Editor’s note: This article was originally posted on April 17, 2020, and is being updated as new information becomes available.
On May 1, the Food and Drug Administration granted emergency use authorization (EUA) for remdesivir, an antiviral medication being developed by Gilead Sciences. The EUA will cover treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.
FDA issued an Emergency Use Authorization (EUA) to Gilead Sciences, Inc. for the investigational antiviral drug remdesivir – which has been shown to shorten recovery time in some #COVID19 clinical trial patients – to treat suspected or confirmed #COVID19. https://t.co/indPpdMi7d pic.twitter.com/4RsJ5YyK07— Dr. Stephen M. Hahn (@SteveFDA) May 1, 2020
A week later, on May 7, Japan became the first country to grant regulatory approval of remdesivir, which will be sold under the brand name Veklury, according to a Gilead press release.
On April 29, the National Institutes of Allergy and Infectious Diseases (NIAID) announced early data from a placebo-controlled clinical trial showing that remdesivir led to quicker recovery in COVID-19 patients with advanced disease. On the same day, Gilead also released promising data from a remdesivir study without a placebo control. In addition, previously leaked results from a randomized trial in China were published in a medical journal, this one showing that remdesivir did not appear to improve clinical outcomes in hospitalized COVID-19 patients.
The NIAID study showed that remdesivir “has a clear-cut, significant positive effect in diminishing the time to recovery,” NIAID director Anthony Fauci, MD, said at an April 29 White House new briefing. “This is a very important proof of concept, because what is has proven is that a drug can block this virus.”
Dr. Fauci says he was told data from a coronavirus drug trial testing Gilead’s remdesivir shows that “remdesivir has a clear cut significant, positive effect in diminishing the time to recovery.” https://t.co/kaovCY312w pic.twitter.com/cXcCcf750l— CNBC (@CNBC) April 29, 2020
Because a majority of people with COVID-19 recover without treatment, it’s important to compare experimental therapies against a placebo in randomized trials to determine how much the new drug helps. Once a treatment has been found to work better than a placebo, it can then become the standard of care and the basis of comparison in randomized studies of other therapies.
Remdesivir is a nucleotide analogue, in the same drug class as the HIV and hepatitis B medication Viread (tenofovir disoproxil fumarate) and the hepatitis C direct-acting antiviral Sovaldi (sofosbuvir), both also manufactured by Gilead. These drugs interfere with the viral polymerase enzyme (which in the case of HIV is known as reverse transcriptase), acting as defective building blocks that prevent a virus from copying its genetic material.
As National Institutes of Health director Francis Collins, MD, PhD, described in a recent blog post, it is not uncommon for drugs to show activity against multiple viruses in the laboratory. But they must be tested in patients to determine if they actually work against a specific disease. Remdesivir was originally developed to treat Ebola virus, but proved ineffective. In animal studies, it showed activity against SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), which are caused by coronaviruses related to the one that causes COVID-19 (officially known as SARS-CoV-2).
Severe COVID-19 illness is caused partly by the coronavirus itself and partly by the immune system’s response to it. Just as antivirals for HIV and hepatitis C work best when used early, before they cause severe immune system or liver damage, remdesivir and other medications that halt SARS-CoV-2 virus replication may be more effective when used before severe lung damage occurs. Later on, combining antivirals with anti-inflammatory drugs that control the excessive immune reaction known as a cytokine storm might (for example, Actemra, or tocilizumab) might produce the best outcomes. Clinical trials of remdesivir in combination with other drugs are currently underway.
NIAID ACTT Trial
The latest findings come from NIAID’s Adaptive COVID-19 Treatment Trial, which has study sites in the United States and several other countries. This analysis included 1,063 hospitalized patients with advanced disease who were randomly assigned to receive remdesivir or a placebo administered intravenously.
On April 27, the study’s independent data and safety monitoring board notified Fauci and the trial investigators that remdesivir worked significantly better than the placebo, meaning the results were probably not attributable to chance. The median time to recovery was 11 days in the remdesivir group compared with 15 days in the placebo group—a 31% improvement. The study also saw a trend toward improved survival, with mortality rates of 8% in the remdesivir group versus 12% in the placebo group, but this did not reach statistical significance. People assigned to the placebo group were then offered remdesivir. The study will next compare remdesivir against the anti-inflammatory drug Olumiant (baricitinib), which is currently approved for rheumatoid arthritis, without a placebo group.
“This is reminiscent of 34 years ago, in 1986, when we were struggling for drugs for HIV. We had nothing, and there were a lot of anecdotal reports that maybe they work, maybe they don’t,” 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 end game. Building on that, every year after, we did better and better.”
Randomized Trial in China
On April 23, STAT leaked results from a randomized clinical trial of remdesivir in China, which was stopped early because there were no longer enough patients once the COVID-19 epidemic there was brought under control. The results were accidentally posted to the World Health Organization website but quickly taken down. Results from that trial were later published in the April 29 online edition of The Lancet.
The study enrolled 237 adults with COVID-19 at 10 hospitals in Hubei, China. They had an oxygen saturation of 94% or less or another measure of impaired respiration as well as confirmed pneumonia as indicated by lung scans. They were randomly assigned to receive IV remdesivir or a placebo for 10 days. They were allowed to also use other medications including Kaletra (lopinavir/ritonavir), interferons and corticosteroids.
Remdesivir did not significantly speed up improvement of symptoms or reduce the likelihood of death compared with the placebo. The researchers also saw no significant differences in length of hospitals stay, time on ventilators or how long to took to clear the coronavirus. The study did suggest faster improvement among those treated earlier—within 10 days of symptom onset—but that difference was not statistically significant. Adverse events were about equally common in both groups, but more people using remdesivir stopped treatment early due to adverse events (12% versus 5%).
“In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies,” the researchers concluded.
Responding to the leaked data, a Gilead spokesperson said that the company still believes “trends in the data suggest a potential benefit for remdesivir, particularly among patients treated early in disease.” However, Andrew Hill, PhD, of the University of Liverpool, told STAT, “If there is no benefit to remdesivir in a study this size, this suggests that the overall benefit of remdesivir in this population with advanced infection is likely to be small in the larger Gilead trial.”
Gilead SIMPLE Trial
Also on April 29, Gilead announced early results its SIMPLE trial, which is comparing five versus 10 days of remdesivir in patients hospitalized with severe COVID-19. At study entry, they had evidence of pneumonia and reduced oxygen levels that did not require mechanical ventilation.
The study aims to enroll about 6,000 people in countries around the world, including the United States, five European countries (including hard-hit Italy and Spain), China and five other countries in Asia. This interim analysis included 397 patients. All participants in this open-label study were randomly assigned to receive IV remdesivir for five or 10 days. There was no placebo group.
Both regimens worked about equally well, according to a Gilead press release. The median time to clinical improvement was 10 days in the five-day treatment group and 11 days in the 10-day group. This was defined as an improvement of two or more points on a seven-point scale, ranging from hospital discharge to the need for increased oxygen support to death.
At the two-week mark, 65% of people in the five-day group and 54% in the 10-day group experienced clinical recovery, defined as hospital discharge or no longer requiring oxygen support and medical care for COVID-19. By two weeks, 60% of people on the five-day regimen and 52% of those on the 10-day regimen had been discharged from the hospital.
Here, too, early treatment led to better outcomes, with hospital discharge rates of 62% for those who started either remdesivir regimen within 10 days of symptom onset versus 49% for those who started later.
Death rates were 8% in the five-day group and 11% in the 10-day group. The results differed somewhat by country, with patients in Italy faring worse. Outside of Italy, the overall mortality rate was 7% across both groups.
Gilead described remdesivir as “generally well tolerated” in both treatment groups, including about 5% with severe (Grade 3 or higher) side effects. The most common adverse events were nausea and acute respiratory failure. About 7% experienced severe ALT liver enzyme elevation, with 3% stopping treatment for this reason.
“Unlike traditional drug development, we are attempting to evaluate an investigational agent alongside an evolving global pandemic,” said Gilead chief medical officer Merdad Parsey, MD, PhD. “The study demonstrates the potential for some patients to be treated with a five-day regimen, which could significantly expand the number of patients who could be treated with our current supply of remdesivir. This is particularly important in the setting of a pandemic, to help hospitals and healthcare workers treat more patients in urgent need of care.”
Parsey added that, “Multiple concurrent studies are helping inform whether remdesivir is a safe and effective treatment for COVID-19 and how to best utilize the drug.” A second SIMPLE trial is evaluating five-day and 10-day regimens of remdesivir in people with moderate rather than advanced COVID-19. Results from the first 600 patients in that study are expected in late May.
More Leaked Trial Data
On April 17, STAT reported on preliminary outcomes at a Chicago hospital that is treating severely ill COVID-19 patients as part of a Phase III trial. This study site enrolled 125 participants, 113 of whom had severe disease. They were all treated with daily IV infusions of remdesivir, with no placebo group.
A Chicago hospital treating severe Covid-19 patients with Gilead Sciences’ antiviral medicine remdesivir in a closely watched clinical trial is seeing rapid recoveries in fever & respiratory symptoms, with nearly all patients discharged in less than a week https://t.co/YeePsK5ymW— STAT (@statnews) April 17, 2020
The report was based on comments from study investigator Kathleen Mullane, DO, PharmD, of the University of Chicago, made during a video discussion with colleagues. Her remarks were not intended for the public, and the study results have not yet been peer-reviewed or published in a scientific journal.
The patients recovered more quickly than would have been expected without treatment. Their fevers decreased rapidly, respiratory symptoms improved and some were able to come off ventilators soon after starting treatment.
“The best news is that most of our patients have already been discharged, which is great,” STAT quoted Mullane as saying in the video. “We’ve only had two patients perish.”
Although preliminary, these results were greeted with optimism.
“Even without a control, if those results hold up, that’s awfully promising,” Bob Wachter, MD, chair of the Department of Medicine at the University of California at San Francisco tweeted after seeing the leaked findings.
Gilead declined to provide further information about the Chicago findings. “We understand the urgent need for a COVID-19 treatment and the resulting interest in data on our investigational antiviral drug remdesivir,” the company said in a statement. “The totality of the data need to be analyzed in order to draw any conclusions from the trial. Anecdotal reports, while encouraging, do not provide the statistical power necessary to determine the safety and efficacy profile of remdesivir as a treatment for COVID-19.”
Compassionate Use Findings
In the April 10 online edition of The New England Journal of Medicine, investigators published early data from Gilead’s compassionate use program, which provided remdesivir to people with advanced disease outside of formal trials.
This analysis included 61 hospitalized COVID-19 patients who had low oxygen levels or were receiving oxygen support. A majority were men over 60 with underlying health conditions including hypertension or diabetes—a population known to be at higher risk for more severe disease.
All patients were treated with a 10-day course of remdesivir given by IV infusion. Post-treatment data were available for 53 of them (22 in the United States, 22 in Europe or Canada and 9 in Japan). Of these, 30 (57%) were on mechanical ventilators and four (8%) were receiving extracorporeal membrane oxygenation, a method that withdraws blood, adds oxygen and returns it to the body.
Over a median follow-up period of 18 days, 36 patients (68%) needed less oxygen support, including 17 who were able to come off ventilators. Nearly half the patients (47%) were discharged from the hospital. Seven people died, yielding mortality rates of 18% among those on ventilators and 5% (representing one patient) among those who did not need ventilators. Everyone who was taken off a ventilator survived.
No unexpected side effects were reported. About a quarter of the patients experienced mild to moderate ALT or AST liver enzyme elevations, and two of the four people who stopped treatment prematurely did so due to elevated liver enzymes. Twelve people on ventilators experienced serious adverse outcomes, including multiple organ failure, septic shock, acute kidney injury or shock.
“Currently there is no proven treatment for COVID-19. We cannot draw definitive conclusions from these data, but the observations from this group of hospitalized patients who received remdesivir are hopeful,” lead study investigator Jonathan Grein, MD, of Cedars-Sinai Medical Center in Los Angeles, said in a Gilead press release. “We look forward to the results of controlled clinical trials to potentially validate these findings.”
Remdesivir in Monkeys
On April 17, NIAID announced findings from an animal study of remdesivir in rhesus macaque monkeys infected with SARS-CoV-2. These results were posted on the preprint server bioRxiv and have not yet been peer-reviewed.
Like human, infected moneys had evidence of pneumonia on lung scans and high viral loads in swab samples from the nose and throat as well as in lung fluid.
Two groups of six monkeys were infected with SARS-CoV-2. Twelve hours later, one group received a dose of IV remdesivir, followed by a daily booster dose for the next six days. Researchers timed the initial treatment to occur shortly before the virus reached its highest level in the lungs, according to a NIAID press release. The other six monkeys did not receive any treatment.
The monkeys who were treated early with remdesivir had significantly less breathing difficulty, lower virus levels in the lungs and less lung damage compared with untreated animals. Twelve hours after the first dose of remdesivir, the six treated monkeys showed mild breathing difficulty while all six untreated animals showed rapid and difficult breathing.
Importantly, although remdesivir improved clinical outcomes, it did not reduce virus shedding. If this finding is confirmed in humans, it would suggest that people can still transmit the coronavirus while being treated with remdesivir.
“The efficacy of direct-acting antivirals against acute viral respiratory tract infections typically decreases with delays in treatment initiation,” the study authors wrote. “Thus, remdesivir treatment in COVID-19 patients should be initiated as early as possible to achieve the maximum treatment effect.”
Commenting on these and other study findings in an April 10 open letter, Gilead chairman and CEO Daniel O’Day wrote, “In studying remdesivir, the question is not just whether it is safe and effective against COVID-19 but in which patients it shows activity, how long should they receive treatment and at what stage of their disease would treatment be most beneficial. Many answers are needed, which is why we need multiple types of studies involving many types of patients.”
Other Drugs in the Pipeline
Researchers are testing dozens of other treatment candidates for COVID-19, many of which are currently approved for other conditions. Hundreds of clinical trials of potential therapies are now underway.
Studies of chloroquine and hydroxychloroquine (Plaquenil), two inexpensive malaria medications touted by President Donald Trump, have so far have yielded mixed but largely disappointing results. A study in Brazil was recently halted after patients receiving high doses of chloroquine experienced serious cardiac side effects.
As POZ recently reported, the HIV antiretroviral pill Kaletra (lopinavir/ritonavir) proved no more effective than standard supportive care in one of the first clinical trials of the drug. The company that manufactures another HIV protease inhibitor, Prezista (darunavir), warned that it is unlikely the drug will have significant activity against the coronavirus.
Doctors are permitted to prescribe drugs that are approved for other conditions “off label” for COVID-19. However, medical experts and advocates urge caution about the premature use of experimental therapies before randomized clinical trials prove they are safe and effective.
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