Keeping Remdesivir in Perspective
It’s not a panacea, but it shouldn’t be dismissed either.
Yesterday, data from three remdesivir studies were reported, with seemingly contradictory conclusions. Nonetheless, the end result was a ringing endorsement by Dr. Anthony Fauci and a stock market surge. So here’s what you need to know about how remdesivir works, what the studies found, and how the drug will affect COVID-19 treatment and our overall ability to respond to the pandemic.
A potentially broad-spectrum antiviral
Remdesivir is nucleotide analog that mimics adenosine, which is one of the building blocks of RNA. The drug is thought to be a broad spectrum antiviral, because it theoretically should block any virus that replicates using RNA-dependent RNA polymerase (RdRP). That’s an enzyme that chugs along the viral genome and strings together a new copy, one nucleotide at a time. If RdRP accidentally adds a nucleotide analog instead of the real thing, it gets stuck, and the virus can no longer replicate. Remdesivir was originally developed by Gilead Sciences to treat Ebola, which, like SARS-CoV-2, is a virus with an RNA-based genome. It showed promise against the disease in the lab, in rhesus monkeys, and in patients, but it wasn’t as effective against the virus as antibody treatment. Nevertheless, the Ebola clinical trials demonstrated that remdesivir is safe to use in humans and somewhat useful as an antiviral.
Since then, the drug has also been shown to be effective against the first two deadly coronaviruses that cause SARS and MERS, in the lab and in animals. So when it became clear that another coronavirus disease was spreading in China, Gilead quickly arranged two Phase 3 clinical trials to test remdesivir against COVID-19, led by the China-Japan Friendship Hospital in Beijing and the National Institute of Allergy and Infectious Diseases (NIAID) in the US. About a month later, as seriously ill coronavirus patients and their loved ones became desperate for new treatments, even an unproven one like remdesivir, Gilead announced it would provide the drug outside of clinical trials for compassionate use. During the month of April, data from these studies began to trickle into the media until they grew into a full on flood yesterday.
Promising results for an experimental therapy
The first hint that remdesivir might be an effective treatment for COVID-19 came from Gilead’s compassionate use study, which I discussed in detail in a previous post. Since this study did not have a control group, it was hard to interpret. But if we compare the results to historical controls (i.e. how similar patients usually fare), it did seem like the treatment was helping patients get off ventilators and improving the mortality rate (with the caveat that Gilead got to pick and choose their patients, and could have enrolled people more likely to recover). And then yesterday, the results of three remdesivir studies were announced in rapid succession. First the Lancet, a prestigious medical journal, published the results of the randomized, double-blind, controlled trial led by China-Japan Friendship Hospital. This trial had to be terminated early because there weren’t enough patients to reach the enrollment goal (they only got about halfway). The researchers assigned patients 2:1 to intravenous (IV) remdesivir (158) or placebo (79) for ten days and the primary endpoint was time to clinical improvement up to day 28. They used a six point scale (from 1=discharged to 6=death) and defined clinical improvement as a decline of two levels or discharge from the hospital. The authors reported that there was no statistically significant difference in time to clinical improvement but there was a trend toward faster recovery in the remdesivir group, and that they might have seen a difference if they were able to fully enroll for the study. Soon after these results were published, Gilead released a statement about another study, which was comparing the safety and efficacy of two different dosing regimens for remdesivir — 5 days vs 10 days of the drug. They announced that there was no difference between the two groups and that the time to clinical improvement was 10 days for 5-day treatment group and 11 days for the 10-day treatment group. This study did not include a control arm but Gilead pointed to historical controls, which had an average recovery time of 14 days.
Then, Gilead released a statement that the NIAID trial had achieved its primary endpoint (which was curiously changed two weeks ago from “clinical efficacy” through 14 days to “time to recovery” through 28 days) and $GILD stock got a healthy bump. NIAID backed up this announcement with some details about the study results, although the data have not yet been peer-reviewed or officially published. This randomized, controlled trial included 1063 patients (about four times as many as the Lancet trial) who were hospitalized for COVID-19 and received either a 10-day course of IV remdesivir or a placebo. The researchers found that the remdesivir group had a 31% faster time to recovery (11 days) compared to the placebo group (15 days) — similar to the other Gilead study discussed above — but the mortality rate was not significantly different between the two arms (8% vs 11%, respectively). With that news, Dr. Anthony Fauci sat for a televised statement at the White House to explain the promising results to the public, and the FDA is expected to quickly approve remdesivir for emergency use for COVID-19 treatment.
My thoughts on the new remdesivir revelations
It is not good science to change the primary endpoint of a trial while it’s ongoing — that’s essentially moving the goalpost. Was Gilead aware of the Lancet trial results at the time that the NIAID endpoint changed? It sure seems like it, because the Lancet trial reported no difference in time to clinical improvement (the original primary endpoint for the NIAID trial) but a trend toward decreased time to recovery (the revised primary endpoint). It sure does sound better to investors to say “we’ve reached the primary endpoint” rather than “we didn’t reach the primary endpoint but we found this other positive thing…” At the end of the day, it doesn’t change the data, but it does raise questions about how Gilead is influencing the trial implementation.
The time to recovery result is modest but solid. It was always unlikely that a drug targeting viral replication would be a cure-all for patients who were already sick enough to be hospitalized. Ideally we would want to give remdesivir to patients early, but since the virus appears to have a long pre-symptomatic incubation time and the drug is administered intravenously, this is just not feasible. So cutting a few days off the recovery time might be our best hope for an antiviral like remdesivir.
A new weapon in the fight against COVID-19
Dr. Fauci has suggested that remdesivir will soon become the new standard of care for COVID-19, which means that everyone who is hospitalized for the disease will receive remdesivir, hopefully shortening their stay. This will presumably ease some of the burden on hospitals by freeing up beds and resources for other patients. And of course it means that patients won’t have to endure COVID-19 symptoms for quite as long. If/when remdesivir becomes the standard of care, it also means that all future potential treatments will be compared to remdesivir rather than a placebo, raising the bar for efficacy. Since there is room for improvement, expect to see new trials testing combination therapies. For example, it might make sense to treat with both remdesivir (to hit the virus directly) and an immunomodulatory therapy (to tamp down an overreacting immune system).
Is remdesivir enough to get us all out of our houses? No, but it will help relieve some pressure on hospitals until a vaccine is developed. Until then, it will be important maintain social distancing measures until we have the spread of the virus under control. This will require a dramatic increase in our ability to test for the virus, trace the contacts of positive cases, and isolate those who have been exposed. Let’s hope the US figures out a way to step it up soon.
