Gilead’s Remdesivir Garners Emergency Use Authorization from FDA for COVID-19

Gilead’s Remdesivir Garners Emergency Use Authorization from FDA for COVID-19
Man and woman, senior man lying in hospital bed because of coronavirus infection, female doctor is giving medicine to a patient.

On Friday, one day after the National Institute of Allergy and Infectious Disease (NIAID) of the NIH released preliminary data showing that Gilead Sciences’ drug candidate remdesivir outperformed placebo in treating COVID-19 in hospitalized patients, the FDA granted the drug emergency use authorization (EUA), to enable broader use of the antiviral drug in hospitalized patients with severe symptoms of the disease.

Gilead Sciences has committed to producing “millions more” treatment courses of its COVID-19 treatment remdesivir in 2021 “if required,” the company said.

“We intend to get that to patients in the early part of this next week,” Gilead chairman and CEO Daniel O’Day said Sunday on CBS’ “Face the Nation.”

Gilead also restated the goal O’Day expressed last month of manufacturing at least 500,000 treatment courses by October—10 times the number of courses now available, he told Bloomberg News on Wednesday—then doubling that number over the following two months, to one million by December.

“We will continue to work with partners across the globe to increase our supply of remdesivir while advancing our ongoing clinical trials to supplement our understanding of the drug’s profile,” O’Day said Friday in a statement. “We are working to meet the needs of patients, their families, and healthcare workers around the world with the greatest sense of urgency and responsibility.”

O’Day spoke soon after President Donald Trump announced from the Oval Office that the FDA had issued an EUA for remdesivir to treat adults and children with suspected or lab-confirmed COVID-19 and severe disease. The agency defined severe COVID-19 as SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

A day earlier on the company’s quarterly earnings call, O’Day told analysts Gilead now expects to spend up to $1 billion this year on manufacturing and development of remdesivir, a figure that could rise even further: “The magnitude of this investment is dependent on the continued evolution of the data, the duration of the pandemic, and other factors,” according to a transcript published by The Motley Fool.

Gilead is also working to build a global consortium of pharmaceutical chemical manufacturers to expand global capacity and production of remdesivir, O’Day added.

“We’ve been ramping up production since January,” O’Day said. “We’ve significantly reduced lead times and expanded our global network of partners. As additional raw materials come available, we’ll have an exponential increase in supplies towards the latter half of this year.”

“Proof of concept”

The FDA based its decision, Gilead said, on available data from two Phase III clinical trials.

One was the Adaptive COVID-19 Treatment Trial (ACTT; NCT04280705), sponsored by the NIH’s National Institute of Allergy and Infectious Disease (NIAID), an adaptive, randomized, double-blind, placebo-controlled trial that is evaluating 1,063 hospitalized adult patients with a broad mix of COVID-19 symptoms.

In that trial, remdesivir outperformed placebo, according to preliminary data showing that the study met its primary outcome of statistically significant improvement in time to recovery by Day 29, based on a 3-point scale: Hospitalized-not requiring supplemental oxygen-no longer requires ongoing medical care; not hospitalized, limitations on home activities and/or requiring home oxygen; and not hospitalized-no limitation on activities.”

Patients who were treated with remdesivir showed a median time to recovery of 11 days compared with 15 days for those who received placebo—a 31% faster time to recovery. “Although a 31% improvement doesn’t seem like a knockout 100%, it is a very important proof of concept,” NIAID director Anthony S. Fauci, MD, said Wednesday.

On Twitter, some researchers took issue with Gilead changing the study’s definition of time to clinical improvement two weeks before the release of data—from the original percentage of patients reporting on day 14 each of eight severity ratings on an 8-point scale, from death to not hospitalized-no limitation on activities.

In a statement shared on Twitter  Thursday by Meg Tirrell of CNBC, NIAID said the shift in endpoint was made before any interim data was available, and reflected growing knowledge by researchers that the course of COVID-19 was more protracted than previously known.

“Further concerns were raised about the reliance on a single time point for evaluating treatment effects. While still blinded to treatment assignment, NIAID statisticians performed modeling of what happens if the right day is not picked for assessment, which revealed that meaningful treatment effects could be missed with that primary endpoint,” the NIH stated. “Time to recovery avoids that issue, and the change in primary endpoint seemed appropriate given the evolving clinical data.”

The other Phase III study whose results swayed the FDA was Gilead’s global SIMPLE trial (NCT04292899) evaluating 5-day and 10-day dosing durations of remdesivir in up to 6,000 patients with severe COVID-19—an estimated enrollment that Gilead more than doubled from 2,400 on Wednesday, and was originally envisioned for up to 400 patients.

While the company has not announced results from the latter trial, leaked results first reported by STAT showed remdesivir treatment in severe COVID-19 patients leading to rapid recoveries in fever and respiratory symptoms with nearly all patients discharged in less than a week. The report was based on a video discussion by the investigator conducting the study at the University of Chicago, one of 169 treatment sites.

5- and 10-day durations

The FDA’s emergency authorization suggests both 5-day and 10-day treatment durations, based on the severity of disease. Gilead previously calculated having 1.5 million doses by the end of May, amounting to 140,000 treatment courses based on a 10-day treatment duration. The company has committed to donating its entire existing supply, but O’Day had no answer to an analyst’s question about the profitability of remdesivir.

“Should we assume the returns are going to be similar to the returns that you’ve generated in other parts of the business?” SVB Leerink director of therapeutics research and senior research analyst, Geoffrey C. Porges, MBBS, asked O’Day on the earnings call.

“There is no rulebook out there, other than that we need to be very thoughtful about how we can make sure we provide access of our medicines to patients around the globe. And do that in a sustainable way for the company for you as shareholders,” O’Day replied.

Brian P. Skorney, CFA, senior research analyst with Baird, on Friday questioned how much profit Gilead can ultimately generate from remdesivir.

“The commercial opportunity, both in terms of initial scale and durability, remains very ambiguous, but we continue to be skeptical that this will be substantially more than a goodwill enterprise for the company,” Skorney wrote in an investor note along with colleagues Jack K. Allen and Luke P. Herrmann.

The EUA also requires that remdesivir be:

  • Administered in an inpatient hospital setting via intravenous infusion by a healthcare provider.
  • Supplied to authorized distributors, or directly to a U.S. government agency, that will distribute to hospitals and other healthcare facilities as directed by the U.S. government, in collaboration with state and local governments.

The U.S. government will coordinate the donation and distribution of remdesivir to hospitals in cities most heavily impacted by COVID-19, Gilead said, adding: “Given the severity of illness of patients appropriate for remdesivir treatment and the limited availability of drug supply, hospitals with intensive care units and other hospitals that the government deems most in need will receive priority in the distribution of remdesivir.”

That level of supply and distribution control is unprecedented, Porges wrote Saturday in an investor note along with colleagues Neil Puri, MD, Ke (Andrew) Yuan, and Bradley Canino: “The biggest surprise in yesterday’s approval was the aggressive stance taken by the federal government in terms of controlling the supply and distribution of this medicine, which is unprecedented in our history of the industry.”

Also unprecedented was how quickly the FDA acted to authorize emergency use of remdesivir, Walid F. Gellad, MD, MPH, associate professor of medicine and director, Center for Pharmaceutical Policy and Prescribing (CP3) at the University of Pittsburgh, asserted Friday in a tweet: “Based on timing, and info in EUA, has FDA hasn’t [sic] even looked at data in the NIH remdesivir trial? Or is it just basing the effectiveness info in its guide to patients on a press release of top line results?”

Porges and his colleagues said the FDA’s emergency action was not a surprise given the positive NIAID preliminary results—which they said were not negated by more negative results in some other studies.

“While this regulatory action is by no means a ringing endorsement of efficacy, we believe the FDA was justified in making the determination that the known and potential benefits of remdesivir outweigh the known and potential safety risks,” the SVB Leerink team added. “We are encouraged to see the FDA opening up treatment with medicines such as remdesivir, and expect other EUA approvals in the coming months.

Gilead is also assessing remdesivir in a third randomized, blinded Phase III study, designed to assess the drug in up to 1,600 moderate COVID-19 patients (NCT04292730), up from the original estimated enrollment of 600.

Remdesivir has also been studied in a pair of Chinese trials that both ended early, with investigators citing low enrollment. The Lancet on Wednesday published results from one of the studies (NCT04257656), showing remdesivir had not reduced the presence of SARS-CoV-2 in the bloodstream of 158 patients treated with the antiviral candidate in the 237-patient trial.

The other Chinese trial (NCT04252664) was designed to assess remdesivir in hospitalized adults with mild-to-moderate forms of COVID-19. Recruitment was suspended in the trial, which had an estimated enrollment of 308 patients.