British regulators cited the new results as they promptly approved the two drugs, tocilizumab and sarilumab, for use in patients in intensive care units. The relative risk of death was reduced by 24 percent when given to people within 24 hours of admission, the data showed.
“Today’s results are yet another landmark development in finding a way out of this pandemic and, when added to the armory of vaccines and treatments already being rolled out, will play a significant role in defeating this virus,” Matt Hancock, health secretary for the United Kingdom, said in a statement.
“These are encouraging preliminary results,” said Jonathan Parr, an infectious-diseases physician at the University of North Carolina at Chapel Hill who was not involved with the clinical trial. Because the results represent patients in dozens of sites across six countries, he suggested they could be generalized to other locations.
David E. Leaf, a Harvard Medical School assistant professor and Brigham and Women’s Hospital physician, said the data were game-changing: “For ICU patients, I think it is a slam dunk that they should be given tocilizumab if it can be given early on.”
The results had an unusual path into the public domain. A week before Thanksgiving, one arm of a large clinical trial called REMAP-CAP was halted, through an announcement on Twitter, after a board monitoring patients in the trial had found that the drugs were so effective that it would be unethical to continue giving placebo to critically ill patients.
The clear finding came as a surprise to one of the investigators running the trial, after conflicting evidence on the utility of the drug tocilizumab from other trials. Most of the patients in the trial had already been on steroids, the inexpensive treatment that had shown to be successful at reducing deaths for people who require oxygen.
“We’re currently live in 290 sites around the world, and so there was no way to quietly whisper to 290 sites: ‘Stop randomizing to control in the immune modulation arm, but don’t tell anyone,’ ” said Derek Angus, chair of critical care medicine at the University of Pittsburgh Medical Center and one of the investigators of the trial.
“We realized that we had to sort of make one sort of statement, even though damned if you do, damned if you don’t — we totally get people were frustrated,” he said. “We didn’t know all the data, but we did promise we’d get on top of the data as fast as possible.”
The data published Thursday showed that patients were given tocilizumab, sarilumab or usual treatment within a day of requiring organ support in the ICU — most typically patients who were on high-flow oxygen or a ventilator. Tocilizumab is manufactured by Roche under the label Actemra, and sarilumab is sold as Kevzara by Sanofi and Regeneron Pharmaceuticals. The drugs, which block certain immune molecules from triggering inflammation, are far more expensive than the cheap steroids already being given to those patients.
The list price of the dose of Kevzara used in the trial is about $3,600. The maximum dose used in the trial of Actemra currently carries a list price of $4,600, but the dose varied by patients’ body weight and could be given either once or twice. Bob Purcell, a spokesman for Genentech, a member of the Roche Group, said that the drug was not approved for use in covid-19 and the pricing might differ if it were approved to treat the illness.
The trial measured the success of the drug by the number of days patients didn’t need organ support, but found that much of the benefit came from preventing death, Angus said.
About 36 percent of patients died in the hospital who received standard care, while 28 percent died on tocilizumab and 22 percent died when given sarilumab. Patients treated with the drugs spent about a week less in the ICU, on average.
Angus said that earlier this week, when the final analysis of the results were ready, there was a discussion about what to do with them.
“We had this extensive conversation Monday night: should we put the results on the preprint server? The National Health Service of the United Kingdom felt like it’s time to give these drugs to patients — we can’t wait for this to go to a journal and peer review,” Angus said.
But he expects physicians in the US may be more conservative, at least waiting for a formal publication — especially given that official treatment guidelines from the Infectious Diseases Society of America currently recommend against giving tocilizumab to patients.
Clinical observations early in the pandemic suggested this class of drugs could curb the immune reactions in critically ill patients with covid-19 that sometimes led to fatal disease. Later, smaller clinical trials found mixed evidence in favor of using tocilizumab to reduce mortality. Two of them published in October, one conducted in France and the other in Italy, reported little clear benefit to patients.
“Other published randomized trials primarily enrolled hospitalized patients with less severe disease,” Parr pointed out, which may explain the difference between those results and these in intensive care patients.
And a large observational study of about 4,000 people, also published in October, suggested that tocilizumab helps critically ill patients. That study compared patients who received tocilizumab within 48 hours of being admitted to an intensive care unit against those who did not. Consistent with the new clinical trial, people treated with the drug were less likely to die.
Leaf, the senior author on the observational study, said the hospital where he works does not advise giving tocilizumab to any patient — but he has “been jumping up and down” to overturn that recommendation for the sickest patients. Leaf will be giving a presentation to the hospital in two weeks in favor of treating those patients with the drug. He said his “job just got a lot easier” with the release of these trial results.
The results may increase interest in a number of drugs that tweak the immune response by acting on different pathways. Angus said he envisioned that future trials could compare tocilizumab against multiple other immune modulating drugs, to see if any work better. The results highlight that while the virus has gotten most of the attention, fine-tuning the immune response may be the key to saving the lives of those facing the worst cases.