Reactions

Letters to the editor

Remdesivir and GS-441524

A recent article describes continued efforts to develop outpatient antiviral COVID-19 treatments to enable early intervention (C&EN, May 24, 2021, page 28). The article summarizes the shortcomings of remdesivir’s obligatory intravenous administration, which restricts its utility to late-stage patients, hindering the magnitude of benefit. So Gilead Sciences expressed a desire to create a “version of the drug that could be taken as a pill,” by “redecorating the core molecule, known as GS-441524, in an attempt to boost its oral bioavailability.”

While Gilead’s efforts are scientifically commendable, its refusal to advance the parent nucleoside, GS-441524, in parallel is questionable. In May 2020, Florian Muller, Steve Kirsch, the scientific advisers at the COVID-19 Early Treatment Fund, and I communicated to the Gilead leadership the several advantages that GS-441524 possesses over remdesivir. These include being orally administrable; significantly safer, which enables up dosing; and easier to synthesize. Despite presenting compelling data, we encountered an unwillingness to proceed with GS-441524 development. We recognize that, at the start of the pandemic, remdesivir was better poised for repurposing given prior clinical experience. However, it is unclear why prompt development of GS-441524 could not be initiated once remdesivir’s marginal clinical efficacy became evident—especially considering the wealth of data on GS-441524 included in remdesivir’s new drug application to the US Food and Drug Administration. Gilead cites suboptimal bioavailability of GS-441524 in nonhuman primates as a deterrent, yet drugs of the same class demonstrating nonideal bioavailability, such as acyclovir, ultimately demonstrated sufficient absorption to yield clinically meaningful activity in humans. In fact (though anecdotal), I demonstrated acceptable bioavailability of GS-441524 in a pilot self-investigation, in which three times daily dosing of 750 mg easily and safely achieves plasma concentrations exceeding that required to eradicate SARS-CoV-2 in vitro. Had development begun in May 2020, GS-441524 would be in Phase 3 trials today—resembling molnupiravir’s development.

It is thus remiss of the article not to mention the significant efforts by the National Center for Advancing Translational Sciences (NCATS) to move GS-441524 to the clinic. Data on the safety of GS-441524 at supratherapeutic doses are on the NCATS OpenData portal. Notably, 1,000 mg/kg twice a day by mouth is well tolerated in dogs and yields plasma concentrations of 100 µM (100-fold higher than the 50% maximal effective concentration against SARS-CoV-2). To Gilead, GS-441524 may not be the “perfect pill,” but now, a bird in hand is worth two in the bush.

Victoria Yan
Houston

Nuclear waste in Fukushima

This letter is in response to the editorial in C&EN’s April 19, 2021, issue (page 2).

The secrecy of the Spanish and US governments regarding the plutonium scattered from the hydrogen bombs destroyed in the crash of 1966 should be contrasted with the openness with which the Japanese government is presenting its plans to dispose of the Fukushima wastewater.

An even more important contrast is the much weaker radioactivity of the wastewater to be disposed of. Already 99.99% of the most radioactive elements, such as strontium and cesium, have been removed, leaving significant amounts of only the tritium, which cannot be removed because it is chemically the same as the hydrogen of the cooling water. However, tritium has among the weakest radioactive rays of all the radioactive elements, being able to penetrate only 6 mm of air and unable to penetrate human skin. Additionally, its half-life is only 12 years. After some dilution, its radioactivity will be insignificant compared with the radioactive potassium and uranium naturally present in the ocean. Hopefully C&EN recognizes all this.

The public’s concern is understandable because to the public, there is something special about artificially created radioactivity. And amounts and types don’t matter.

John Tanner
Idaho Falls, Idaho.