Short supplies and limits on who qualifies mean more options are needed to end the pandemic
Remdesivir production
Gilead Sciences plans to ramp up production of remdesivir, one of the first antiviral drugs to help COVID-19 patients recover, in order to provide 1 million 10-day course of treatment by year’s end.

GILEAD SCIENCES

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By Tina Hesman Saey

MAY 13, 2020 AT 6:00 AM

Though remdesivir, a new treatment for COVID-19, has been hailed as a game changer, most people sick with the coronavirus will have to recover or die without getting the drug.

“Everyone won’t be able to get it, because there just isn’t enough of it at this point in time,” says Raymond Woosley, a cardiologist and clinical pharmacologist at the University of Arizona College of Medicine Phoenix.

Supplies are limited and the federal government is asking state health departments to distribute the drug to hospitals treating COVID-19 patients. Vials of the still-experimental medication have been distributed to 13 states so far. But the Infectious Diseases Society of America has warned that tens of thousands of people each month may need the treatment throughout the summer.

Remdesivir shortened recovery time for seriously ill patients by four days in a clinical trial comparing the drug with a placebo. Those results were considered so promising that a safety oversight committee stopped the clinical trial early to give people taking the placebo a chance to get the drug. Remdesivir will become the standard of care for the coronavirus, Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, predicted at a news conference at the White House on April 29 announcing the results (SN: 4/29/20). On May 1, the U.S. Food and Drug Administration issued an emergency use authorization, allowing remdesivir to be used for hospitalized people with confirmed cases of COVID-19, whose blood oxygen levels fall to 94 percent or lower.

Remdesivir is an antiviral drug that works by mimicking building blocks of the coronavirus’s genetic material, RNA. As the virus copies its RNA, remdesivir takes the place of some building blocks, stopping or slowing viral replication. In laboratory and animal tests, remdesivir has been effective against a wide variety of coronaviruses, and human trials showed that it helped some people survive Ebola (SN: 3/10/20). Now, the new trial suggests the drug can also fight SARS-CoV-2 infections.

“While the remdesivir news is positive — anything that is helping patients is positive — this is not the coronavirus cure for everyone,” says Esther Krofah, executive director of FasterCures, a Washington, D.C.-based nonprofit that’s part of the Milken Institute think tank. The center is tracking hundreds of drugs and vaccines being tested against the coronavirus. Because the drug is given intravenously, only hospitalized patients can get it. “If you’re moderately ill or you’re showing very mild symptoms, it would continue to be the case that you would quarantine at home and monitor your symptoms.”

Limited supplies of remdesivir can stretch only so far to meet great demand.

Gilead Sciences, the maker of remdesivir, has donated its entire supply of the drug, which could treat about 140,000 people for 10 days each. The company, based in Foster City, Calif., ran its own clinical trial and found that treating for five days may be enough, potentially stretching the drug’s supply to more than 250,000 people worldwide. The company anticipates scaling up production to make more than 1 million treatment courses of remdesivir by year’s end. That’s based on using the 10-day treatment regimen. Using a shorter course might mean 2 million people could access the drug this year.

“Gilead has committed to manufacturing however many doses are needed. But it’s a complex drug from a manufacturing perspective,” Krofah says. The company warned in a May 5 statement that making remdesivir requires scarce raw materials, and disruptions to supply chains for those materials might slow production or limit the amount of remdesivir that can be produced.

Lessons from trials
In addition, it’s not at all clear that remdesivir is the best treatment against SARS-CoV-2, some scientists say, and its widespread use might even make finding better treatments harder. A proven treatment is welcome, but stopping the pandemic will require more than remdesivir, experts agree.

A clinical trial conducted in Wuhan, China, did not find any statistically meaningful difference in recovery for people getting remdesivir infusions compared with people receiving a placebo. Still, the larger study conducted by Fauci’s institute indicates remdesivir may really help people get better faster. Because it followed more patients, the larger trial probably is closer to getting the right answer, researchers say. But scientists are concerned that the trial data are not yet available for review.

Another problem is that the trial twice changed the measure by which it judged the drug’s success. That’s usually a warning sign. In general, “if you change the goal posts it makes you wonder … if this is a real effect, or just one of many that they chose to be the outcome, ignoring the one the study was originally designed for,” Woosley says.

Initially, the trial was supposed to measure improvement on day 14 after treatment began. Once it became clear that COVID-19 is a lingering illness, the researchers changed the judgment date. But they also realized that picking just one date may have problems of its own, the institute said in a statement. While the trial was still under way and before anyone knew which patients were getting remedesivir or a placebo, “NIAID statisticians performed modeling of what happens if the right day is not picked for assessment, which revealed that meaningful treatment effects could be missed with that primary endpoint,” the statement explains. On April 16, the outcome goal was changed to gauge an improvement in recovery time. “The change in primary endpoint seemed appropriate given the evolving clinical data,” the NIAID statement says.

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But that still leaves researchers with many questions about remdesivir, says William Powderly, an infectious disease doctor at Washington University School of Medicine in St. Louis. Among those questions are how effective the drug really is, who are the patients that will benefit most from the treatment, when is the best time to give the drug, and what are the side effects, Powderly says. “We have a drug that appears to have an effect. Is it a slam dunk? Is it a home run? No.”

Remdesivir did not have a statistically meaningful effect on preventing death. In the NIAID trial, 8 percent of people on remdesivir died, while 11 percent in the placebo group died. “It’s great to see progress,” Powderly says, “but what we would really like to see is a much more dramatic effect on survival.”

Strategies and potential
Some scientists think giving remdesivir very early in the infection before the virus’s replication peaks may be the best bet. But that would probably require new forms of remdesivir, such as nasal sprays, liquids to be injected into muscle, or even pills.

Remdesivir’s success will have consequences for future clinical trials of other drugs. Researchers and committees tasked with looking out for patient safety will need to decide whether it is ethical to conduct placebo-controlled studies when there is an existing treatment in remdesivir, Powderly and Woosley say. Trials may need be stopped or altered to add remdesivir to the mix. That may have the effect of slowing the research because trials would need to examine the new drugs’ effects in larger numbers of patients to determine whether the new regimen is better than remdesivir.

On the other hand, having an antiviral drug such as remdesivir may allow scientists to more safely test therapies that suppress the immune system. Such drugs may help calm cytokine storms, floods of immune chemicals that can trigger organ-damaging inflammation. But hampering the immune system may allow the virus to proliferate and cause damage of its own. If remdesivir could hold the virus in check, that might allow immune-suppressing drugs to limit damage caused by patients’ own immune systems, potentially saving some people, Powderly says.

A trial combining remdesivir with an anti-inflammatory drug has started signing up participants, NIAID reported May 8. The drug, baricitinib, is approved as a treatment for rheumatoid arthritis. Marketed by Eli Lilly under the brand name Olumiant, the drug may help calm the cytokine storm.

The drug, taken as a pill, also interferes with one mechanism by which cells bring the coronavirus inside themselves, Peter Richardson, a biochemist and pharmacologist who is the vice president of pharmacology for the UK-based biotechnology firm BenevolentAI, and colleagues reported February 4 in the Lancet. The drug has been used to treat at least four seriously patients in Northern Italy, Richardson says. “They’re all fine, walking and discharged, but it wasn’t a randomized placebo-controlled trial so we can’t claim anything from it,” he says. Still, baricitinib “has a chance” to help COVID-19 fight both the virus and their bodies’ own immune system attacks, he says.

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Participants in the new trial will get either remdesivir and placebo tablets or remdesivir and baricitinib tablets. The study will be blinded so neither doctors nor patients will know which patients are taking both drugs.

Whether remdesivir alone or in combination can save lives still isn’t known. But researchers are hopeful that giving people the drug earlier in the disease might stop them from becoming sick enough to need a ventilator or die, Krofah says. “If we can help those who are most ill recover, and potentially recover faster, and potentially see a decline in mortality, that’s good news. For everybody else, we still have to continue to develop a whole arsenal of different therapies.”

Remdesivir treatment may help some very sick people recover, but it probably won’t end the pandemic, she says (SN: 3/24/20). That may take a vaccine and public health measures such as widespread testing, contact tracing and isolating those who are infected (SN: 4/29/20). Antivirals such as remdesivir or other therapeutics will just help manage symptoms, Krofah says.

“It’s positive news, but it’s not going to be sufficient for the general public to say everything is clear, we can go back to work.”

Questions or comments on this article? E-mail us at [email protected]

CITATIONS
T. P. Sheahan et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Translational Medicine. Vol. 12, April 29, 2020, p. eabb5883. doi: 10.1126/scitranslmed.abb5883.

P. Richardson et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet. February 4, 2020. doi: 10.1016/S0140-6736(20)30304-4