This month, the world should get the first results from a clinical trial testing the drug remdesivir against Covid-19. They will get a lot of attention.
Remdesivir, made by the California biotech Gilead Sciences, is one of the potential Covid-19 therapies that is furthest along in the development process. The results, from studies in China, could signal whether the drug can effectively combat the infection — and under which circumstances. So far, there is no proven treatment for the coronavirus.
But just how much can be gleaned from these announcements? Will they be the final word on remdesivir? And how can the company supply the drug to patients around the world who might need it?
Below, STAT outlines some of the key questions that the announcement will raise.
Remind me what remdesivir is.
Remdesivir is an experimental antiviral that was first cooked up over a decade ago. In lab experiments, it’s shown potential against an array of viruses, including other coronaviruses, so it was sped into clinical trials in the early days of the pandemic.
The drug is designed to interfere with the process the virus, called SARS-CoV-2, uses to make copies of itself. The resulting copies of the virus lack their full RNA genome, so they can’t go on to replicate themselves or infect other cells.
Inspired by the West African Ebola outbreak, Gilead once pushed remdesivir as a potential therapy for that infection. But in a clinical trial, remdesivir did not produce the survival benefits that two other drugs did, and it was dropped as an Ebola therapy.
In addition to researchers at Gilead, scientists at the National Institutes of Health, University of North Carolina, and Vanderbilt University have been involved in studying and readying remdesivir for coronavirus clinical trials.
What’s being announced?
Sometime this month, Chinese scientists will share results from two trials in that country, one looking at patients with severe Covid-19, and one with patients with mild and moderate infections.
The severe Covid-19 trial enrolled 453 patients, and is expected to read out results first, perhaps as early as this week. The patients were allowed to enter the study up to 12 days from the onset of Covid-19 symptoms. Once enrolled, the patients were randomized in a double-blind fashion and were treated with daily infusions of remdesivir or a placebo for 10 days.
The primary goal is to show that the drug is better than placebo at improving symptoms within 28 days. That improvement is measured with a six-point scoring system ranging from hospital discharge (a score of 1) to death (a score of 6). In order to count as someone who responded to the drug, a patient must improve by at least two points. Patients can remain hospitalized at the end of the 28-day period of the clinical trial but still improve enough clinically — no longer needing intubation or supplemental oxygen, for example — to count as a responder.
What are the possible outcomes?
Handicapping the results of the severe Covid-19 study requires some deep-in-the-weeds modeling of biostatistics. Thankfully, Umer Raffat, a biotech analyst at Evercore ISI, has done the heavy lifting for his investor clients.
If people who take the placebo show clinical improvement after 16 days, remdesivir would have to track at 13 days to demonstrate superiority with statistical significance, Raffat said. This would be described in what researchers call a “hazard ratio.” The magic number would be 1.2, meaning that patients do 20% better on remdesivir than placebo.
There is already one red flag. The investigators running the severe Covid-19 study in China have already taken an interim look at the data, but they did not stop the study early. This suggests remdesivir isn’t working as well as hoped, and dampens optimism for an overall positive outcome, Raffat said.
It’s also possible the trial will produce mixed results.
What do you mean, “mixed”?
If the data from the remdesivir trials show the drug did not have clear benefits overall, experts will still look to see what kind of impact it had for patients who were treated early in the course of their illness. Remember, patients were allowed to enter the severe Covid-19 study even 12 days after they started showing symptoms.
Generally, antivirals are most effective if they are given soon after a person is infected. This allows them to slow the replication of the virus while it is still at low levels. If a treatment is given too late, and the virus has had a full chance to proliferate, it’s possible that the cascade of health consequences cannot be stopped.
So a key question for the remdesivir data will be if the timing of treatment had an impact on its performance.
What’s the status of the other remdesivir clinical trials?
As mentioned above, there is a second study of remdesivir underway in China that enrolled just over 300 patients with mild or moderate Covid-19. That study is also expected to read out results this month. The patients will be treated with remdesivir or a placebo for 10 days and then followed to determine how quickly they show signs of “clinical recovery” — defined as normal readings for fever, respiratory rate, oxygen saturation and alleviation of cough.
At least four additional clinical trials of remdesivir are underway, including two sponsored by Gilead, both of which are expected to read out in May. Another comes from the U.S. National Institute of Allergy and Infectious Diseases. The World Health Organization is also running the “Solidarity” trial that is testing remdesivir as well as other drugs and drug combinations. So this is not the final word on remdesivir’s potential to fight Covid-19.
If it’s approved, would remdesivir be recommended for all patients with Covid-19?
It depends on what the data from the clinical trial show, but there’s a sense that there’s a sweet spot for remdesivir. The drug is given intravenously, and because of that, there’s the thought that it only makes sense for patients who are sick enough that they wind up in the hospital. Others seem to be able to fight the infection off on their own at home, even if they feel very ill for a few days.
But the patients who are so sick they need hospital care might not progress to that point for perhaps a week after showing symptoms. There’s a concern that by that time, remdesivir won’t be as effective as it would have been if given earlier. So experts will be looking closely at the data to try to parse out how and when to give the drug.
If remdesivir works, there’s going to be a huge demand for it. How will the company deal with that?
Gilead has been ramping up production of the drug since January and, as of now, has 1.5 million doses, which is enough for 140,000 patients, CEO Daniel O’Day wrote in an open letter released Saturday. He said the company has converted some of its facilities to churn out remdesivir and is working with partners around the world to boost its manufacturing. The company’s goal is to have 1 million treatment courses available by the end of the year.
Why is getting a proven therapy important?
At an individual level, people who get sick from Covid-19 will want a drug that can stave off more severe disease and help them recover faster. But more broadly, an effective drug that gets people out of hospitals faster will help reduce the burden on health care systems. Knowing there is something that can aid people who do get sick could also help countries feel more comfortable reopening their economies. In a way, effective therapies can buy the world time before a vaccine is approved.
If remdesivir is approved, how much will it cost?
Gilead hasn’t commented on pricing, though it’s said it does not expect remdesivir to be a commercial boon if it’s approved. There will be immense pressure on the company to make the drug widely available, particularly if the pandemic starts to lead to health crises in less developed countries that cannot afford pricey drugs.
Have people been getting remdesivir outside of clinical trials?
Yes, including the person with the first known Covid-19 case in the United States. Gilead has been supplying the drug through expanded access programs (essentially, a way to get an experimental drug outside of a clinical trial), and in the letter Saturday, O’Day wrote that “more than 1,700 patients have now been treated through these programs.” Still, some clinicians and family members of patients have said they have been unable to obtain the drug.
What would remdesivir’s success mean for Gilead?
The last few months of remdesivir news have played out like Gilead’s corporate history in miniature. In the early days of the outbreak, the company quickly mobilized clinical trials, treated thousands of patients for free, and committed to making the drug available to anyone who needs it. Then, in late March, the FDA granted Gilead’s request for a special designation that would extend remdesivir’s patent protection if it’s approved, news that brought familiar accusations of profiteering and exploiting regulatory loopholes.
Gilead quickly asked the FDA to rescind that designation and has since echoed its earlier promises to make remdesivir accessible. But the blip of controversy underlines the delicacy of Gilead’s position. Over the past three decades, the company’s work has helped make HIV a manageable chronic disease and turned hepatitis C into a curable infection. But the prices for both of those drugs were heavily criticized, and the resulting revenue transformed Gilead into a multibillion-dollar biotech success story. It also invited protest, castigation, and legal action, most recently in a patent dispute with the Department of Health and Human Services.
Remdesivir, if it works, is poised to put Gilead in a difficult PR situation. Investors expect a return, as the promise of remdesivir has added $16 billion to Gilead’s market value since the start of the year. But public health advocates, already skeptical of Gilead’s business model, will be watching closely for even a whiff of profiteering.
What other treatments are being tested and might have results soon?
There are hundreds of different studies testing treatments against Covid-19, but only a few of them are likely to read out this year. The Food and Drug Administration recently approved a program to make it easier for patients to receive blood plasma from those who have recovered from the illness as a treatment.
Some of the first studies available after remdesivir’s readouts will be of immune modulating drugs, such as Roche’s Actemra and Regeneron’s Kevzara. Both are aimed at helping patients in severe respiratory distress. There are also studies ongoing of other antiviral drugs, including older medicines like the malaria drug hydroxychloroquine. But studies that start now may not read out for months, meaning that new medicines may not be available until summer or later.
Outstanding and I am delighted to see there is at least one commentators with some regulatory expertise (that is you)!
I would like to add that withholding from the place arm patients a drug that is clearly effective would also be morally and ethically unacceptable, and that stopping a harmful drug during trials can also require by the FDA.
More importantly, stopping a trial to the drug being tested to the placebo arm patients have happened with GIlead in the past with its superlative HIV nd HCV drugs.
With all due respect, how many times have you heard Dr. Fauci stating very clearly and explicitly that he feels vaccine is at least 18 months away? Of course vaccine is better than any drug treatment but are you willing to wait for it rather than being treated by say hydrochloroquine or remdisivir even if they are only mildly effective? Not to be callous but how long would you be willing to be hooked up to a ventillitator until there is an effective vaccine?
An FDA approved vaccine may be 12 months, or 18 months, of for all I know, 81 months away, but that does not mean people will not be creating vaccines much sooner.
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