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Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 1 of 7Remdesivir and interferon fall flat inWHO’s megastudy of COVID-19treatmentsBy Kai KupferschmidtOct. 16, 2020 , 3:45 AMPatients get tested for COVID-19 in India, one of 30 countries that took part in the Solidarity trial.AP Photo/Altaf QadriScience’s COVID-19 reporting is supported by the Pulitzer Center andthe Heising-Simons Foundation.SIGN UP FOR OUR DAILY NEWSLETTERGet more great content like this delivered right to you!One of the world’s biggest trials of COVID-19 therapies released its longRemdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 2 of 7awaited interim results yesterday—and they’re a letdown. None of the fourtreatments in the Solidarity trial, which enrolled more than 11,000 patients in400 hospitals around the globe, increased survival—not even the muchtouted antiviral drug remdesivir. Scientists at the World Health Organization(WHO) released the data as a preprint on medRxiv last night, ahead of itsplanned publication in The New England Journal of Medicine.Yet scientists praised the unprecedented study itself and the fact that ithelped bring clarity about four existing, ”repurposed” treatments that eachheld some promise against COVID-19. “It’s disappointing that none of thefour have come out and shown a difference in mortality, but it does showwhy you need big trials,” says Jeremy Farrar, director of the Wellcome Trust.“We would love to have a drug that works, but it’s better to know if a drugworks or not than not to know and continue to use it,” says WHO’s chiefscientist, Soumya Swaminathan.RelatedRemdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 3 of 7The prospects of two of the four treatments—the malaria drughydroxychloroquine and the HIV drug combination ritonavir/lopinavir—hadfaded after another large study, the United Kingdom’s Recoverytrial, showed they did not increase survival in June. After analyzing thatstudy and its own data up until then, WHO decided to drop both from thestudy.There was still hope for remdesivir and for interferon-beta, which hadinitially been given in combination with ritonavir/lopinavir but was tested asa standalone drug after the Recovery data came out. But neither of thosetreatments lowered mortality or delayed the moment patients neededventilation to help them breathe. The results in these two treatment armsare likely to be the most scrutinized.Remdesivir, which attacks a specific enzyme in several RNA viruses andwas previously tested against Ebola, was initially seen as a promisingcandidate. In a U.S. trial with more than 1000 COVID-19 patients publishedlast week, those who received remdesivir had a shorter recovery time thanpatients in the control group, but there was no significant difference inmortality. Two smaller trials found few significant benefits. Remdesivirreceived an emergency use authorization from the U.S. Food and DrugAdministration (FDA) in May for severe COVID-19 patients that was laterexpanded to include all patients.But the Solidarity trial suggests the drug does little in severe cases. Of 2743Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 4 of 7hospitalized patients who received the drug, 11% died, versus 11.2% in acontrol group of roughly the same size. The difference is so small it couldhave arisen by chance.When the authors pooled Solidarity’s data with those from the three othertrials, they found a slight reduction in mortality that wasn’t statisticallysignificant either. “This absolutely excludes the suggestion that remdesivircan prevent a substantial fraction of all deaths,” the authors write. “Theconfidence interval is comfortably compatible with prevention of a smallfraction of all deaths but is also comfortably compatible with prevention ofno deaths.”“This trial doesn’t help remdesivir, that’s for sure,” says Eric Topol, directorof the Scripps Research Translational Institute. “It’s not a dead duck asmuch as hydroxychloroquine, but it certainly is not the hope that wasinitially signaled.”But the drug’s manufacturer, Gilead Sciences, casts doubt on the study.“The trial design prioritized broad access, resulting in significantheterogeneity in trial adoption, implementation, controls and patientpopulations,” the company says in a statement, “and consequently, it isunclear if any conclusive findings can be drawn from the study results.”Gilead received the manuscript about Solidarity on 28 September,according to WHO. On 8 October, before the results became public, thecompany signed a $1 billion deal with the European Commission for a 6-month supply of the drug.Solidarity’s “most disappointing results,” however, are those for interferonbeta, Topol says. Mortality among the 2050 people who received that drug(either alone or in combination with lopinavir/ritonavir) was 11.9%, versus10.5% in the control group. Prior studies have suggested interferon can onlyRemdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 5 of 7help if given early, however, and not once patients have been hospitalized.“So I think that’s still an open question,” Topol says.“Treating COVID late is very difficult,” Benjamin tenOever, a virologist at theIcahn School of Medicine at Mount Sinai, wrote in an email to Science. “Atthis point in the disease the issue is more about inflammation and clotting,which is likely why these four drug regimens showed little value.”The silver lining may be that the trial itself, unprecedented in several ways,succeeded. Set up in a short time in March as the pandemic engulfed theworld, it used a simple protocol that allowed doctors in overstretchedhospitals anywhere to randomize their patients to whatever study drug wasavailable or to standard care. “To get four different drug strategies naileddown, and in this short period of time and across the world, is justfantastic,” Topol says. “I give them a lot of praise for getting us these resultswith extraordinary velocity.” “I think that Recovery and the Solidarity trialbetween them have set the standard of the scale that’s required in order togive you clear answers,” Farrar adds.To get four different drug strategies nailed down, and in this shortperiod of time and across the world, is just fantastic.Eric Topol, Scripps Research Translational InstituteThe biggest hurdle was the long time it took to get regulatory approval forthe study in some countries, says WHO’s Marie-Pierre Preziosi. “Regulators,as well as the ethics committees for that matter, need to rethink theirapproaches in pandemics and need to be much more ready to cope withthis because sometimes the duration for authorization is really notappropriate.”Still, the trial has ramped up to more than 11,000 patients from 30Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 6 of 7countries, including Argentina, Peru, India, the Philippines, and Spain, withmore slated to join. About 2000 patients are now included every month. Forthe moment, the remdesivir arm will continue “to get more preciseevidence,” says John-Arne Røttingen, CEO of the Research Council ofNorway, who heads the executive group of Solidarity’s steering committee.But new drugs will be added, he says.As early as next week, Solidarity participants could start to receiveacalabrutinib, a cancer drug that inhibits an enzyme that plays an importantrole in the human immune system. The hope is to soon include targetedtherapies such as monoclonal antibodies as well because they are morelikely to be successful than repurposed drugs. “Trying to find off-targetbenefits from FDA-approved drugs is not a great strategy (althougharguably the best we can do under these conditions),” tenOever wrote.Solidarity built on experience from the 2014–16 Ebola epidemic in WestAfrica, says Ana Maria Henao Restrepo, who heads the Research andDevelopment Group at WHO. Back then, there were many debates aboutwhether it was even ethical to do randomized clinical trials—which withholda potential therapy from patients in control groups—during a deadlyoutbreak. “Now, you don’t see any debate” on that question, she says. “Thecommunity, all of us, we have moved, we have learned a lot since WestAfrica.”The study’s global reach has important benefits, says Nahid Bhadelia, aphysician at Boston Medical Center. Conducting a trial in many placessimultaneously means more patients can be included, leading to fasterresults but also to more robust data, she says. “You’re including manydifferent types of subgroups and populations in different parts of theworld.”Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PMhttps://www.sciencemag.org/news/2020/10/remdesivir-and-interferon-fall-flat-who-s-megastudy-covid-19-treatments Page 7 of 7Another advantage: The 1300 participating doctors worldwide will have asense of ownership of the results, Henao Restrepo says. “When they seethe results in The New England Journal of Medicine, [they will] say, ‘I’vecontributed to that and I understand why that drug works or doesn’t work. Iknow, I trust it,’” she says. “That is different from some NorthernHemisphere group publishing, and they say: ‘Somewhere in a rich countrythey did a trial and now we all have to believe the results.’”

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