As the coronavirus spreads, a drug that once raised the world’s hopes is given a second shot

a decade ago, a group of chemists cooked up a compound they simply called 3a and that, in lab experiments, fought off a number of different viruses. One was a type of coronavirus.


Now, the descendant of that molecule — Gilead Sciences’ remdesivir — is being rushed to patients with infections from the novel coronavirus in hopes that it can reduce the intensity and duration of Covid-19 and ease the burden of the pandemic on health systems.


Remdesivir, in the spotlight as scientists and governments scramble to find a treatment for the disease, took a circuitous route to center stage. Born as a general antiviral candidate, researchers threw it at an array of viruses and saw where it stuck. It bounced along from Gilead’s labs to academic centers, nudged by both federal taxpayer dollars and support from the company. It kept turning up whiffs of potential in cells and animals infected by other coronaviruses like SARS and MERS, but these bugs weren’t causing sustained global crises. For years, Gilead was primarily focused on ushering remdesivir into trials and toward approval for a different kind of infection: Ebola.

But there’s nothing like a pandemic to break the emergency glass on all possible options.


Remdesivir is now being tested in five Covid-19 clinical trials that have been set up at breakneck speed. It’s been delivered through a compassionate use program to some patients, including the first case in the United States. The first trial results are expected next month, though some analysts have already raised concerns about the prospects based on the drips of data emerging from a small number of patients.


Others’ hopes are high for the drug. As of now, there are no approved therapies for any coronavirus infection, and remdesivir is the farthest along in the development process of any candidate.


“There’s only one drug right now that we think may have real efficacy,” Bruce Aylward of the World Health Organization said last month. “And that’s remdesivir.”

Remdesivir’s odyssey illuminates the complicated trajectory drugs can take as they are forged, refined, scrutinized, and moved into human studies. But its long, meandering path also underscores why drugs need to demonstrate their efficacy in these studies. The drug similarly had lofty expectations as an Ebola treatment, and strong data from animal studies to boot. But in a landmark trial that compared four experimental therapies and was published last year, two other treatments were shown to dramatically reduce deaths from the infection, while remdesivir faltered, producing less impressive survival benefits.


“Drug discovery and development is usually a very long and tedious process and you could have many failures on the path to an approved product,” Tomas Cihlar, Gilead’s vice president of virology, said in an interview with STAT.


As for remdesivir’s chances in Covid-19, Cihlar said:  “It would be wonderful if it works. But it needs to be proven.”

When the patient with the first known U.S. case of Covid-19 was admitted to Providence Regional Medical Center in Everett, Wash., on Jan. 20, he wasn’t all that sick.


The 35-year-old man had the respiratory infection’s most common symptoms of fever and cough, but had no trouble breathing and no evidence of pneumonia — inflammation of the lungs’ air sacs. But around that time, his doctors saw a report from China that detailed that some patients there developed more severe symptoms several days into their illnesses.


“That perked our ears to the worsening of this disease,” said George Diaz, the infectious disease section chief at the hospital.


Within a few days, the man — who had visited family in Wuhan, China, where the outbreak is believed to have started, and returned home to Washington Jan. 15 — started experiencing shortness of breath and requiring oxygen. An X-ray revealed pneumonia.


Diaz informed officials at the Centers for Disease Control and Prevention, with whom he had been conferring daily, that the patient was taking a turn for the worse. The CDC suggested trying an experimental drug, and mentioned Gilead’s remdesivir.


Hospital officials got in touch with Gilead about providing the drug, and then got the approval from the Food and Drug Administration to treat the patient through a compassionate use program, which allows unapproved drugs to be given under select circumstances outside of clinical trials. Gilead overnighted the drug to the hospital.


“Treatment with intravenous remdesivir was initiated on the evening of day 7, and no adverse events were observed,” the medical team wrote in a case report in the New England Journal of Medicine. The man started feeling better the following day.


“We were aware that he was the first patient on the planet getting the drug for this infection, so we were super interested to see, hopefully, if he would improve,” Diaz recalled.


The apparent success in one patient does not prove the drug is effective. That is where the large trials that will compare remdesivir to placebos come in.


Remdesivir has been able to advance into clinical studies so quickly for two key reasons. For one, thanks to its use in Ebola, it was known to be generally safe in humans. And two, it had a large body of preclinical evidence — that is, data from studies in cells in lab experiments and in infected animals — that indicated it could temper coronavirus infections. One study published just last month by researchers from Gilead and the National Institute of Allergy and Infectious Diseases showed remdesivir inhibited the replication of MERS, a related coronavirus, in infected monkeys.


Much of this preclinical research has been conducted through collaboration among the National Institutes of Health, academic labs, and Gilead, steered by the Antiviral Drug Discovery and Development Center, or AD3C. The center is an NIH-funded program run out of the University of Alabama at Birmingham that, since 2014, has been on the hunt for new treatments for emerging viruses.


Since drug screens revealed that remdesivir had potential as a coronavirus fighter, it was routed into the arm of AD3C focused on this family, a project led by Mark Denison at Vanderbilt University and Ralph Baric at University of North Carolina. Starting in about 2015 and with the backing of Gilead, they and scientists in their labs have pulled back the curtain on how exactly remdesivir curtails coronaviruses and demonstrated that it can block the viruses from multiplying in infected animals.

The researchers got an additional NIH grant to ready remdesivir for clinical trials, and thought the target could be MERS, which has caused 858 deaths and nearly 2,500 cases, mostly in Saudi Arabia, since it started infecting people in 2012. But even with that focus, they were also thinking about how the drugs they were studying could be used for the next spillover — when a virus jumps from animals to people.


“We’ve always thought that coronaviruses were a family on the move,” said Tim Sheahan, a UNC coronavirus expert.


Even with that expectation, though, the researchers who have toiled away for years on these projects without much fanfare find themselves caught off guard now.


“People like me, people doing basic science, oftentimes the work that we’re doing has no obvious direct translation to improving human health,” Sheahan said. “It’s hard to imagine that the work we’ve done in a lab in North Carolina could be saving people’s lives around the world. It’s incredibly gratifying, but it’s surprising and unusual for someone like me to experience this.”


But if remdesivir had hopes as an Ebola treatment, how can it also work against coronaviruses? Their viral families are so different, “it’s like saying a giraffe versus an elephant,” said Gene Olinger, a former U.S. Army Ebola researcher, who is now the scientific advisor at MRI Global, a nonprofit research organization.


The trick is that remdesivir does not go after the virus directly. Instead, it targets the system the virus uses to replicate itself, hijacking it like you would your office’s copy machine as part of a company-wide prank.


These viruses have a genome that consists of a strand of RNA. To make copies of themselves, they rely on a molecule called a polymerase to string together the individual building blocks of the viral genome. These are like the “letters” that we think of composing DNA.

Remdesivir is an “analog,” designed to mimic the appearance of one of the RNA letters, adenosine. It looks so similar that the polymerase can unknowingly pick it up instead of the real adenosine and insert it into the strand of viral genome that’s being constructed, like bringing home the wrong twin from summer camp. Once in place, the analog acts as a cap, preventing any additional pieces from being strung on. This leaves the strand short of the full genome. The virus can’t go on to replicate or infect other cells.


“The polymerase grabs it almost accidentally and uses it in place of adenosine,” said Maria Agostini, a postdoctoral researcher in Denison’s Vanderbilt lab. “The polymerase can kind of get it mixed up sometimes.”


The drug can inhibit coronaviruses as well as Ebola because their polymerases are similar enough that its cloak-and-dagger operation fools them all. (Remdesivir does not appear to work on other viruses with more unrelated forms of polymerase.)


Like a bad song clears out a dance floor, remdesivir can clear the viral levels in a person, as long as it can interrupt enough replication. The key, researchers say, is that it has to be delivered somewhat early in an infection, as the virus is still proliferating. In patients who develop severe disease, it’s not the virus that’s always the main problem. The body’s own immune system can react by heading into overdrive and causing secondary complications like organ damage. An antiviral can’t head that off once it’s begun.


“If you wait to treat someone until they’re in the ICU on a ventilator, it’s too late, you’re not going to do a darn thing,” said Richard Whitley, an infectious disease expert at UAB who coordinates the antiviral consortium.

When remdesivir stumbled in the Ebola trials last year, it was a disappointment, Gilead’s Cihlar acknowledged. But he argued it refocused the company’s attention to other targets for the drug.


They didn’t have to wait long.


In December, reports popped up from Wuhan of mysterious pneumonia cases. In early January, word came of a new coronavirus. “At that point, we started getting ready,” Cihlar said.


And when Chinese scientists published the virus’ genome, Gilead zeroed in on the portion that contained the recipe for the replication machinery — the polymerase. They saw it was nearly identical to the version in SARS — evidence that remdesivir might work against this virus as well. “That was a really strong signal for us,” he said.


There are now five clinical trials of remdesivir in Covid-19: two run by Chinese scientists, one looking at severe infections, and one at mild and moderate infections; one sponsored by NIAID; and two sponsored by Gilead in countries around the world with a large number of cases, looking at different disease severities and dosing regimens.

Date : 16 Mar 2020 06:27 PM