Despite conflicting studies, results from largest trial yet show the antiviral speeds up recovery, putting it on track to become a standard of care in the United States
An experimental drug — and one of the world’s best hopes for treating COVID-19 — could shorten the time to recovery from coronavirus infection, according to the largest and most rigorous clinical trial of the compound yet.
The drug, called remdesivir, interferes with the replication of some viruses, including SARS-CoV-2, which is responsible for the current pandemic. On 29 April, Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID), announced that a clinical trial in more than 1,000 people had showed that those taking remdesivir recovered in 11 days on average, compared with 15 days for those on a placebo.
“Although a 31% improvement doesn’t seem like a knockout 100%, it is a very important proof of concept,” Fauci said. “What it has proven is that a drug can block this virus.”
There were also fewer deaths among trial participants who received the drug, he said, but that trend was not statistically significant. The shortened recovery time, however, was significant, and was enough of a benefit that investigators decided to stop the trial early, he said, to ensure that those participants who were receiving placebo could now access the drug. Fauci added that remdesivir would become a standard treatment for COVID-19.
The news comes after weeks of data leaks and on a day of mixed results from clinical trials of the drug. The drug’s maker, Gilead Sciences of Foster City, California, announced on the same day that in its own trial, more than half of 400 participants with severe COVID-19 had recovered from their illness within two weeks of receiving treatment. But the study lacked a placebo-controlled arm, making the results difficult to interpret. Also on 29 April, a smaller trial run in China announced that it had found1 no benefits from remdesivir when compared with a placebo. But that trial was stopped early owing to difficulty in enrolling participants as the outbreak subsided in China. Nevertheless, onlookers are hopeful that the large NIAID trial provides the first glimmer of promise in a race to find a drug that works against the coronavirus, which has infected more than three million people worldwide.
“There is a lot of focus on remdesivir because it’s potentially the best shot we have,” says virologist Stephen Griffin at the University of Leeds, UK.
Fast-flowing, conflicting information on remdesivir in the past few weeks has left people reeling. In the rush to find therapies to combat COVID-19, small clinical trials without control groups have been common. “I’m just very annoyed by all of these non-controlled studies,” says Geoffrey Porges, a biotechnology analyst for the investment bank SVB Leerink in New York City. “It’s reassuring that 50–60% of patients are discharged from the hospital, but this is a disease that mostly gets better anyway.”
With so much uncertainty, the remdesivir-watchers were waiting anxiously for final results from the NIAID trial, which were not expected until the end of May. In lieu of a vaccine, which could still be more than a year away, effective therapies are crucial in reducing deaths and limiting economic damage from the pandemic. Yet, despite the flood of small clinical trials, no therapy has been convincingly shown to boost survival in people with COVID-19.
The NIAID results put a new sheen on remdesivir.The NIAID did not release detailed safety data. The study in China found no significant difference between remdesivir and placebo in the frequency of adverse events, but 12% of people who received remdesivir dropped out of the study due to side effects including nausea and cardiopulmonary failure, compared to only 5% on placebo.
“It may not be the wonder drug that everyone’s looking for, but if you can stop some patients from becoming critically ill, that’s good enough,” says Griffin.
Fauci said the finding reminded him of the discovery in the 1980s that the drug AZT helped to combat HIV infection. The first randomized, controlled clinical trial showed only a modest improvement, he said, but researchers continued to build on that success, eventually developing highly effective therapies.
Remdesivir works by gumming up an enzyme that some viruses, including SARS-CoV-2, use to replicate. In February, researchers showed2 that the drug reduces viral infection in human cells grown in a laboratory.
Gilead began to ramp up production of remdesivir well before the NIAID results came out. By the end of March, the company had produced enough to treat 30,000 patients. And by streamlining its manufacturing process and finding new sources of raw materials, Gilead announced, it hopes to produce enough remdesivir to treat more than one million people by the end of the year.
That calculation was based on the assumption that people would take the drug for ten days, but the results announced from Gilead’s trial on 29 April suggest that a five-day course of treatment could work just as well. If so, that would effectively double the number of people who could be treated, says Porges.
Many drugs needed
In the long term, clinicians will probably want a bevy of antiviral drugs — with different ways of disabling the virus — in their arsenal, says Timothy Sheahan, a virologist at the University of North Carolina in Chapel Hill, who has teamed up with Gilead researchers to study remdesivir. “There is always the potential for antiviral resistance,” he says. “And to hedge against that potential, it’s good to have not only a first-line, but also a second-, third-, fourth-, fifth-line antiviral.”
Researchers are furiously testing a wide range of therapies, but early results, although not yet definitive, have not been encouraging. The malaria drugs chloroquine and hydroxychloroquine, both of which have anti-inflammatory effects, drew so much attention from physicians and the public that some countries have depleted their supplies of the drugs. Yet studies in humans have failed to show a consistent benefit, and some have highlighted the risks posed by side effects of the drugs that affect the heart.
Early interest in a mix of two HIV drugs called lopinavir and ritonavir flagged when a clinical trial in nearly 200 people did not find any benefit of the mix for those with severe COVID-193. Another promising therapeutic hypothesis — that inhibiting the action of an immune-system regulator called IL-6 could reduce the serious inflammation seen in some people with severe COVID-19 — has met with mixed results thus far.
Still, a host of other therapies are being tested in people, and many researchers are hunting for new drugs at the bench. Sheahan and his colleagues have found4 a compound that is active against SARS-CoV-2 and other coronaviruses, including a remdesivir-resistant variant of a coronavirus, when tested in laboratory-grown human cells.
But much more testing would be needed before the compound could be tried in people. “What we’re doing now will hopefully have an impact on the current pandemic,” he says. “But maybe more importantly, it could position us to better respond more quickly in the future.”
1. Wang, Y. et al. Lancet https://doi.org/10.1016/S0140-6736(20)31022-9 (2020).
2. Wang, M. et al. Cell Res. 30, 269–271 (2020).
3. Cao, B. et al. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2001282 (2020).
4. Sheahan, T. P. et al. Sci. Transl. Med. 12, eabb5883 (2020).
Cover photo: Coronavirus causes severe respiratory illness in some people.Credit: Zhang Yazi/China News Service via Getty