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In the midst of a pandemic like Covid-19, for which there are no FDA-approved drug treatments, hope is important. That’s one reason why remdesivir, an antiviral drug that Gilead Sciences originally made to fight Ebola, has been propelled into the spotlight with the hope that it can stop, or at least curtail, the ravages of SARS-CoV-2, the virus that causes Covid-19.

Data from the open-label SIMPLE trial, sponsored by Gilead, and the randomized controlled Adaptive Covid-19 Treatment Trial, sponsored by the National Institute of Allergy and Infectious Diseases, show that remdesivir may accelerate recovery rates among patients with advanced Covid-19. The drug’s modest effects are a far cry from the strong antiviral activity it demonstrated in preclinical primate models of coronavirus (both MERS and SARS-CoV-2). Yet that has been enough for the Food and Drug Administration to grant emergency use authorization for remdesivir and for the Japanese Ministry of Health, Labour, and Welfare to approve it for the treatment of Covid-19.

As chemists, we are troubled by the challenges to mass producing remdesivir. We aren’t alone. On the day that results from the two trials emerged, Gilead CEO Daniel O’Day praised the chemists behind the drug, saying he is “proud of the team because this is a complicated chemical process. It takes many, many steps.”


But does it really have to be that complicated? O’Day’s admission is interesting given that Gilead has another compound in its pipeline that is easier to make, has been shown to be effective against coronavirus in animal models, and is potentially as effective as remdesivir, if not more so.

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.

Researchers initially thought that remdesivir would be activated more quickly than GS-441524 in human cells infected with the SARS and MERS coronaviruses. Yet data from primary human airway epithelial cells — one of the most clinically relevant cell-based models of the human lung — showed no statistically significant difference in potency between the two compounds. These data align with previous reports on the similar effectiveness of remdesivir and GS-441524 in coronavirus-infected cat cells. 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.

Recent research in coronavirus-infected nonhuman primates demonstrated problems with remdesivir that inadvertently showed the antiviral effectiveness of GS-441524. In multiple studies testing remdesivir in coronavirus-infected mice or rhesus macaques, it was rapidly converted to GS-441524 in the bloodstream.

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.

Data in cats and primates have pointed to GS-441524’s safety. In the study using GS-441524 to treat feline coronavirus, the researchers noted its “impressive” safety profile when administered at high doses, and reported that no systemic signs of toxicity were observed over 12 to 30 weeks of treatment. In primates, GS-441524 was found to be present at high concentrations in the blood (1,000-times higher than remdesivir) with no apparent adverse effects.

The first step in the bioactivation of GS-441524 is the rate-limiting step, something that remdesivir was designed to avoid. But that doesn’t matter clinically because of remdesivir’s rapid transformation to GS-441524 in the bloodstream.

Remdesivir’s lackluster results in patients with advanced Covid-19 in the NIAID-sponsored trial and the finding that it provided no statistically significant benefit in a clinical trial conducted in China among patients with severe Covid-19 symptoms are likely due to the suboptimal level of active GS-441524 triphosphate in the lungs. Patients with advanced or severe Covid-19 generally have a high viral load in their lungs and would need a high concentration of GS-441524 triphosphate to combat it. The benefit of using GS-441524 over remdesivir is that GS-441524 can almost certainly be given at much higher doses due to its lower toxicity. This would result in more conversion to the active compound, GS-441524 triphosphate, in the lungs.

When viewed through a different lens, the initial results from the NIAID-sponsored trial are more encouraging than they would seem. The active agent, GS-441524 triphosphate, clearly exerts antiviral activity against SARS-CoV-2 in humans, as supported by the accelerated recovery rates in advanced Covid-19 patients enrolled in the trial. Our analysis of preclinical and clinical trial data strongly suggests that early and direct administration of GS-441524 should be considered as a synthetically simpler and potentially more effective alternative to remdesivir, especially as GS-441524’s remarkable safety would enable higher dosing.

We see numerous advantages to using GS-441524 rather than remdesivir as an anti-Covid-19 therapy. GS-441524 is easier to synthesize and dissolves in water, which can speed manufacturing and enable higher dosing. It is a smaller molecule than remdesivir, which would make it easier to produce an aerosolized formulation for inhalable therapeutic and prophylactic treatment — this would be particularly attractive for achieving a high concentration of the drug in lung cells while minimizing systemic toxicity or side effects. And it is also less toxic than remdesivir. For these reasons, we do not see the point of making a significantly more complex drug like remdesivir when what actually reaches infected lungs is GS-441524.

The attractive profile of GS-441524 from both manufacturing and clinical perspectives raises this question: Why hasn’t Gilead opted to advance this compound to the clinic? We would be remiss for not mentioning patents, and thus profits. The first patent on GS-441524 was issued in 2009, while the first patent for remdesivir was issued in 2017.

We aren’t the only ones questioning Gilead’s strategy. We have spoken with a number of chemists, biochemists, veterinarians, and others who are also surprised that GS-441524 has remained out of the spotlight. Veterinarians we spoke to have noted that the strong antiviral activity of GS-441524 has resulted in a “miraculous turn of events” for cats infected with feline coronavirus, which was once considered a death sentence.

Given GS-441524’s optimal properties, we — along with the millions of people awaiting an effective treatment for Covid-19 — are left to wonder why Gilead isn’t giving it the same attention it is giving remdesivir. The world can only hope it isn’t for the sake of protecting its intellectual property.

Victoria C. Yan is a graduate research assistant specializing in phosphonate chemistry at the University of Texas MD Anderson Cancer Center in Houston. Florian L. Muller is an assistant professor specializing in cancer drug development in MD Anderson’s Department of Cancer Systems Imaging.

  • I would really like to know what not only Dr. Fauci thinks about your idea, but also Dr. Bright. As well, I worry about its potency. How could a person with 3 auto immune diseases and a non-functioning pancreas due to it being abnormal formed with no wide duct and blocked gallbladder which should have been removed in January, 2019 but could not because absolutely no family or friend could care for my permanently disabled husband who needs me to care for him 24/7. Nursing homes are out of the question. We are not well off financially and I know most of the ones are poorly run. For example the Kirkland Life Care Center and others near me. I also have severe non-binding migraines and a heart or vascular problem from high cholesterol. I am a bleeder and do not clot well. My mother had this problem and my daughter also has this problem. I have a long history of bleeding stomach ulcers and Diverticulitis. I have already suffered from pancreatitis twice. My family has a history of high blood pressure and mine became worse when my gallbladder and pancreas stopped working. I am also extremely sensitive to numerous medications with either allergic or adverse reactions. But aneurysms also run in my mother’s family. Since I have very fragile health WHICH OPTION WOULD EPIDEMIOLOGISTS RECOMMEND FOR ME. MY DR. SAYS I BARELY HAVE AN IMMUNE SYSTEM AT ALL. THANKING YOU IN ADVANCE. ANITA FRIEDENBERG

  • Are you saying that GS-441524 is approved for human consumption and can; therefore enter into Phase III trials? If GS-441524 is not yet approved for human consumption what is the point of abandoning remdesivir which can be given to people while GS-441524 cannot. With respect to patent protection, GS-441524 would be protected by patent for the purpose described in the patent. If GS-441524 were to be used for a different purpose it would benefit from patent protection from the day Gilead decided to use it for that different purpose. If the GS-441524 patent covers treatment of any virus then repurposing to treat a new virus won’t provide Gilead with any patent benefits. If the original patent is more specific then Gilead may well be able to extend the patent by finding another purpose for GS-441524. I think it would have been prudent to examine the terms of the patent before making judgments on what IP Gilead actually owns.

    I am more curious; however, as to why you would advise abandoning the only drug that works that is approved for human consumption?

    • I am puzzled by why Gilead would promote a drug with a longer patent time, over another drug they also hold the patent on, which seems to work better.

      It seems to not really make much sense. If i have a drug which works, then I can sell it, a lot of it, in a pandemic, and it appears they will hold the patent on the GS 441524 for longer than the pandemic is likely to last. Most people expect a vaccine within two years.
      So, given a choice of selling a whole lot of the better medicine, or maybe selling a lot of the less effective one, why would the company pick the latter?
      Can anyone comment on the economics of this?

    • Steve White, I suspect the fact Remdesivir is fiendishly more difficult to manufacture has something to do with it. They can 1) charge more for it and claim it is to recoup greater manufacturing costs/capex (but make a massive margin on that greater cost) and 2) Be comfortable in the knowledge it will be harder for other companies to manufacture it even if they were to licence the IP out to independeny manufacturers.

      Of course they probably haven’t thought of the likelihood China will likely just ignore their patents and just manufacture generic GS-441524 and sell it to the rest of the developing world.

      After all Trump seems determined to trash the relationship. Why not just move on from the US market, poke the US in the eye and lock in billions of people’s goodwill in the developing world…

    • @OC- Of course remdesivir has “worse” cellular toxicity. But this is an artifact of 441524’s poor cell permeability. If a chemical can’t get into cells it will not show cellular toxicity.

    • A few things to say here.

      @Philip: You are right to point out that remdesivir is farther along in the clinical trial pipeline. I mentioned to some other commenters that there is precedence in FDA history of fast-tracking approval of prodrug/drug pairs (see: leflunomide/terifluonomide). Both remdesivir and GS-441524 produce the same active metabolite (GS-441524 triphosphate). GS-441524, while it has not officially gone through phase 1 is not quite a “new” compound. A similar fast-track approach for this drug pair could be looked into as well. It’s something for Gilead to consider.

      I do have some thoughts on the GS-441524 patent but, as I am not an expert on IP matters, I will refrain from commenting on that. We did link the 2009 patent in the article, so I think you may find some answers to your questions there.

      Remdesivir is an immediate triage to this problem. Producing it, however, is not easy. This hampers supply and distribution. Multiple studies have documented the strong antiviral effects of early/prophylactic treatment (eg: PrEP for HIV). With some of the properties I mentioned in the article, GS-441524 would seem to fit the bill for an aerosolized prophylactic/treatment. The concern here is that Gilead will focus on remdesivir to the exclusion of GS-441524.

      @Josh: GS-441524 is a nucleoside analogue, so it actually does not have poor permeability, as it can either enter the cell through passive diffusion or through nucleoside transporters. Many (but not all) in vitro studies have shown that remdesivir has a lower EC50 compared to GS-441524: this likely results from the ability of remdesivir to bypass the slow first phosphorylation step that GS-441524 has to go through.

  • Agree with everyone’s comments this is a “war” so conventional methods, trials, and approvals should be modified and facilitated. However drug treatments and trials and approvals have now become a political issue also. Unfortunately, Nothing is straightforward and what should be “objective non-biased” science has been hijacked by policies and politics.

    I applaud Gilead’s transparency and management so far. They have done a phenomenal job opening up the Remdesivir trials for compassionate use, donating the Million Vials, and now licensing Remdesivir to the world.

    Remdesivir is not useless and should will show stronger benefits and decreased mortality when the final studies come out. As a Hospitalist at a very large institution/ health plan in CA, I thought I was imagining things for the Covid Pneumonia patients who have received Remdesivir. It really does something (fevers melt away and all the inflammatory markers drop), but with my N = 12, thought perhaps I was just imagining things. Thought maybe this is just a weak version of Tamiflu for influenza. But the more earlier Covid patients we enroll, the more I am convinced it is beneficial. Then the Chicago U Med school anecdotal result were leaked out. I then knew I was not imagining things. I can NOT comment on mortality. That will truly take larger trials over multiple institutions and detailed analytical analysis.

    Would highly love to see and do trials with this Remdesivir precursor. I definitely know there would be plenty of patients who would sign up. Every hospital and institution in the world would sign up for it.

    Remember it has only been 2 months since this pandemic has hit the US, 3 months for Europe, and 4 months for China. Given this very short time frame in the scope of traditional drug trials and approval, this really is amazing. We did not need perfect in the beginning. We just needed something anything. So Remdesivir was an answer in a pinch but it may not be the perfect drug. At least we do have this added to our toolbox to not only try to save lives but also to improve them.

    • I believe I may have responded to one of your more recent comments, so apologies if I repeat myself here. Doing my best to answer the backlog of comments.

      First, thank you for what you’re doing on the front lines. I also commend the expedient progress that drug developers are making. Our intent with this article was to highlight a key point that seems to have been overlooked by many researchers and Gilead itself.

      Remdesivir is an immediate triage to this problem. Producing it, however, is not easy. This hampers supply and distribution. I actually have listened to some physicians who have said that, because supply is limited, remdesivir is being saved for patients who are the sickest. To me, this seems counterproductive to when the drug would work best, as multiple studies have documented the strong antiviral effects of early/prophylactic treatment (eg: PrEP for HIV). With some of the properties I mentioned in the article, GS-441524 would seem to fit the bill for an aerosolized prophylactic/treatment. The concern here is that Gilead will focus on remdesivir to the exclusion of GS-441524. My hope is that this article may prompt Gilead, or anyone, to investigate GS-441524 as an anti-Covid-19 prophylactic/therapeutic in phase 1 or for the FDA to consider fast-tracking it in the way they did for the leflunomide/terifluonomide prodrug/drug pair.

  • I have a bit of a problem with you referring to both remdesivir and GS-441524 as pro-drugs. While technically they are, pro-drugs are supposed to address a pharmacokinetic problem, like GI absorption or poor cell permeability, not make it worse. In this sense, even though 441524 does get converted to 442524TP its cell permeability will be lower, so in effect, it is a “negative pro-drug.” Or maybe an “anti-drug.” Can you explain why you’d expect it to work as well given less desirable physical properties and also the absence of the first phosphate group? (Also: what do you think of a disoproxil approach as in tenofovir?)

    • I agree with you on the intended purpose of pro-drugs. Connotation and nuance aside, both remdesivir and GS-441524 are still pro-drugs in the denotative sense.

      A clarification point: GS-441524 is a nucleoside and should thus still permeate the cell either via passive diffusion or nucleoside transporters. As for whether its membrane permeability is lower than remdesivir: I am not aware of any kinetic studies that have been conducted to figure this out.

      The benefits that I see with GS-441524 include the potential to dose higher and—more importantly—the ability to more easily aerosolize the drug to generate an inhalable prophylactic for direct delivery to the lungs.

      GS-441524 may lack the phosphate. But the in vivo data show that most, if not all, remdesivir gets dephosphorylated prior to reaching the lungs. My thinking is that if remdesivir is getting dephosphorylated prior to reaching the lungs, then there is little purpose in: 1.) having the phosphate on and 2.) making the synthesis more difficult by adding McGuigan pro-drugs.

      With regards to POM/POC pro-drugs: I am quite confident that they will give a similar—if not the same—PK result as remdesivir: the vast majority will be rapidly converted to GS-441524. This is because POM/POC pro-drugs are even more susceptible to esterase hydrolysis than the McGuigan pro-drug. In general, it seems the issue with phosphate pro-drugs is that, once the first pro-drug group is removed, the drug is susceptible to de-phosphorylation in serum.

  • This makes me think, during this emergency at least, overlooked drugs for which patents are held should be temporarily UNpatented by a special law, so that, for purposes of treating this disease, any entity can start testing or using the drug to see if it is of benefit.
    I am not sure how to work that out, obviously you have a case right here where the earlier drug competes with the later – I do not know how to resolve that -but we can not have the drug companies sitting on drugs now. In times of war, businesses have to support the war effort.

  • “We would be remiss for not mentioning patents, and thus profits.”

    Bold accusations against Gilead in yet another article criticizing the only company that so far provided an effective treatment to hospitals. At least you could explain how many years of patent protection they would have with each drug so that readers can judge by themselves.

    • We are not accusing Gilead, but rather trying to consider the (puzzling) matter from multiple perspectives. Frankly, I have enjoyed the papers that they have published on remdesivir/GS-441524 and think that they have performed/collaborated in a number of very informative experiments.

      We did mention the patent filing years and provided the appropriate citations for all to see.

  • The clear reason for prioritizing Remdesivir over GS-441524 which was left out of this article is that Remdesivir has already gone through phase I and phase II clinical trials in the context of the ebola outbreak. Remdesivir has already been shown to be safe in the clinic in human patients giving it a dramatic head start in proving clinical safety and efficacy (within an emphasis on clinical). Translating from animals (even non-human primates) to humans is so fraught with unexpected problems and challenges that the importance of this head start should not be underestimated.

    • Remdesivir is an immediate triage to this problem. Multiple studies have documented the strong antiviral effects of early/prophylactic treatment (eg: PrEP for HIV). With some of the properties I mentioned in the article, GS-441524 would seem to fit the bill for an aerosolized prophylactic/treatment. The concern here is that Gilead will focus on remdesivir to the exclusion of GS-441524.

      I mentioned to some other commenters that there is precedence in FDA history of fast-tracking approval of prodrug/drug pairs (see: leflunomide/terifluonomide). Both remdesivir and GS-441524 produce the same active metabolite (GS-441524 triphosphate). GS-441524, while it has not officially gone through phase 1 is thus not quite a “new” compound. A similar fast-track approach for this pair could be looked into as well. It’s something for Gilead to consider.

  • I’m not an expert in these drugs, but I can say we’re in a war, which can dramatically change the drug development/testing playing field. For example, I believe a large number of volunteers, like in other wars, will become available to help rapidly accelerate the end of the war. Heroes, no doubt, wanting to risk their lives (even if a small risk in some cases) for the greater good. Intelligently use them. Why not try this other remdesivir-like drug ASAP? Just yesterday I watched CNBC’s show that interviewed such a volunteer to get intentionally exposed to CV after getting an experimental vaccine, with word that 16,000 volunteers have evidently stepped up for the effort—pending approval. This might shave months off of the normal, “wait for them to get ‘naturally’ infected” approach used during peacetime.

    Every day matters in this war, much less months. Use every tool and technique we can think of to get an effective drug and vaccine out ASAP.

    • I agree, whole heatedly with Troy, this is no time to worry about what it usually takes to get a drug out, this is the time to do unprecedented things, because these are unprecedented times, I think we should get everything thing out ASAP that we know could very well helps thing go smoother and get the Nation supplied with it so we all can get back to our lives and taking care of our loved ones!

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