A monoclonal antibody treatment for Covid-19 developed by Regeneron saved lives among hospitalized patients who had not mounted their own immune response, a finding that could dramatically change the way that doctors will use the therapy, researchers in the United Kingdom announced Wednesday.
The new data mark the first time that a medicine that works by fighting the SARS-CoV-2 virus has been shown to reduce mortality. Other treatments, such as the steroid dexamethasone, have been shown to save lives by tamping down the immune system’s overactive response to the virus.
“Imagine a patient goes into hospital, they’re diagnosed as having Covid and then one does a test to say, well, in response to the Covid, have they got antibodies or not?” Martin Landray, a University of Oxford professor and one of the lead investigators of the trial, explained on a call with reporters. “If they have, there’s no need to give them more. If they haven’t got antibodies of their own, then giving them this combination of two antibodies by an intravenous infusion then actually reduces their chances of dying by a fifth.”
Regeneron said it would open discussions with the Food and Drug Administration to expand the emergency use authorization of the antibody cocktail, called REGN-COV, to hospitalized patients. Currently, REGN-COV is authorized for use in patients with mild to moderate Covid who are at risk of progressing to having more severe disease.
Previous studies of monoclonal antibodies have shown that the treatments, given early in the course of the disease, can prevent patients from being hospitalized. But they have not been shown to help hospitalized patients. A study conducted by the National Institutes of Health using the antibody developed by Eli Lilly in hospitalized patients was stopped for futility. A Regeneron study had shown a benefit in the group of patients without their own SARS-CoV-2 antibodies, but had been too small to produce definitive results.
The new study, part of a larger U.K. trial called RECOVERY, randomly assigned 9,785 patients to receive either the Regeneron antibody cocktail or usual care. Doctors were allowed to give all patients standard treatments like the steroid dexamethasone and the antiviral remdesivir. The main analysis was in only about a third of the total number of patients who tested negative for antibodies to Covid-19.
In these so-called seronegative patients, who were infected but who had not mounted their own antibody response, the benefit was dramatic. The addition of the monoclonal antibody cocktail reduced the percentage of patients who died from 30% to 24%. That is a 20% relative reduction. It means that for every 100 patients who were treated with the antibody cocktail, six fewer died.
There was other evidence the antibody cocktail helped these seronegative patients. Their duration of hospital stay was reduced from 17 days to 13 days, and the proportion who left the hospital within 28 days increased from 58% to 64%.
This benefit was more dramatic because these seronegative patients were in general more likely to die than those who did mount an antibody response. The mortality rate among these so-called seropositive patients was only 15%.
But in the seropositive patients, there was no benefit from the antibody cocktail. When both groups were combined, death within 28 days occurred in 20% of patients who received the antibody cocktail and 21% of those who received usual care but not the antibody.
Landry compared this phenomenon to vitamin deficiency, while cautioning the analogy is imperfect. “If your vitamin levels are fine, taking more vitamins is expensive but useless. If you’re vitamin deficient, [in many cases] getting vitamins is lifesaving,” he said. Similarly, replacement SARS-CoV-2 antibodies only work if a person’s antibody levels are low.
Monoclonal antibodies are generally given through an IV drip and are difficult to administer to healthy people. They are, however, much easier to give to people who are already hospitalized for their illness. Up until now, it has been difficult to identify which patients would most benefit from antibody treatment. Similar concerns exist for convalescent plasma, in which antibodies from people who have been sick are used instead of factory-manufactured antibodies. Previously, the RECOVERY trial failed to find a benefit from convalescent plasma.
“There’s been a lot of questions about the potential for antiviral drugs in general in hospitalized patients,” said Peter Horby, an Oxford professor and co-investigator of the RECOVERY trial. “There has been a perception that it may be too late at that stage for an antiviral drug to work.” He noted that neither remdesivir nor convalescent plasma has shown a mortality benefit in hospitalized patients.
The RECOVERY effort, in which U.K. hospitals are used to run a large, low-cost clinical trial, has yielded many of the most important findings of the pandemic, including the efficacy of the steroid dexamethasone and the arthritis drug Actemra in treating hospitalized patients with Covid-19, as well as inefficacy of the malaria drug hydroxychloroquine for the same purpose.
That the antibodies would work better in patients who had not mounted their own antibody response was an idea that came from Regeneron’s earlier studies. But a change suggested by an independent committee charged with safeguarding patients made the study difficult to enroll, said George Yancopoulos, Regeneron’s chief scientific officer and president. When results were released last December, Yancopoulos said that a much larger trial would be required to prove that benefit, and that he believed RECOVERY would provide those answers.
Now he says he wonders if a larger trial could have been completed sooner, and says it’s “a shame” it wasn’t. “Maybe we could have saved a lot more lives,” he said.