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Infectious disease

What can initial remdesivir data tell us about tackling COVID-19?

Gilead Sciences’ antiviral is in multiple late-stage trials to treat coronavirus infections. Don’t expect a home run, say infectious disease experts

by Lisa M. Jarvis , with reporting by Bethany Halford
March 27, 2020 | APPEARED IN VOLUME 98, ISSUE 13

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Credit: Newscom
Gilead's antiviral remdesivir is being tested in multiple late-stage studies in China and the US to treat COVID-19.

In the coming weeks, the world will get a sense of whether Gilead Sciences’ remdesivir, an antiviral developed for Ebola, is useful against the novel coronavirus. With the coronavirus pandemic spiraling—during the week of March 23, worldwide infections crossed 500,000 and deaths shot towards 25,000—initial results emerging from several late-stage studies will be under the microscope.

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But infectious disease experts on the front lines warn that the data are unlikely to clearly answer the question of whether remdesivir works in COVID-19, the respiratory illness caused by the SARS-CoV-2 virus. Those first tests are in the sickest, hardest-to-treat, patients. Moreover, antivirals don’t have a great track record at taking down coronaviruses, which can be a little more sophisticated than your average RNA virus.

Still, some industry watchers hope the studies signal enough success to convince the US Food and Drug Administration to approve Gilead’s experimental drug.

When a new infectious disease threatens the world, researchers’ first move is to look for any existing therapies that might work against it. As Sina Bavari of Edge Bioinnovation Consulting and Management puts it, when you’re really hungry, you’d rather take a lasagna out of the freezer than make one from scratch. Bavari previously spent many years as chief scientific officer at the US Army Medical Research Institute of Infectious Diseases.

As the coronavirus began to spread, one of the first compounds to be pulled from the freezer was remdesivir. Discovered by Gilead and the Army institute during the 2014 Ebola outbreak in West Africa, the RNA polymerase inhibitor seemed like a sound choice. Although it turned out not to work in Ebola—a failure many blame on how late in the progression of the disease it was given—studies in both healthy and infected people showed the drug is fairly safe.

And researchers point to solid science for why remdesivir might still work against COVID-19.

The SARS-CoV-2 genome is made up of a string of nucleotides that, during replication, are reconstructed, one by one, by the viral polymerase. The RNA-dependent RNA polymerase is a good drug target because it is “almost exclusively associated with the virus,” says University of Wisconsin–Madison virologist Andy Mehle. Polymerase inhibitors will be highly specific for infected cells, sparing healthy ones.

Enter remdesivir, which acts like a mimic for adenosine—one of the nucleotides in that string.

The virus is tricked into incorporating the active form of the drug into its genome, preventing it from making more copies of itself. The mechanism by which remdesivir does that is still unclear, but “polymerase inhibitors primarily work by causing mutations of the genome, or by blocking polymerase function,” Mehle says.

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Although Gilead developed remdesivir for Ebola, which belongs to a different family of viruses than SARS-CoV-2, the “viral machinery has elements in common,” Erica Ollmann Saphire, a virus expert at the La Jolla Institute for Immunology, said in an email. Those common elements include polymerases, meaning that for any “safe, bioavailable and manufacturable molecule, the only remaining question is will it work against this other virus,” she said.

While remdesivir was being tested in people with Ebola, several academic and government groups were exploring its potential to take down other viruses, including the coronaviruses that cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). They showed in both lab experiments and animal studies that remdesivir could treat infections and prevent them altogether—what scientists call prophylaxis.

In fact, remdesivir is one of only two highly effective compounds to come out of six years of screening against coronaviruses, says Mark Denison, a coronavirus expert and director of the Division of Infectious Diseases at Vanderbilt University Medical Center. Denison has collaborated with labs at the University of North Carolina and elsewhere to find small molecules that keep coronaviruses from replicating—and still work if the virus mutates. The other effective compound, EIDD-2801, was discovered by Emory University chemists and recently licensed to Ridgeback Biotherapeutics.

One reason so many compounds failed is that coronaviruses are a little smarter than other RNA viruses. They’re the only ones with a polymerase that can fix errors in their genomes, meaning they can spot and ignore the mimics that drug hunters typically design. Denison’s lab found that remdesivir, like EIDD-2801, can bypass that proofreading function.

Those studies, combined with the Ebola safety data, provided a rationale for trying the compound against the new coronavirus.

At the moment, five Phase III studies are testing the drug against COVID-19. Two began in China in early February—one in people with severe disease, the other in those with mild to moderate disease. One is a US National Institutes of Health–led study that started in February to test the drug in anyone hospitalized with evidence of lung involvement. And two are Gilead-led studies that started in March—one in severe disease and the other in moderate disease.

The first data should come from the studies in China, followed quickly by an initial report from Gilead. With so much pressure to find a COVID-19 treatment—even a modestly effective one—the results will be closely scrutinized. But many on the front lines caution that, even though the studies were carefully designed, the answers might not be clear cut.

“I don’t think the ongoing trials will tell us a lot,” says H. Clifford Lane, clinical director at the National Institutes of Allergy and Infectious Diseases, who is overseeing ongoing studies at the NIH, including its remdesivir study. “The studies might give us some hint, but I do think it will be important to get a study launched that focuses on early disease”—before it becomes severe.

A likely scenario is that several studies “don’t reach statistical significance but show a similar result, and that might be enough to say we should probably be using this,” Lane says. “It’s really hard to know what to do.”

Libby Hohmann, associate professor of medicine and infectious diseases at Massachusetts General Hospital, is similarly cautious. “It’s going to be a challenge to review the data because the protocol allows a wide range of illness into it,” says Hohmann, who leads the hospital’s participation in NIAID’s remdesivir trial. “Unless it’s sort of a home run, it may be difficult to parse at the get go.”

One issue is that the first studies to read out are the ones focused on the most severe cases, people whose disease might have progressed past the point of help by an antiviral.

“Everything we do in infectious disease is better treated when it’s early on and the bacterial or viral burden and the damage done is lesser,” Hohmann says. Doctors are realizing that COVID-19 is a two-phase illness, she says, that starts with upper respiratory symptoms that worsen after a week to two weeks. At some point during that period, patients “fall of a cliff,” Hohmann notes. “There’s a lot of data and speculation that it’s a kind of immunological phenomenon,” where certain people’s immune or inflammatory response goes awry.

So if those first data in severe or even moderate cases are unclear, it doesn’t necessarily mean the drug doesn’t work. Rather, it could just mean it isn’t being given early enough.

But even if patients are treated early, the benefits could be minimal, Lane warns. Consider, for example, the limitations of Tamiflu (oseltamivir), a common treatment for another virus, influenza. To have any effect, the drug must be taken within 48 hours of symptoms appearing. And even then, “the overall impact on clinical outcomes is not very dramatic,” Lane says. “We don’t have a lot of success in treating RNA viruses.”

In the ideal scenario where the trials do look good, caveats still abound. Ideally, doctors would deploy the drug either prophylactically or just after exposure, but before symptoms appear. Edge Bioinnovation’s Bavari calls it “something to give before you actually go to the hospital so you don’t end up in the hospital.”

But remdesivir can only be given intravenously, so “it’s not like we’re going to be able to give it to people with the sniffles out in the real world,” Hohmann says.

Nonetheless, her team has been trying to enroll people with a better chance of responding to the drug. Among the 16 patients her clinic has signed up so far, she’s emphasized younger people and those with mild to moderate disease—the ones with shortness of breath rather than those being intubated in the emergency room. “I think we will be able to tell if we’re making a difference in those people,” Hohmann adds.

Gilead says it has no plans to turn remdesivir into a pill. “Based on our understanding of remdesivir from preclinical studies, intravenous administration allows for the most stability and appropriate levels of the drug in the blood system,” a company spokesperson tells C&EN.

Another roadblock is manufacturing. Gilead’s spokesperson notes that “there are currently limited available clinical supplies of remdesivir, but we are working to increase our available supply as rapidly as possible.” For example, the firm is beginning in-house manufacturing of the drug, which had been made only by contract manufacturers. The biotech firm has also added new manufacturing partners around the world to enhance sourcing of everything from raw materials to the finished drug.

Despite the many caveats attached to remdesivir, stock analysts who cover Gilead say it has a reasonable chance of reaching the market. “No one expects it to be a magic bullet,” says Piper Sandler analyst Tyler Van Buren. “But if it works at all in a portion of patients, especially in severe ones, that is very meaningful.” If remdesivir can reduce the need for ventilators or time on supplemental oxygen, Van Buren argues, it could alleviate burden on the healthcare system.

While the FDA approval process typically takes 6–12 months, “this is an unprecedented, once-in-a-century situation,” Van Buren says. Gilead has been submitting as much data as possible to regulatory agencies to expedite approval, he notes. “If the data does look good, there will be tremendous pressure for FDA to make a decision within days.”

If that happens, could the world end some of the more extreme social distancing measures and start getting back to business? “I think it will depend on the level of efficacy,” NIAID’s Lane says. “The goal remains to prevent the spread of infection. While an effective therapy might have some effect, I doubt it would have a major impact.”

Even in the best-case scenario, where remdesivir moves the needle for patients in a meaningful way, successful deployment will require a health care workforce capable of administering it. Because of shortages of personal protective equipment (PPE) and other supplies, Mass General’s Hohmann says, conditions are already difficult—and the worst is yet to come.

“It’s just a challenge because the clinical workforce is overworked, nervous, worried about their own health, worried about the lack of PPE, and about the tsunami of patients that’s coming,” she says. “If we had all the PPE we need, such that nobody had to worry about going into the room of a patient with known disease, life would be a lot easier around here.”

UPDATE

This story's byline was updated on March 31, 2020, to recognize additional reporting by Bethany Halford.

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Comments
Daniel Wigger (March 27, 2020 4:27 PM)
I agree with the analysis but disagree with the conclusion. Even if the drug will only have limited success, it's still our best hope. Think about: Even if you can only save 10% from death, that would be already 10 000s! And most study show that it helped in half the cases. Who are these specialists that they can wait for the final study while people are actually dying, 1000s every day! This is a cruel experiment with human lifes. FDA should step in and accept Remdesivir for emergency use and in huge amounts.
Haresh Patel (April 26, 2020 2:52 PM)
I speculate that Remdesvir works if given soon after infection rather than in advanced stages. Viruses and bacteria grow at a fast rate like doubling every 30 minutes in an infected body. If a drug kills 50% of the virus cells, the remaining one will double in 30 minutes so you cannot keep up. Initially, there may be a smaller number of cells that Remdesvir can kill most of them with a safe dose. Once the number has grown so large that a dose that will kill most cells will damage or destroy body cells. I am not a bioscientist but we know that an antibiotics course must be completed to ensure complete elimination of the bacteria otherwise they will regrow.
Buzz (March 28, 2020 9:53 AM)
“We don’t have success at treating RNA viruses”

The myriad of treatments for HCV suggests otherwise...
antivirals (March 28, 2020 10:05 AM)
This article is pretty much HACK bs.
First of all Remdesivir has been used by china for 2 months. THERE IS DATA to be shared. are you kidding.
second of all gilead said they are short on supply which is bs. they sent 2million doses to china illegally.
third, they have used it on dying patients in the united states and it worked great. doctors want it but Gilead has cut them off over money.
remdesivir works and people are dying because gilead is playing games.
not only does it work, it works WELL
Niels (March 31, 2020 11:59 AM)
You say that, and we all hope you are right. But I found myself wanting to know the source. The absence which makes it more difficult to believe.
Mike (March 28, 2020 4:38 PM)
typo alert: "fall off a cliff" not "fall of a cliff"
B. FREEMAN (March 28, 2020 9:36 PM)
If I heard correctly, hospitals in Thailand were using this drug -- and combinations of drugs (from the 'freezer'). They weren't waiting for any studies. Studies are great and need to be done, but data from the field can also be examined. Ideally, pull the lasagne out of the freezer AND have another group start a new lasagne from scratch.
James Andrews (March 28, 2020 10:48 PM)
I am encouraged by the use of Hydroxychloroquine, Azithromycin and zinc as early as possible. At a cost of 20 usd per treatment it may not be profitable, but it would be possible. Late stage treatment is not the answer.
Cathy (March 30, 2020 11:56 AM)
Why are you hopeful? There is very little evidence for it.
Christian (April 19, 2020 8:32 AM)
I’m not a medical pro but have some questions. Can you explain the strategy of treating a viral outbreak with an immune suppressant and (prophylactic?) antibiotic treatment? Are patients dying from opportunistic bacterial infections or organ failure due to the virus itself? Seems like cost is the major motivation for pushing this cocktail when attacking the virus should be a priority.
Tom (March 29, 2020 5:14 AM)
Interestingly, if we were using better and more widespread testing, you wouldn't have to guess if someone needed it. Test EVERYONE, even those not showing symptoms. If someone is tested and is positive, send them to the next line to get their IV, like giving blood in trailers. People can decline the treatment until they have symptoms, such as shortness of breath, but I am guessing if you're over 50 that youd be getting that IV.
AS (April 3, 2020 3:59 PM)
My understanding is the test might not be that reliable, that there are a lot of false negatives. It also seems that, much like the flu test, testing too early leads to a higher rate of false negatives.

I also realize that people who are asymptomatic are probably not receiving the test, so we don’t know at what point the test will detect that they have COVID-19 in the first place.

I think that there are still a lot of questions, more questions than answers certainly at this point. If you have any articles that address any of the issues that I have brought up, please reply with the links and I would be happy to read them!
Simon Levy (April 19, 2020 4:46 PM)
After four days an infected person is already has the virus on their tongue (the virus is present on their tongue, in their mouth)
David Benjamin, PhD (March 30, 2020 1:29 PM)
Since remdesivir is not yet FDA approved, it is being studied under and IND, the costs of which are usually covered by the manufacturer. With no approved drug for this virus, compassionate use of remdesivir can be studied under a compassionate IND, and open label, uncontrolled studies are perfectly acceptable since efficacy parameters such as viral load and survival rates can be quantified. But, I have not heard a word about toxicity. What is the safety profile of this drug like? Finally, why not try to develop an oral dosage form which can be equally efficacious as an IV dosage form although the dosage would have to be determined in Phase I/II piggyback clinical trials? Ultimately an oral dosage form would be less expensive and more easily manufactured. None of the arguments against this drug written above hold any merit in comparison to its potential benefit in the therapeutic setting. What's the matter with you?
Allan (April 1, 2020 8:04 PM)
I guess you have no idea how much effort is required to develop an oral drug. A lot of promising compounds did not make it because of poor bioavailability.

Looking at the structure of Remdesvir, it appeared that it is a "prodrug" already (someone please correct me if I am wrong).

Everyone likes to solve their problem by taking a pill. It is not that simple
Ed (April 4, 2020 5:34 AM)
I'm not a medical professional. I guess remdesivir needs to have precise dosage, otherwise maybe it's poison or useless. When taking pills, the absorption will depend on what you eat, how much, when and how your stomach works. So it's much easier, safer to dose via infusion.
Jeff Campbell (March 30, 2020 3:16 PM)
Please give Gilead a chance so many people are depending on any relief at all. After it was Gilead who partnered to find the most efficient HCV cocktail. I just hope the drug pricing is controlled so the poor of all countries can afford the treatment.
Brian H Llamar (March 31, 2020 1:27 AM)
The fed flag is when we have to pick the brain of a stock analyst to inquire as to whether this drug will be available. This is corporate America. If anyone thinks any if this is being done without a profit margin at the top of the list your head is in the sand. Remdesivir has already saved lives. People are dying as I type this. Get this drug out there!
DANIEL TAN (April 2, 2020 12:34 PM)
As of this moment, without any magic pill or treatment we need to give whatever medicine a shot to help save life. Saving life is critical at this juncture and we need it to be executed without profit
in mind. For god sake, we live in this world together and humanity is at stake. Profit will come later, saving life is the priority now.
Efrain Pizarro (April 2, 2020 1:48 PM)
I will like to tell the lab. Gelead to produce plenty of the drug remdesivir to save the world and people for dying.
If already used on China and is work, let do it here in USA. What is the problem? I suggest to FDA to go and let the drug be use. SAFE the massacre.
Jean-Pierre White (April 18, 2020 1:54 PM)
So this article concludes that even if we are able to find a viable treatment for Covid-19 its not worth bothering because we aren't able to administer medicines, all we can hope to do is just watch people die. Very uplifting conclusion.

How about we figure out how to administer the medicine once we have it in hand and know it is useful. We'll find a way to administer it when we get there. Heck give each nurse administering the treatments a dose themselves to ensure they don't succumb to the disease.

Pat Jordan (April 29, 2020 8:28 PM)
Remdesivir has proven to be an excellent prophylactic in many studies. It has few secondary effects when dosage is correct. Problem: its development is time consuming and complex, when compared to competitive antivirals; and its method of use requires medical personnel. As a 69 year old with medical complications, I wish this was available to administer by my family doctor. It would get me out of quarantine!

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