Posted on 05/16/2020 9:12:27 PM PDT by nickcarraway
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 That’s one reason why remdesivir, an antiviral drug that Gilead Sciences originally made to fight Ebola, has been propelled into the spotlight with the hope that it can stop, or at least curtail, the ravages of SARS-CoV-2, the virus that causes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.
Related: Cats can catch Covid-19 from other cats, study finds. The question is: Can we? 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.
Or they could just use what works—hydroxychloroquine with azithromycin and zinc.
There may be more than one protocol that works. We should keep researching. Plus, there could be mutations.
nope
cmon you know the reasons why
From the article reasonisfaith posyed:
“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. “
reasonisfaith wrote:
“Or they could just use what works—hydroxychloroquine with azithromycin and zinc.”
Try both approaches; HCQ/azith/zinc early on, this GS-441524 in an aerosol/inhaler for someone having more difficulties.
Didn’t President Trump mention something about “get the medicine into someone’s lungs”?
That’s the beauty of capitalism. Gilead will work on a new, improved, more effective derivative product to capture market share and improve its profits. Sick patients will benefit. Doubt “government labs” or socialist countries with stilted drug companies will do much. Yet you can count on leftist politicians to curse capitalism and to try to tax and regulate Gilead out of productive existence. Pandemic or no pandemic, some things don’t change.
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.
“Am I stupid, or is this contradictory information?
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.”
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No, you’re not stupid and the article does not contain contradictory information.
The following is extracted from the linked article:
“...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....”
The author is asking the important question of why Gilead isn’t making the effort to market the more effective, safer, and easier to manufacture drug that was patented in 2009 instead of the newer one patented in 2017. The answer is almost certainly more profit for a longer period due to earlier patent expiration of the 2009 patented product.
And I know that it is hard to follow, but both drugs deliver the identical therapeutic molecules at the cellular level. I highly suggest all FReepers read closely the linked article.
I ave a friend from college who has been working at Remdsivir at Gilead. Of course, they didn’t know it was for this.
… by extracting $340 Billion from US citizens, and Trillions more from the people of other nations for Gilead.
so you are telling me that the FIVE steps mentioned (and I highlighted IN RED)for Remdesivir in the first sentence I highlighted is the same as the SEVEN steps I highlighted in red in the last sentence.
Oooo kay. Five equals seven. Not contradictory at all.
“so you are telling me that the FIVE steps mentioned (and I highlighted IN RED)for Remdesivir in the first sentence I highlighted is the same as the SEVEN steps I highlighted in red in the last sentence.
Oooo kay. Five equals seven. Not contradictory at all.”
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It’s confusing but not contradictory.
The 5 Remdesivir steps refers to the number of METABOLISM “steps” that Remdesivir undergoes, after it is intravenously infused into the patient, before part of it finally becomes “GS-441524 triphosphate” which is the active element that acts against the Covid-19’s virus. It’s good to know that one of the interim METABOLIC steps (of the 5 steps in Remdesivir’s metabolism) yields GS-441524.
Producing Remdesivir in a drug manufacturing facility requires 7 STEPS before the Remdesivir is yielded.
Compared to Remdesivir, GS-441524 only requires 3 steps (versus 5 for Remdesivir) until the body has METABOLIZED it into the needed active form “GS-441524 triphosphate”.
And manufacturing GS-441524 takes only 3 STEPS (versus 7 for making Remdesivir).
I think the authors (or perhaps one of their commenters) said that because GS-441524 is a smaller molecule than Remdesivir and is soluble in water it would be given by sub-cutaneous injection and possibly could also be delivered directly to the lungs as an aerosol.
GS-441524, like remdesivir, binds to the virus’s nucleotide chain as the RNA dependant RNA polymeras goes down the chain, synthesizing the nucleotide compnents that make up the nucleotide strand. This “transcription” process of the virus’s nucleotide will not change due to any mutation. Once the GS-441524 binds to the chain, the RNA dependent RNA polymerase is unable to further its process. That stops the duplication process and the virus is terminated.
However, those trying to create a vaccine, do have to worry about mutations. It is the vaccine that creates the antibodies that target the DNA components that are unique to the virus. If those components change from a mutation, those antibodies have no components to target.
It’s all about the dollar. Why make the cheap stuff when the harder to make stuff will bring you more profit?
That’s like saying let’s try to find something other than tetracycline for bubonic plague.
Tetracycline is the reason we don’t worry about bubonic plague.
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