The big dip in mortality shown in the trial of about 800 patients has caught some experts by surprise because previous studies of the drugs showed little benefit.
The British government on Friday issued new guidance encouraging health care providers to use two arthritis drugs to treat severely sick Covid-19 patients, following the release of promising data from a clinical trial that has not yet undergone formal scientific review.
The findings in a new paper show that treatment regimens involving the drugs tocilizumab or sarilumab reduced the death rate among Covid patients in intensive care to about 27 percent, compared with 36 percent among patients who did not receive the drugs. Based on these results, about one death would be prevented for every 12 I.C.U. patients treated early with these drugs. All of the patients in the trial received the drugs within 24 hours of entering intensive care.
“I think it’s a huge result,” said Dr. Anthony Gordon, an anesthesiologist and critical care physician at Imperial College London and the trial’s lead researcher. “Showing that drugs that are available and can be used to save lives, in this pandemic, is a wonderful achievement.”
The results raise the profile of these drugs as among the few so far, apart from steroids like dexamethasone, that have reduced Covid deaths in a well-designed clinical trial. (Most of the new study’s participants also took steroids during their hospital stay.)
The big dip in mortality shown in the trial of about 800 patients caught some experts by surprise. Other studies testing the effects of tocilizumab and sarilumab have ended in disappointment, showing little to no benefit in people hospitalized for Covid.
Against the backdrop of other trials, some of which were more rigorously designed than this one, “I guess I would interpret with caution until this was published in a peer-reviewed journal,” said Dr. Lauren Henderson, a rheumatologist at Boston Children’s Hospital who wasn’t involved in the study.
Because all treatment trials are run with their own quirks and patient populations, “it’s difficult to compare across different studies,” added Dr. Emma Kaplan-Lewis, an infectious disease physician with the New York City Health and Hospitals Corporation. She has helped to conduct trials on tocilizumab, including one that didn’t show an improvement in patient survival, but wasn’t involved in the new study.
“My general impression is that tocilizumab and sarilumab do work for some patients,” she said. “But there is a sweet spot — it’s not for everybody, at all times.”
While many treatments for Covid target the coronavirus itself, tocilizumab and sarilumab work to quiet the immune system which, when triggered by an infection, can overreact and start to destroy the body’s own tissues. This immunological friendly fire is thought to fan the flames of many of the most serious Covid cases.
Given to seriously sick patients, these drugs can act like molecular mufflers, quieting the signals, or cytokines, sent and received by immune cells and keeping inflammation in check. Tocilizumab and sarilumab specifically block the signaling of a cytokine called IL-6, and are common arthritis treatments.
But against Covid-19, the drugs have produced mixed or lackluster results. Researchers testing tocilizumab in hospitalized patients found that while it seemed to slow the sicknesses of some people, it did little to curb death rates. Clinical trials run by companies like Roche, Regeneron and Sanofi testing the drugs were ultimately halted when their benefits didn’t pan out as expected. Disappointed by the treatments’ spotty performance, many experts lost interest in deploying them in clinical settings, and the National Institutes of Health issued guidelines recommending against their use, except in clinical trials.
But the findings of the new study add a welcome wrinkle to this pattern of results. When the researchers added tocilizumab or sarilumab to the typical I.C.U. Covid treatment regimen, patients were more likely to survive. The IL-6 blocking drugs also helped Covid patients come off machines and medications necessary to support their heart or lung function, and hastened their departures from the hospital by several days.
Because most of the people in the new study were also taking steroids like dexamethasone, the study’s results suggest that tocilizumab and sarilumab can compound the benefits of existing drug regimens, said Dr. Ilan Schwartz, an infectious disease physician at the University of Alberta, who called the findings “impressive.”
About one-third of the patients in the trial also took the antiviral drug remdesivir, which in October became the first Covid treatment to be approved by the U.S. Food and Drug Administration. Remdesivir on its own, however, doesn’t seem to reduce deaths.
The new study, which was posted to the preprint server medRxiv on Thursday, has not yet been vetted by experts for publication in a scientific journal. But its findings were compelling enough to prompt a shift in guidance in Britain, where officials have partnered with Roche, the tocilizumab manufacturer, to keep hospitals stocked with the drug.
“Organizations are encouraged to consider prescribing either tocilizumab or sarilumab in the treatment of patients admitted to intensive care with Covid-19 pneumonia,” the new guidance from British health authorities said. Dr. Gordon noted that this is the strongest official advice issued to date on the pair of immune drugs.
Some experts outside of Britain are treading more cautiously. Both Dr. Schwartz and Dr. Kaplan-Lewis noted that although the data might be enough to persuade the F.D.A. to authorize tocilizumab and sarilumab for emergency use in the United States, the jury is still out on these drugs. And Dr. Boghuma Kabisen Titanji, an infectious disease physician at Emory University, pointed out that only about 4 percent of the study volunteers identified as Black, which may make the results less applicable to the general population given the heightened vulnerability of communities of color to Covid-19.
More studies will be needed to clarify when, and in which patients, tocilizumab and sarilumab work best, and to untangle why their benefits cropped up clearly in some studies, but not others, Dr. Kaplan-Lewis said. It’s also challenging to compare studies coming out now to earlier trials that were conducted when the virus was much less understood, treatments were doled out with less know-how and mortality rates were even higher.
“If patients get better supportive care, maybe their outcomes would be much improved,” said Dr. Krutika Kuppalli, an infectious disease physician at the Medical University of South Carolina who was not involved in the study. “Yes, therapeutics are helpful. But it’s also about improving the standard of care for people.”
The new study and others have hinted that the drugs’ window of opportunity is narrow — within the first day or so of admission to an I.C.U., Dr. Kaplan-Lewis said. Given too early, the drugs might not make a measurable dent in the immune response; delivered too late, and the damage may have already been done. “Maybe it’s when a person has just tipped over into being critical,” she said.
That inflection point isn’t always easy to define. Patients enter intensive care in different states, and the threshold for critical illness may not be uniform across hospitals. And, like all other immunosuppressive drugs, tocilizumab and sarilumab can raise the risk of infection by other viruses or bacteria.
The data is “encouraging,” Dr. Kuppalli said. “But I think we need to understand why this data looks different from other studies, before we start implementing this as widespread policy.”
0 Comments