Despite conflicting data, results from largest trial that show the antiviral speeds up recovery will make the treatment a standard of care in the United States.
An experimental drug — and one of the world’s best hopes against COVID-19 — could shorten the time to recovery from coronavirus infection, according to the largest and most rigorous clinical trial of the compound.
The experimental drug, called remdesivir, interferes with replication of some viruses, including the SARS-CoV-2 virus responsible for the current pandemic. On 29 April, Anthony Fauci, director of the US National Institute of Allergy and Infectious Disease (NIAID), announced that a clinical trial of more than a thousand people showed that people taking remdesivir recovered in 11 days on average, compared to 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.”
Deaths were also lower in 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 for ethical reasons, 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. In a trial run by the drug’s maker, Gilead Sciences of Foster City, California, more than half of 400 participants with severe COVID-19 recovered from their illness within two weeks of receiving treatment. But the study lacked a placebo controlled arm, making the results difficult to interpret. Another smaller trial run in China found no benefits from remdesivir when compared with a placebo. But the trial was stopped early due to the difficulty in enroling participants as the outbreak subsided in China. Nevertheless, onlookers are hopeful that the large NIAID trial provides the first glimmer of hope in a race to find a drug that works against the coronavirus, which has infected more than 3 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 in the UK.
The fast-flowing, conflicting information on remdesivir has left people reeling over the past weeks. 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, an 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 critical to 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. “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 only showed a modest improvement, he said, but researchers continued to build on that success, eventually developing highly effective therapies. For now, he said, remdesivir would become a standard treatment for COVID-19.
Remdesivir works by gumming up an enzyme that some viruses, including SARS-CoV-2, use to replicate. In February, researchers showed 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. By the end of March, the company had produced enough to treat 30,000 patients. By streamlining its manufacturing process and finding new sources of raw materials, Gilead announced that it hoped to produce enough remdesivir to treat more than a million people by the end of the year.
That calculation was based on the assumption that people would take the drug for 10 days, but the results announced from Gilead’s trial today suggest that a 5-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 likely want a bevy of anti-viral 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, while not yet definitive, have not been encouraging. The malaria drugs chloroquine and hydroxychloroquine, both of which also 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 on 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-19. Another promising therapeutic hypothesis — that inhibiting the action of an immune system regulator called IL-6 could reduce the severe 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 found 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 need to be done 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.”
By: Heidi Ledford
Photo: Coronavirus causes severe respiratory illness in some people.Credit: Zhang Yazi/China News Service via Getty
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