With the world in the grips of the novel coronavirus, drug companies are launching studies of existing drugs with the potential to alleviate the most serious cases of the related respiratory disease COVID-19. The latest trials to be launched focus on Sanofi and Regeneron’s Kevzara (sarilumab) and Roche’s Actemra (tocilizumab), both rheumatoid arthritis treatments that block a cytokine called IL-6.
When the coronavirus infects a cell, it dumps its genetic payload—a single strand of RNA containing the recipes for making the proteins it needs to replicate—into its host. The immune system mobilizes to kill infected cells before too many copies of the virus can be made. But sometimes, that defense mechanism overreacts. Not only are sick cells killed, but healthy ones, too, and a lot of them, explains Naimish Patel, Sanofi’s global head of development for immunology and inflammation.
“On average, most patients do develop their own response against the virus and recover from it, but some patients just have a very brisk response and get really sick,” says Patel, who is a pulmonologist by training.
Doctors in China noted that in some of those really sick patients, viral levels dropped, but levels of IL-6, one of the distress signals used to call the immune system to action, remained high. A small study tested whether Actemra could stop the immune over-reaction.
“The initial results from tocilizumab’s China study were remarkable—75% of patients (15 out of 20) reduced their need for supplemental oxygen within days after receiving tocilizumab,” SVB Leerink stock analyst Geoffrey Porges wrote in a note to clients.
Although those results come with caveats—for example, the study lacked control arms and was very small—it was enough to prompt Sanofi and Regeneron to explore the use of Kevzara in COVID-19.
The study will first enroll 50 to 60 people who meet certain criteria: they must have lab-confirmed COVID-19 that is considered severe, or have multiple affected organs, and they must have pneumonia and a fever. Patients will be given either a low dose of Kevzara, a high dose, or a placebo.
As they look for signs of efficacy, researchers also want to pinpoint the characteristics of COVID-19 patients who can benefit from Kevzara. If patients “have high level of cytokines, suggesting their inflammation is sort of ramped up, but they’re not that sick yet, maybe that’s a good time to intervene,” Patel notes. That way, inflammation can be dampened just enough to allow the body to still fight off the virus. To that end, the companies plan to look at a host of biomarkers related to inflammation.
If results from that initial group look positive—meaning the drug appears to reduce fevers, and fewer patients need oxygen—the study will be expanded to roughly 400 patients.
Regeneron, which manufactures Kevzara at a facility in the US, is running the study, which will enroll patients at hospitals in New York. Sanofi is in talks with health authorities in Italy, France, Germany, and Spain about opening sites in those countries.
Choosing study sites amid a pandemic can be tricky, Patel notes. Although a COVID-19 hot spot might be able to swiftly enroll patients, doctors at those hospitals don’t have time to collect and record data needed to understand if the drug is working. “We have to pick sites with lots of cases, but that aren’t overwhelmed,” he says.
On March 19, Roche said it was collaborating with the US Biomedical Advanced Research and Development Authority to launch a Phase III study of Actemra in hospitalized patients with severe COVID-19 pneumonia. The trial, which will enroll 330 people around the world, is expected to start in early April.
Several other trials are also under way to test drugs or drug candidates against COVID-19. Gilead Sciences’ remdesivir, which was discovered during the 2014 Ebola outbreak in West Africa, is the most advanced. The antiviral, which is not yet approved in any countries, is being tested in four Phase III studies—two in China and two in the US. Data from one of the China studies are expected to be reported in April.
And this week, Chinese researchers reported encouraging results from a study of Fujifilm’s favipiravir, which is approved in Japan to treat the flu. According to media reports, an official from China’s Science and Technology Ministry said the trial of 340 people with COVID-19 suggests the antiviral can shorten the time it takes for the body to clear the virus from 11 days to 4.
On March 18, the World Health Organization said it was launching a large, multinational trial to test four drug candidates’ efficacy against COVID-19. It has taken the unusual step to tease out better evidence of the value of older therapies being tried in smaller, often unblinded studies. “Multiple, small trials with different methodologies may not give us the clear, strong evidence we need about which treatments help to save lives,” Director-General Tedros Adhanom Ghebreyesus said during a press conference. The WHO study will look at the potential benefits of remdesivir, the HIV antivirals lopinavir and ritonavir, interferon beta added to treatment with lopinavir and ritonivir, and the antimalarial chloroquine.
This story was updated on March 19, 2020, to include information about a newly announced Roche drug trial.