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 That’s one reason why remdesivir, an antiviral drug that Gilead Sciences originally made to fight Ebola, has been propelled into the spotlight with the hope that it can stop, or at least curtail, the ravages of SARS-CoV-2, the virus that causes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.”

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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.

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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 am VERY disappointed in some of these NON-constructive comments. As treasury secretary Mnuchin said, “And what have you done for the country lately?” STOP politicizing this. STOP the negative conspiracy “the company is just trying to make a greedy profit” comments.

    Please be constructive. Add some original thoughts and opinions if you are going to comment.

    Yes, this article opens up some questions and doubts. Yes this article raises future potential for another medication.

    I ask all of you what you would do?
    There is a pandemic coming In 2-4 weeks that will infect 8.5 billion people and probably kill 3% of them = 100 million+ when all said and done.

    You have a potential medication (Used for another disease) already tested, set and ready to go and be ramped up in 1 month. You are 90% certain it will help but know that it may not be the best medication for this pandemic. You also have another 20 potential untested medications that should be better for this pandemic infection BUT know that it will take at least 1 year to get it ramped, tested and approved.

    What medication would you put all your resources into if you wanted to save the world NOW ASAP! They so-so one that is ready to go NOW? Or the possible better one but untested that will not see the light of day for about 1 year?

    I am 100% grateful for something NOW. Something is better that nothing. All lives are valuable.

    So for all you “Monday Morning Quarterbacks” out there: STOP IT!!!

    • I think in a war zone rules change, experimental medicines can be easier aplied to the many people who have no hope left. Also, there is no need to double-check with placebo control groups. As we know its deadly its more efficient to set side by side the result of 8 types of medication all at once, then pick the bests. Preferably multiple (as its harder for a virus to adapt to multiple agents, after the first victim evolution evolves in such a way that it will improve, better adapt to futher human hosts ea to better infect us )
      The author points out that this drug is hard to fabricate, we’re now 5 month’s later….. All we need to do is compare the various medications used so far and work togther on this on a worldwide. This should not be about a company making milions, its about making the next drug opensource to save the world, because the human race is under fire. If we dont work together the virus wins.

      And if you want to cure milions having a medicine that can be made quickly is a life saver. The more IC beds are in use, the other diseases turn deadly as well, (no cancer operations, screening testing). So getting the IC beds quickly available again is a high prio. we need to reduce IC time.

      If breathers can be deadly use perfluorocarbon instead (it tissue cleaned TBC patients as well in the past) , …bring back those IC beds !

    • Concur! During this unprecedented novel COVID-19 pandemic health crisis, it is essential for us all to unite, be informed/innovative, and stay strong & healthy TOGETHER.

      Authors, Keep up the “Think out of the box” endeavors! Toil Yields Fruits 🍎

      on the positive

    • Thanks for the reply and keeping the conversation focused on the science/logistics. Remdesivir is an immediate triage to this problem. We may “have” the drug now (not FDA-approved yet) but making it is no small feat, which 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.

      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), so something similar could be done in this situation as well. It’s something for Gilead to consider.

  • Reading this, seems you are right to highlight the merits of the earlier agent, and to question the manufacturers concentration on their latest.
    First. How can we be sure that the triphosphate metabolite is the one and only active lung agent common to the two agents?
    Second, if the GS-441524 patent of 2009 is out or nearly, have the company not reached any human-test stage testing on it alone?
    Given what you say, which is logical and credible, the company’s original pro-drug will be extensively tested in vivo by someone?

    • I read another article recently about this drug in the Atlantic. Gilead won’t license it for cats, even though it’s been shown to be the only working treatment for a universally fatal cat coronavirus. That article stated that this was because they want to be able to get remdesivir approved for humans and are afraid something negative might happen with this one to risk that. Anyway, somebody or other in China has ripped it off and multiple sellers are selling versions of it sideways for cat treatments. To me that suggests that if it can treat Covid, especially if it’s easy to make – it’s going to be tried out soon, and maybe already has been.

    • Based on the mechanism of RNA synthesis (ATP hydrolysis required by RNAP for polymerization), the triphosphate is almost certainly the only active species for the viral RNAP, as it has extremely high affinity for the viral RNAP (see: Gordon et al. JBC 2020).

      To the very best of my knowledge, there are no reports of directly testing GS-441524 in humans even though the patent came out in 2009. The most likely reason for this is because much of the rationale/pipeline seems to rest on in vitro data. In many (but not all) cases, remdesivir appeared to be more potent than GS-441524. However, with regards to SARS/MERS/respiratory virus: any differences in potency between the two in vitro are irrelevant in vivo if only GS-441524 reaches the lungs. The moment that Gilead got in vivo PK data on remdesivir and saw that it GS-441524 was the main species in circulation, I think they should have begun comparing the two species in vivo.

  • I think this may be a good drug for treatment of Covid19 over Remdesivir but how long will it take for FDA TO Approve this drug and many will continue to die while they are going through the process I say keep using Remdesivir until Fda find and approve which drug is most effective but in the mean time continue to use Remdesivir we are at dire state at this point to stop massive of Americans and around the world to stop them from dying of this virus.

    • Agreed that Remdesivir is an immediate triage to the Covid-19 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.

      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), so something similar could be done in this situation as well. It’s something for Gilead to consider.

  • The authors are clearly quite ignorant of clinical drug development and clinical safety but adopt an arrogant know-it-all tone.

    Remdesivir has clinical safety data from being tried in Ebola… so it could go right into a Ph2/3 study. It was an of the shelf option

    A new compound with no clinical safety data would generally need to be tested in healthy volunteers and there is no guarantee that it would prove safe…
    A dedicated discovery effort aimed at SARS-CoV-2 will of course likely yield more potent options compared to a repurposed drug- again Remdesivir could go directly into Ph2 given the prior clinical safety data.

    Also it’s great that they spoke to chemists and Veterinarians… why not ask physicians taking care of COVID patients if the would rather have something rather than nothing.

    • We did not mean to come off as pretentious and I’m sorry that you perceived it this way. Overall, I think all of us want there to be an effective treatment. We’ve researched the remdesivir development quite thoroughly and were puzzled by the surprising PK results.

      Remdesivir is an immediate triage to this problem. We may “have” the drug now (not FDA-approved yet) but making it is no small feat, which 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.

      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.

  • This is the big problem because companies are willing to use less affective treatments to get a longer patent period!!! This way they make more money before generic version are allowed!!

    • Your comment insinuates low motives of greed but has nothing, nothing – I repeat, to say about the scientific issues addressed. This is cheap and meaningless.

  • This is the big problem because companies are willing to use less affective treatments to get a longer patent period!!! This way they make more money before generic version are allowed!!

  • The one who wrote this opinion should be ashamed of him/her-self. You are just a loser on the background trying to be an expert and impose your authority. If you really know what works, then try to invent your own vaccine. Your criticism will not change your status as a loser trying to sound like you know better than those great scientist who actually invented true vaccines. Please remember this before you try to write again about these things, you’re a loser!

    • I do not doubt that. 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.

  • Of course profit could itself be a serious deciding factor. Look at how the HCQ/AZ/ZN combination variant was downplayed despite showing promise in yet another study just now, with even the promoters of such being slammed by some, but then Remdesivir is suddenly hyped by those who’ve invested time and/or money in it (Some of whom conveniently trashed the former). Money, maybe even ego as well, wouldn’t ever be a deciding factor here, surely not, right?

    Regardless of the legitimate promise shown, it’s interesting how certain individuals have jumped all over one treatment while trashing the other one, despite their own touted warnings of “needing more time to study” the one they’ve trashed (a philosophy which they never applied to the one they’ve touted).

    If one treatment truly is better than the other, so be it, but I absolutely do remain skeptical when I see someone fail to apply their own mantra in an equal manner across the board (especially when their their own institution is involved in studying the treatment which they’ve hyped in such a manner).

    • I applaud your skepticism.

      We did not mean to come off as presumptuous and I’m sorry you perceived it that way. Overall, I think all of us want there to be an effective treatment. I don’t believe we trashed remdesivir in our discussion of the data. We’ve researched the remdesivir development quite thoroughly and were genuinely puzzled by the surprising PK results. Our main concern is that Gilead will focus on remdesivir to the exclusion of GS-441524, despite the reality of the PK situation is in vivo.

  • I have not commented before. WHY ARE YOU NOT ACCEPTING MY COMMENT? I WOULD LIKE TO KNOW BECAUSE NO ONE HAS ASKED ABOUT THE RISKS OF YOUR ALTERNATIVE TO A PERSON WHOSE HEALTH IS VERY FRAGILE. I WOULD LIKE TO KNOW.

    ANITA E. FRIEDENBEG

    • For the record, the contents discussed in our article should not be taken as professional medical advice.

      Even though GS-441524 has been inadvertently studied due to rapid degradation of remdesivir, formal studies in humans still need to be conducted with GS-441524. Given the favorable properties of GS-441524, the hope is that this article may prompt Gilead/any organization to further investigate its use in phase 1 as a prophylactic or therapeutic. Perhaps the FDA may consider fast-tracking it/remdesivir in the way it had done with leflunomide/terifluonomide.

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