A giant trial of COVID-19 treatments is restarting. Here are the drugs it’s betting on – Science Magazine

A suspected COVID-19 patient receives care in Turku, Finland, the first country to join Solidaritys new phase.

By Kai KupferschmidtAug. 5, 2021 , 1:25 PM

After months in the doldrums, one of the worlds largest trials of COVID-19 treatments is finally restarting. Solidarity, a global study led by the World Health Organization (WHO), will test three new drugs in hospitalized COVID-19 patients: the cancer drug imatinib, an antibody named infliximab that is used to treat autoimmune diseases, and artesunate, an antimalarial.

The medicines have been shipped to Finland, the first country to have all approvals in place, says John-Arne Rttingen of the Norwegian Institute of Public Health, who chairs the studys executive group. I expect that the first patients will probably be recruited there any day, he says. Other countries could soon join SolidarityPlus, as the new phase has been dubbed; more than 40 are in the process of getting ethical and regulatory approvals.

When the original Solidarity trial started in March 2020 it was a first: an effort to test drugs in dozens of countries simultaneously in the middle of a pandemic. By late in the year it had delivered verdicts on four treatmentsnone showed a benefitbut then became mired in negotiations with pharmaceutical companies and regulatory delays. Its great that Solidarity is proceeding with randomized clinical trials again, as they have already made an important contribution to our therapeutic approach during the pandemic, says Eric Topol, director of the Scripps Research Translational Institute. We cant be at all complacent about needing better therapies for patients with severe COVID.

Although COVID-19 vaccine development has been a huge success story, only two drugs have proved to reduce COVID-19 mortality in hospitalized patients. In June 2020, the United Kingdoms Recovery trial found that dexamethasone, a cheap steroid, reduced deaths in that group by up to one-third. In February, Recovery investigators announced that tocilizumab, a monoclonal antibody that blocks the receptor for interleukin-6, reduced mortality a bit further. Both drugs work by dampening the overshooting immune response in severely sick patients.

The new drugs also target the immune system rather than the virus itself. In the severely ill patients included in Solidarity, its probably too late for an antiviral drug to work, Rttingen explains. (Monoclonal antibodies to SARS-CoV-2, for example, are most effective when given before serious disease develops.) But sicker patients could benefit from additional drugs that target the immune system, says Anthony Gordon, a critical care specialist at Imperial College London. Although dexamethasone broadly dampens the immune response and tocilizumab powerfully shuts off one particular pathway, There are still other pathways that we can block and maybe make a difference, Gordon says.

Imatinib, an oral drug used to treat some leukemias and other types of cancer, can also protect the epithelium lining the alveoli, where oxygen crosses from the lungs into the blood. A placebo-controlled trial in 400 hospitalized COVID-19 patients in the Netherlands, published in June, showed patients on the drug spent less time on ventilators and were less likely to die. Although not statistically significant, the data were encouraging enough to spur larger studies, says Gordon, who is part of another international trial called REMAP-CAP that is also planning to test the drug.

Infliximab is an antibody given as a single infusion that blocks tumor necrosis factor alpha, a pivotal signaling molecule in the immune system, and is used to treat autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. Some observational data from large patient populations suggest the drug can also protect against COVID-19, Rttingen says.

Artesunate, an injected derivative of artemisinin and a powerful killer of malaria parasites, has also shown some antiviral activity in laboratory studies of SARS-CoV-2. But Solidarity is testing it because of another effect: The drug appears to reduce inflammation and counteract signals that attract immune cells into tissues. That could stop the immune reactions that damage the lungs in severe COVID-19.

Solidaritys revival was a long time coming. In October 2020, it published results from more than 11,000 patients in 400 hospitals that deflated hopesand punctured hypeby showing no benefit for four treatments: the HIV combination therapy lopinavir/ritonavir, the malaria drug hydroxychloroquine, interferon-beta, and Gilead Sciencess antiviral drug remdesivir. The remdesivir arm was continued for a while to gather more datafull results are expected in the coming weeksbut by late January all arms had been stopped.

An independent expert committee picked the three new drugs soon after. The delay is due partly to negotiations with the manufacturers to ensure that the drugs would be available at affordable prices worldwide if they turned out to work, Rttingen says, and partly due to the time needed for regulatory and ethical approvals in participating countries.

We have definitely seen that there was a strong willingness to sort of work outside the normal system and really speed up processes in the beginning of the epidemic, and that seems to be less the case now, Rttingen says. Thats understandable, he adds, But it also demonstrates that these processes are not fit for emergencies. We need fast-track systems for the future, in all countries.

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A giant trial of COVID-19 treatments is restarting. Here are the drugs it's betting on - Science Magazine