International COVID-19 trial to restart with focus on immune responses
World Health Organization will test whether three existing drugs can save lives of hospitalized people.
A patient who spent nearly a month in the COVID section of an intensive-care unit at Sarasota Memorial Hospital in Florida.Credit: Shannon Stapleton/Reuters/Alamy
A landmark programme to test potential COVID-19 therapies in dozens of countries is restarting with a fresh roster of treatments — this time aimed at tempering the raging immune responses that can worsen severe disease.
The clinical trial, named Solidarity and coordinated by the World Health Organization (WHO), will test three drugs that dampen inflammation, an approach that has already shown promise in people hospitalized with COVID-19.
All three drugs were carefully chosen on the basis of the promise they showed in smaller clinical trials and widespread availability, says John-Arne Røttingen, scientific director of the Norwegian Institute of Public Health and chair of the Solidarity trial's international steering committee. “You need at least promising signals that some of them will work,” he says. “And we need study drugs that we can deliver in a broad group of countries.”
When the WHO launched Solidarity in March 2020, the study was focused on antiviral drugs. By October, the trial had enrolled more than 11,000 participants hospitalized with COVID-19 in 30 countries. But it also found that none of the four drugs that it tested (remdesivir, interferon, the malaria drug hydroxychloroquine, and a combination of HIV drugs called lopinavir and ritonavir) saved lives or shortened hospital stays1.
“None of the antivirals have shown strong effects in hospitalized patients,” says Røttingen. “The emerging consensus is that it’s too late. Where the antiviral medications could have a benefit is quickly after a positive test.”
Now, after a pause to sort out which therapies to try next, the trial hopes to focus instead on reining in immune responses that can contribute to severe forms of COVID-19.
Tweaking immune responses
As viral infections progress, the body’s own immune responses can cause harm, damaging healthy tissue in the quest to kill infected cells. In June 2020, a large UK-based study called RECOVERY found that the immune-suppressing steroid dexamethasone reduced deaths among those on ventilators or receiving supplemental oxygen owing to coronavirus infection2. And a large international trial called REMAP-CAP found that drugs that block a key immune protein — the interleukin-6 (IL-6) receptor — can reduce deaths among those critically ill with COVID-193.
Treatment with dexamethasone, or with both dexamethasone and IL-6-receptor blockers, has become standard care in some countries for hospitalized people with COVID-19 who need breathing assistance, says Anthony Gordon, an anaesthesiologist at Imperial College London and a member of the REMAP-CAP steering committee. But there is still room for improvement: “We know that some patients still remain sick even with those treatments,” he says.
So researchers are looking for other ways to shut off particular immune responses. One of the drugs to be tested is infliximab, used to treat autoimmune conditions, including Crohn’s disease and rheumatoid arthritis. It blocks a protein called tumour necrosis factor alpha (TNF-α), which is released by immune cells called macrophages and promotes inflammation.
A second treatment in the trial is a cancer drug called imatinib. Researchers hope that it will target both the coronavirus and inflammation, blocking viral infiltration of human cells and reducing the activity of pro-inflammatory proteins called cytokines. Finally, Solidarity is testing artesunate, an anti-malaria drug with potential anti-inflammatory effects. Each of these drugs will be given alongside standard care, which in many regions includes dexamethasone, says Røttingen.
REMAP-CAP also plans to test imatinib, which could help to prevent leaking of fluids in the blood vessels surrounding the lungs, says Gordon. The trial will also test a different drug that targets TNF-α, as well as a drug called namilumab that blocks a protein called GM-CSF and that could reduce cytokine activity.
With all of these ways to cool down the immune system, researchers have to be careful that they don’t suppress immune responses so much that people become vulnerable to other infections, says Djillali Annane, an intensive-care physician at the University of Versailles in Saint-Quentin-en-Yvelines, France, and a member of the REMAP-CAP international steering committee.
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In the REMAP-CAP trial, participants will first be given a steroid, such as dexamethasone, and a drug that blocks IL-6 receptors. Participants will be given an additional drug to target the immune system only if they fail to improve after the first two. “This is targeting those patients who do not respond,” says Annane. “Then the question is, if we add on another way to modulate the inflammatory response in these patients, can we save additional lives?”
The race for antiviral drugs to beat COVID — and the next pandemic
Despite dire warnings, a stockpile of ready compounds to fight viral pandemics was sorely lacking. Can drugmakers finally do the right thing?
The year 2003 was an ominous one for emerging infectious diseases. A pair of deadly influenza strains had leapt from birds to humans in Hong Kong and the Netherlands. And a new coronavirus was spreading around the world causing a mysterious illness that became known as severe acute respiratory syndrome, or SARS. Many experts feared they were watching the start of a global pandemic.
Fortunately, the worst-case scenario never materialized. But it was a close-enough call for Robert Webster, a leading authority on avian influenza, to start urging scientists and policymakers to prepare for the next outbreak. One of his top recommendations: develop and stockpile drugs that target a wide range of viral pathogens1.
Drug researchers did not heed his call. After the SARS threat subsided, interest evaporated — and the world paid the price. “The scientific community really should have developed universal antivirals against SARS,” says Webster, now an emeritus member of St Jude Children’s Research Hospital in Memphis, Tennessee. “Then we would have had something in the stockpile for the emergence of COVID,” which is a caused by SARS-CoV-2, a close relative of the virus responsible for SARS.
Another warning shot came in 2012, when Middle East respiratory syndrome (MERS) — caused by another relative of SARS-CoV-2 — started spreading through a handful of countries. Still, the drug shelves remained largely bare — a fact that Jay Bradner, president of the Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, regards as “regrettable”.
“Shame on us,” he says of the pharmaceutical industry. “We can be better prepared.”
Aside from one qualified success in remdesivir, a therapy originally developed to treat hepatitis C and Ebola, there were practically no strong antiviral drug candidates to quickly test and deploy against SARS-CoV-2. Researchers bemoan that there weren’t more options. “We need an arsenal,” says Kara Carter, head of discovery biology at the biotech company Dewpoint Therapeutics in Boston, Massachusetts, and president of the International Society for Antiviral Research.
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