As someone who has been on the corporate side of this type of debate, I can assure you that Gilead has several magnitudes of more information about both of these molecules than the author has.
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.
Sure, and that can include unpublished negative data.
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 It was a negative result, and was unpublished.
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.
I’m not sure your example of increased risk of suicide is a good one - the FDA already responded to that data and increases warnings. Sounds like the system worked.
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.
As a contrast, and since you've mentioned Good Pharma, I suggest reading also "Bottle of Lies: The Inside Story of the Generic Drug Boom" ( https://www.amazon.com/dp/0062338781/ )
This book discusses the supply line of generic drugs on US shelves today.
This is exactly why Gilead won’t allow the similar drug to be used in cats. They don’t want to know about negative side effects that might then hinder the drug’s approval for use in humans.
If ever there has been a business decision to illustrate the whole “putting profits over people” this is it. And sunk costs, too.
Where are you getting this from? The only mention of cats in the article is actual data of the drug in cats.
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.
> They don’t want to know about negative side effects that might then hinder the drug’s approval for use in humans.
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 are a ton of studies that show side effects in non-human animals are not a good predictor of side effects in humans; and this becomes more true with rarer side effects.
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.
The book “Medical Nihilism” by Jacob Stegenga similarly covers the subject of hiding negative results, how even apparently carefully performed double-blind studies can be manipulated to favor pharmaceutical companies and how those companies “invent” deceases to get more prescriptions of their drugs.
None of that really addresses the public health policy question of what to do about drugs/compounds that are identified as strong candidate treatments.
> As someone who has been on the corporate side of this type of debate, I can assure you that Gilead has several magnitudes of more information about both of these molecules than the author has.
Which is a neverending scandal that should outrage everyone.
Yeah, that’s almost certainly true. But it’s human nature to second-guess organizations that should know what they’re doing, and it makes for a fun mental diversion.
Remdesivir and GS-441524 triphosphate are nucleoside analogs that inhibit polymerase activity. These are notorious for breeding resistance due to polymerase variability amongst viruses.
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.
The article only mentions tests of GS-441524 on animals, but not humans, whereas remdesivir empirically seems to be reasonably safe in humans. Switching from the one thing that actually possesses efficacy in humans to something that has mainly been tested on cats seems like an unnecessary gamble at this point.
Ideally we could work on both. Remdisivir is apparently nightmareish to produce - it's unlikely that that Gilead can fully capture all the value on the market with it alone, especially if another another therapeutic becomes available.
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.
Are we in a world of limited resources in this specific sense? We're in a world of 3 trillion dollar re-ignite the economy. Whats the resource limitation here?
Money does not magically create the personnel qualified in scaling up drug production, nor does it magically make the necessary, specialized machinery appear. Furthermore, as described in the article, the manufacturing appears to rely a lot on various businesses which each perform one specific step with a compound and hand over the result to the next, and Gilead's core work seems to be to find these businesses, provide missing know-how, and coordinate all of their work such that the timelines and amounts produced line up. Just dumping money into an economy also does not magically make such specialized businesses appear all of a sudden; self-organizing systems like modern capitalistic economies require time to adjust to big changes in demand or supply of certain goods or services.
I dislike Trump on principle and from the other side of the fence. I am a natural born 'big government' person. From my side of the fence, the one thing Trump said which made sense was: "there are 15 good candidate vaccines: we are pursuing all of them"
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
Its "upstream" in terms of being a 3 step drug not a 5 step drug and more of the active principle enters the bloodstream.
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?
I think you need to re-read the whole article. Literally the next paragraph explains something relevant. Take the latest controlled study conducted in rhesus macaques infected with SARS-CoV-2: After remdesivir was administered intravenously, GS-441524 was present in serum samples at concentrations 1,000-fold greater than remdesivir. Upon completion of the study, the researchers found that only GS-441524 — not remdesivir — was detected in the macaques’ lungs, yet they exhibited no signs of respiratory disease, significantly reduced viral loads, and a distinct reduction in damage to lung tissue. Such results reinforce those obtained from a prior study, also in macaques, and data from other species that GS-441524 exhibits strong antiviral activity.
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.
Sure but they're both currently under patent protection. Since much of the value of the drug is likely to come in the next 18 months, they're both equally protected.
"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"
Also "Gilead is providing the entirety of this existing supply at no cost, to treat patients with the most severe symptoms of COVID-19. The 1.5 million individual doses are available for compassionate use, expanded access and clinical trials and will be donated for broader distribution following any potential future regulatory authorizations."
Doesn't matter if it's so hard to manufacture that the generics miss the train. If they did the same for the other drug then I'd trust their motives more. If you were a generics manufacturer would you invest in a complex process that will definitely turn into a wasted investment within just a few years when Gilead starts demanding royalties?
Not all of them, but who would set up a production line for something that will have unknown royalties required to keep it running within the next year or two? It'll take them that long just to get it up and running smoothly.
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.
Why do you think back catalogs of nucleoside analogues exist?
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.
There's plenty of arguments against patents in software and other innovations. But not many people complain about it for drug research where the timelines and type of research actually make sense for such a system.
Interesting article, but it could have done a better job of explaining the chemistry.
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.
Your first 6 paragraphs are not clearer than the article:
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.
> An oral drug would allow you to buy pills and convalesce at home, conserving valuable hospital resources.
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.
As an aside, you typically use a prodrug because you think it will lead to better drug properties than the parent compound.
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.
This seems like the sort of argument that should be distributed in the peer-reviewed literature to scientists, not on a news website.
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.
This Atlantic piece has excellent background, including the astonishing effectiveness in cats against FIP, and questions about Gilead's motivations for prioritizing studies of one vs the other: https://www.theatlantic.com/science/archive/2020/05/remdesiv...
Edit: I see goatinaboat also posted the link (I searched for a bit of the url that was elided).
Does it work in the feline at all? FIP is a deadly disease, if the compound was any good word of mouth would spread amongst veterinarians. Unfortunately, the outcomes are not encouraging.
Okay so...I'm actually in a rare position where I might be able to contribute to discussion on this! Brief caveats: am undergrad pre-med, but also took an infectious diseases grad class at Penn that spent a week diving into one of the papers cited in this article (when the authors mentioned the two compounds "showed no statistically significant difference in potency"). I think it's worth exploring what the authors of that paper actually meant to assess for. (also @HN please shoot me down if anything I say is inaccurate, also I do think the authors make other valid points, just not so much in reference to this particular aspect)
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?
There are a few things that cause me serious frustration. One is when a lay person will talk about medicine.
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.
Both are involved in discovering novel drug targets, but not in bringing drugs to market. I know a significant amount of individuals in medical research that don't know the nuances behind bringing drugs to market.
My best friend is working on novel targets for hepatocellular carcinoma. Does he know science? Yes. Does he know how to bring a drug to market? God no. Everyone outside of your field is a lay person.
>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.
There's actually a lot of easy ways to combat viral infections. This was well known in an alternative medicine forum I used to hang out in, which probably no longer exists because it was a Yahoo group.
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.
If I thought I could get any real traction, I would run a website talking about what works. But that's not likely to get traction, so that idea hasn't gone anywhere. I'm scared to try to develop it because I get so much absolute shit from people for trying to talk at all about health stuff.
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.
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.
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.