EARLY. NO EXCEPTIONS AND NO EXCUSES!
Also, there is enormous resistance to running the control, because of course it can't work - it's the control and doesn't conform to the neat-o hypothesis.
In this case, the control is R-OH. It was run, but not early enough it seems to prevent the R-OPX train from leaving the station. Once a team starts running with a compound it can be very difficult to pull them back.
Now, this is just speculation taking the article as gospel. It's almost impossible to know for sure what really happens inside drug companies because the trade secret/IP protection culture is so ingrained. Not only that, but I could be misinterpreting the facts presented in the article.
Of course, none of this addresses the main problem with Remdesivir: it can't be orally dosed. You need to get injected multiple times. And that's probably going to be in a clinic, and done by people wearing full PPE. An oral drug would allow you to buy pills and convalesce at home, conserving valuable hospital resources.
As an aside, you typically use a prodrug because you think it will lead to better drug properties than the parent compound. An interesting example is the case of Claritin/Clarinex. The former is the prodrug form of the latter. It turns out the latter is at least as good if not better than the prodrug. Another case of not running the control early, I suspect.
Some background: Remdesivir works by interfering with the cellular machinery that allows viruses to replicate inside a human host. It is a pro-drug, meaning it must be metabolized and undergo a sequence of five bioactivation steps before it becomes GS-441524 triphosphate, the active compound that impedes viral replication.
Remdesivir isn’t Gilead’s only antiviral nucleoside analogue. The company has also developed GS-441524, another pro-drug that, as its name suggests, the body also converts into GS-441524 triphosphate, but in just in three steps. GS-441524 is easier to synthesize than remdesivir, requiring three steps instead of the seven needed for remdesivir.
You've omitted the "antiviral nucleoside analogue" jargon but run off into the weeds relative to the comparisons of the number of bioactivation and synthesis steps.
That's why the new results (sadly without proper placebo) of lopinavir/ritonavir/ribavirin that came out are interesting (IIRC, they can be administered orally). The first studies (published in NEJM) flopped completely, likely because they were administered too late (as noted by the authors themselves).
The new study on Lancet tells that the tide can be turned if they're administered within 7 days of symptom onset. Unfortunately, the authors did not use a placebo arm, and compared the cocktail alone against cocktail + subcutaneous injection of interferon-beta. The latter seems better, but as I said before, we don't know if it's identical to "no administration".
The current trials in the USA and China of favipiravir (Avigan), which seemed to halve hospital stay in a small (80 patients) Chinese study suffer from the same problem, as they're compared to standard of care (which means loads of things). I don't know anything about the Phase III study started in Japan, though.
Rather, always run the trial in animals (and early). If you don't have both a control group and a experimental group, you don't have a trial.
This is really key. Sometimes you make a prodrug because the active drug isn't soluble enough or you can't crystalize it nicely or it unstable and degrades quickly.
The Claritin example is a good one. The prodrug requires metabolism into the active compound, but genetic variation can mean some people don't metabolize it well. There are also interactions with other drugs too. So they just changed to the active drug.
I am far from average in my consumption of medical literature--I read several papers every week and have some (limited) background in biophysics. Nonetheless, this debate is miles over my head. One would need to know a great deal about pharmacology to evaluate this article. There are lots of reasons to use one prodrug over another; likewise, there are a great deal of differences between animal models and humans.
See also this reddit comment:
http://reddit.com/r/chemistry/comments/fv8p4k/comment/fmhydy...
Edit: I see goatinaboat also posted the link (I searched for a bit of the url that was elided).
The paper in question is here (https://mbio.asm.org/content/9/2/e00221-18) and they're looking at table 1. First of all, the paper didn't set out to actually determine whether GS-441524 is better than GS-5734 (aka remdesivir). It mainly set out to show that remdesivir could work against coronaviruses in general (this was written back in 2018, so they were focusing on SARS and MERS only). Furthermore, all of these experiments were in vitro with a model betaCoV, murine hepatitis virus, so results shouldn't necessarily mean much for human populations. But down to the nitty-gritty:
In figure 1 of the paper, the authors do in vitro experiments to show that both GS-441524 and remdesivir reduce their model CoV viral titer. However, they show a major difference. Remdesivir has an EC50 (dose at which 50% of viral replication is inhibited) that is much lower than GS-441524. This is great because you don't need as much remdesivir to inhibit viral replication. One area where GS-441524 did beat remdesivir was cytotoxicity (CC50 = dose at which 50% of cells w/the drug is killed). You want as high a CC50 as possible. So that would mean that remdesivir is technically more toxic to cells; however, it's effective dose is so low that you wouldn't need to give a dose large enough to kill off any cells. You can use a handy metric known as the selective index (CC50/EC50) to measure the tradeoff. High selective index = high efficacy without killing off your own cells. In this case, remdesivir has a higher selective index compared to GS-441524.
Now onto what the article referred to. The authors made their in vitro studies slightly more relevant to humans by using human epithelial cells and this time actual SARS CoV and MERS CoV virus and measured EC50 and CC50 again for both GS-441524 and remdesivir. The authors report some +/- standard deviation ranges. From intro stat, I think one of the conclusions about looking at overlapping standard deviation bars is that no conclusion can be made about whether or not the differences are statistically significant or not! I encourage people to take a look at the table itself and make your own conclusions (https://mbio.asm.org/content/9/2/e00221-18#T1)
The rest of the paper focused on remdesivir and showed a number of things. It showed it was most effective early post infection (in vitro) and it highly inhibited viral replication when viral exonuclease was knocked out (indicating that remdesivir messes with the function of that). It also showed (via serial passage experiments...basically think about it as mini-artificial selection) that nucleoside analog drugs will tend to favor the selection for two RNA-dependent RNA polymerase mutant viruses that confer resistance to the nucleoside drugs! But they showed in the next figure that these mutant viruses have a reproductive disadvantage compared to their wild type CoV.
Now for my 2 cents: I think that remdesivir was favored primarily because it was being used for anti-viral treatment in Ebola virus trials...but it was falling out of favor for Ebola treatment because of other monoclonal antibody cocktail treatments that show better survival rates (ref PALM trial: https://www.nejm.org/doi/full/10.1056/NEJMoa1910993). Sooo I guess gilead had this drug lying around, and they had a good idea as to its mechanism of action...so why not apply it for Sars CoV2?
and Senegal https://youtu.be/iBma_0oAiMI
Making drugs is a ridiculous process. I had the pleasure of listening to a physical chemist describe every single step it took for his team at Abbott labs to take Lopinavir/ritonavir to market. It is incredible how difficult it is to go from novel molecule to phase IV. Every single thing he did he had to, by FDA guidelines, be written and documented appropriately. Everything is highly scrutinized. With medicine we need to be right and we need strong scrutiny, because when there isn't oversight shortcuts are made. That's just the federal guidelines, the chemistry behind drug production, and this is something I find interesting but strongly dislike the amount of math behind physical chemistry, is intimidating. Some of the questions that need to be answered are: Does this molecule affect any enzyme? Is this enzyme hypothesized to be in a disease process? What is the structure of this molecule? How is it made? How can we make more? How can we make more more efficiently? Does this drug work in people? What's the dose that needs to be given to have an effect? What is the dosing ranges for a given drug? What are the serious side effects? What are the moderate/mild side effect? How is this drug cleared/excreted? Are there certain populations which this is contraindicated in?
These are some of the main questions that are answered when taking a drug to market, which is why it usually takes 10 years and billions to go from novel molecule to FDA approved drug.
>Med school doesn't qualify you to opine about novel therapeutics
Actually, it does. Especially when we tried hydroxychloroquine and it didn't work. When you go to a hospital with medical students 60% of the time our recommendation to the attending is what the care plan ends up being.
Just had the pleasure of watching both of Robert Lustig`s lectures on fructose back to back this week.
Are you sure the medical industry as a whole is not stupid?
It doesn`t really resemble healthcare from many of the angles.
(I agree that brilliant minds make the world go round, but being complicated is not one of their signatures)
I still don`t think high-fiving lepers on their good arm while the rest of their body rots is the PR view they were going for, but, it is what it is.
I don't really understand why the world is approaching this problem the way it is. A lot of the things we are doing are very much in the vein of that Einstein quote about being unable to solve a problem from the same level of thinking that created.
This pandemic grew out of modern life. It grew out of 7 billion people living on planet Earth and global travel and Affluenza. We just keep bulling on ahead with more of the same.
There are fixes, but they aren't likely to come from our current main stream approaches. And this is problematic because everything we are doing is making the economy top heavy in a way that's actively hostile to the little guy. This makes it hard to start small somewhere.
I have a serious medical condition. I'm getting well.
I've done remote work for years. That's a good idea that's helpful for controlling infection for vulnerable people.
Social distancing is good, but one side effect of all this lock down stuff is that hours are shortened and this means there are bigger crowds. It has eliminated the option for me to shop at 2am to avoid people.
I'm for contactless food orders. I have been actively promoted Little Caesar's pizza portal, ordering ahead (by phone or online) and picking up takeout.
I know lots of things that work. It's not any one thing. I can't tell you in a single comment. I've been developing these practices for 19 years and I get nothing but the crap kicked out of me, even when I am just asking questions for my own edification.
The enormous hostility with which I am met for just trying to talk to people online is part of a larger pattern of thinking and behavior. It's not just hostile to me. It's hostile to anyone with a non-main stream approach to health issues.
Main stream approaches are what got us here. They won't likely get us out.
I will probably be okay. But other people don't need to suffer this much.
You'd still face traction and backlash issues, but it seems like a lot less effort and commitment to get started.
I have a subreddit called HealthWorks. It has no real traction.
I have had several health sites over the years. They get no real traction.
The problem is not setting up a website. I have a zillion of them.
The problem is mostly positioning and framing and getting audience engagement. I've never figured that piece out.
I know a lot about health stuff, so much so that when I begin talking about what you can do for yourself at home, people get all up in arms and accuse me of "practicing medicine without a license" and things like that.
I started a site a few weeks back in reaction to the pandemic called Stop Touching Your Face and someone kindly gave me feedback on positioning it, but I never developed it. I don't think it works to talk about the pandemic and try to address the pandemic directly.
I have a health site about my medical condition. I rarely update it.
I am continuing to think on the problem space and I hope to eventually find a way to talk about stuff and have it go well. But I find it crazy making that people are openly hostile to the stuff I want to talk about. I don't get that.
You know someone with potential solutions in a life threatening situation and your response is rage and downvotes instead of trying to help them figure out how to better talk about it? Are you, like, trying to die or something?
I just honestly don't get that. I never have. It's the same reaction people with my medical condition give me and it makes no sense to me at all.