Following revelations that a randomized, placebo-controlled study of the Gilead Sciences Inc.’s antiviral, remdesivir, reduced time to recovery for hospitalized patients with "advanced" COVID-19, along with additional data from an open-label phase III trial from its maker, the FDA is "working with Gilead to figure out a mechanism to make this easily available to people who need it," Anthony Fauci, director of the NIH’s National Institute for Allergy and Infectious Diseases (NIAID), said April 29.

Describing an adaptive trial sponsored by the NIAID that met its primary endpoint of time to recovery, Fauci said that "remdesivir has a clear-cut significant positive effect in diminishing the time to recovery," calling the outcome "quite important."

The study showed remdesivir improved median time to recovery by four days, with patients receiving the experimental drug recovering in a median 11 days vs. 15 days for those in the placebo arm (p=0.001). "Although a 31% improvement doesn't seem like a knock-out 100%, it is a very important proof of concept, because what it has proven is that a drug can block this virus," Fauci said. The trial included sites in the U.S., Germany, Denmark, Spain, Greece and other countries.

"The mortality rate trended towards being better, in the sense of less deaths in the remdesivir group: 8% vs. 11% in the placebo group," Fauci said, adding that the data need to be further analyzed. Nonetheless, he added that "all of the other trials that are taking place now have a new standard of care."

Anthony Fauci, director, NIAID

Notification of the study's outcome from the trial's data safety monitoring board "was reminiscent of 34 years ago, in 1986, when we were struggling for drugs for HIV and we had nothing" beyond anecdotal reports of people testing different kinds of drugs, Fauci said. "We did the first randomized placebo-controlled trial with AZT, which turned out to give an effect that was modest. But that was not the endgame, because building on that every year after, we did better and better. We had better drugs of the same type and we had drugs against different targets," he said.

Gilead, which has developed remdesivir since at least 2015, was also an early though controversial pioneer in the development of life-saving treatments for people with HIV. Today, it is one of the world's leading sellers of HIV medicines, reporting $16.44 billion in revenue tied to the indication in 2019.

Though scientists and the public will have to wait for results of the NIAID-sponsored COVID-19 trial to reach publication in a peer-reviewed journal, Fauci said the initial results could be viewed as "really opening the door to the fact that we now have the capability of treating, and I can guarantee you, as more people, more companies, more investigators get involved, it's going to get better and better."

Gilead cites recoveries, but without comparator

In addition to the results Fauci shared from the NIAID-run trial, Gilead shared results from its own open-label study of the drug, as company shares (NASDAQ:GILD) tilted higher Wednesday, ending the day at $83.14, up $4.47.

Results of Gilead's own phase III SIMPLE trial, evaluating five-day and 10-day dosing of remdesivir in patients with severe cases of COVID-19 are hard to interpret since the trial didn't include a comparator, though Evercore ISI analyst Umer Raffat said during a Tuesday morning webinar that he does expect it to win FDA approval. "But it's not going to be a silver bullet," he added.

Gilead said that, among 200 COVID-19 patients who received a five-day course of remdesivir in SIMPLE, 65% achieved a clinical recovery, with most discharged from the hospital after treatment. Results for a 10-day course of treatment yielded similar results. Though no new safety signals were identified with remdesivir across either treatment group, 8% of patients receiving the five-day regimen and 11% of those in the 10-day treatment arm died.

Furthermore, an exploratory analysis revealed that patients who received remdesivir within 10 days of symptom onset had improved outcomes compared with those treated after more than 10 days of symptoms, the Foster City, Calif.-based company said. Pooling data across treatment arms, by day 14, 62% of patients treated early were able to be discharged from the hospital, compared with 49% of patients who were treated late.

The study is the first of two randomized, open-label, multicenter SIMPLE studies Gilead is running to test remdesivir in countries with high prevalence of COVID-19 infection. The second is evaluating the safety and efficacy of five-day and 10-day dosing durations of remdesivir administered intravenously in patients with moderate manifestations of COVID-19, compared with standard of care.

"While additional data are still needed, these results help to bring a clearer understanding of how treatment with remdesivir may be optimized, if proven safe and effective," said Aruna Subramanian, a clinical professor of medicine and chief of Immunocompromised Host Infectious Diseases at Stanford University School of Medicine. Subramanian is one of the lead investigators of the study.

A contrasting picture

Despite the positive picture of remdesivir emerging from Gilead and its report of the NIAID trial's outcome, a top-line view of results from the first randomized trial of the drug conducted at 10 hospitals in Wuhan, China, and published in The Lancet presented an alternative perspective on remdesivir effects.

The study was stopped early due to the difficultly of recruiting patients after the outbreak was brought under control, causing investigators to caution that interpretation of the findings could be limited. Still, "unfortunately, our trial found that while safe and adequately tolerated, remdesivir did not provide significant benefits over placebo," said Bin Cao, professor at China-Japan Friendship Hospital and Capital Medical University in China, who led the research.

"Future studies need to determine whether earlier treatment with remdesivir, higher doses, or combination with other antivirals or SARS-CoV-2 neutralizing antibodies, might be more effective in those with severe illness," he added.

Asked about the China trial Wednesday during an Oval Office meeting, Fauci criticized it, saying that it was underpowered and "not an adequate study."

Fortuitously, more adequate studies are underway, though interpretation could be made difficult by the vast number of variables impacting the emergent course of the pandemic. Varying degrees of disease severity, source of infection and differing regional approaches to care have all been identified as confounding factors in the interpretation of COVID-19 trial data.

"In the end, the details will be critical to put the true potential of this antiviral into context," said J.P. Morgan analyst Cory Kasimov, "but we suspect regulators could move fast to make the product available given the low bar/unmet medical need. The ultimate implications for GILD remain unclear."

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