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More data needed to determine best use of remdesivir in COVID-19 patients

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The latest remdesivir data in moderate COVID-19 patients suggest that the therapy’s Emergency Use Authorization should cover only a five-day course of treatment, which would stretch supplies to treat more patients. But the question remains of how to prioritize which patients receive the antiviral in order to reduce the overall number of deaths, especially in light of limited supply.

Gilead Sciences Inc. (NASDAQ:GILD) said Monday that in the Phase III SIMPLE study, patients with moderate COVID-19 who received remdesivir for five days were 65% more likely to have clinical improvement by day 11 compared with standard of care (p=0.017; 95% CI: 1.09, 2.48). However, the 10-day treatment course failed to achieve statistical significance (odds ratio=1.31, 95% CI: 0.99,1.95; p=0.18).

No patients died in the five-day arm, while two and four patients died in the 10-day and standard of care arms, respectively.

The open-label study enrolled 584 hospitalized patients with confirmed COVID-19 infection and evidence of pneumonia without reduced oxygen levels. The primary endpoint was improvement in clinical status at day 11 as measured by a seven-point ordinal scale.

Remdesivir’s EUA, which FDA granted on May 1, covers both five- and 10-day treatment courses for adults and children hospitalized with lab-confirmed COVID-19 and severe disease. Severe disease is defined as blood oxygen saturation <94% on room air, requiring supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

The authorization was based on data in severe COVID-19 patients reported in April from NIH and Gilead.

In the National Institute of Allergy and Infectious Diseases’ Phase III ACTT study, remdesivir met the primary endpoint, leading to an 11-day recovery time vs. 15 days for placebo (p<0.001). Gilead’s Phase III trial found that 65% of severe COVID-19 patients treated for five days had a two-point or greater clinical improvement on day 14 vs. 54% of those treated for 10 days (odds ratio=0.75, 95% CI: 0.51,1.12) (see “Remdesivir’s Challenge”).

Neither of the biotech’s two trials was placebo-controlled.

Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center, told BioCentury that while strong, unbiased data for remdesivir are still lacking, the evidence seems to suggest so far that a five-day course of treatment is as good or better than a 10-day course.

Modifying the EUA to cover only a five-day course would allow a larger number of people to be treated.

“We don’t have as much remdesivir as we have COVID-19, and we have left the allocation decisions somewhat in the hands of clinicians,” said Bach, who called for data-driven guidance on how to distribute remdesivir. “If it’s a treatment of limited supply, every dose should provide as much life as possible.”

Open questions
A figure that could shed more light on remdesivir’s efficacy, and who should receive the antiviral, is number needed to treat (NNT) -- a statistic that describes how many people need to receive a treatment for one person to live instead of die.

Applying a 0.74 hazard ratio for remdesivir to the SIMPLE study’s 1% mortality rate, the antiviral would have an NNT of 400, “which means you have to treat 400 people to prevent one death,” Bach said.

The hazard ratio was reported as part of the detailed ACTT trial data published in The New England Journal of Medicine last month. The study also showed that remdesivir led to no difference in patients receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) as well as high-flow oxygen or non-invasive mechanical ventilation (see “NIH’s Detailed Remdesivir Data”).

“Probabilistically, people who aren’t very sick at the get-go are very unlikely to die,” Bach said. “We also know from the NIH trial that people who are severely ill don’t get a benefit.”

There is a patient “sweet spot” between the moderate and severe poles for whom remdesivir should be prioritized, Bach hypothesized: a patient who needs oxygen but is not severely ill, who is in the early stages of disease and has had symptoms for only a handful of days at most.

However, it’s still unclear the maximum number of days a COVID-19 patient can have symptoms before it’s too late to receive a benefit from remdesivir. Gilead did not report the time from symptoms to first dose in SIMPLE Monday.

“We are trying to read tea leaves when we should have highly accurate information,” Bach said.

Remdesivir is being evaluated in two ongoing master protocols: The World Health Organization’s Solidarity trial, and the Discovery trial run by the Institut National de la Santé et de la Recherche Médicale (INSERM) (see U.K. Sets the Bar for COVID-19 Master Protocols).

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