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

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 That’s one reason why remdesivir, an antiviral drug that Gilead Sciences originally made to fight Ebola, has been propelled into the spotlight with the hope that it can stop, or at least curtail, the ravages of SARS-CoV-2, the virus that causes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