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 remedesivir 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.
Data for Gilead’s potential coronavirus therapy are coming soon. Here’s what you need to know
