Gilead should ditch remdesivir and focus on its simpler and safer ancestor

STAT News ^ | May 14, 2020 | Victoria C. Yan and Florian L. Müller

[House Atreides]

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.

[House Atreides]

The authors point out that Remdesivir isn’t Gilead’s only antiviral nucleoside analogue. Gilead has also developed GS-441524, another pro-drug that, as its name suggests, the body also converts into GS-441524 triphosphate. As far as drug production goes, GS-441524 is easier to synthesize than remdesivir, requiring only three steps instead of the seven needed for remdesivir.

After reading the linked article I have to ask why Gilead is running to market Remdesivir instead of GS-441524 (a drug both easier to make and more effective than Remdesivir). Beats me. Perhaps because GS-441524 could have fewer years of patent protection remaining?

[thoughtomator]

But the whole point of releasing the virus, at least from Fauci’s and Gates’ point of view, was to sell Remdesivir.

Why start a global plague if you can’t get rich off it? What would be the point?

[logi_cal869]

The more time that passes, the more weight is granted to my hypothesis that the key to preventing complications in those at-risk is elimination of the virus in the lungs. Such an approach would lower the odds of dying from SARS-CoV-2 infection to a mere fraction of the odds of dying in a vehicle crash for the entire population, not just the young & healthy.

To-wit:

"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."

Btw:

Wuhan Coronavirus: Propylene Glycol as Possible Therapy for Eradication of RTI and Prevention of Complications [vanity]

But then again, fear is a useful tool, isn't it? /s