LONDON – The U.K. is to make treatment with interleukin-6 (IL-6) inhibitors standard of care for critically ill COVID-19 patients after a randomized trial found the arthritis drugs significantly improve survival.
The Remap-Cap study showed that, in addition to an 8.5% reduction in mortality, the drugs improved recovery. On average, surviving patients were discharged from intensive care about a week sooner than controls.
“We found that among critically ill adult patients receiving breathing support in intensive care, treatment with these drugs can improve their chances of survival and recovery,” said Anthony Gordon, professor of anesthesiology and critical care at Imperial College London and clinical lead for Remap-Cap.
The data, published in a non-peer reviewed preprint, relates to 353 patients treated with Roche Holding AG’s Actemra (tocilizumab), 48 who received Regeneron Inc./Sanofi SA’s Kevzara (sarilumab), and 402 controls. There was an odds ratio of 1.64 for a better outcome with Actemra and 1.7 for Kevzara, compared to no immune modulation.
Mortality was 27.3% among patients treated with IL-6 inhibitors, compared to 35.8% for the control group.
The findings are at odds with phase III trials conducted by the companies. Regeneron stopped development of Kevzara in COVID-19 in July 2020, after it failed to show a significant benefit.
Similarly, Roche has reported middling to inconclusive results for Actemra, with the monoclonal antibody failing to meet the primary endpoint in the Covacta study that also reported in July, while showing a slight effect in reducing the number of hospitalized patients requiring mechanical ventilation over 28 days, but failing to meet key secondary endpoints, including reducing time to hospital discharge and time to clinical failure, in another study published in September.
Gordon suggested the reason previous trials of IL-6 receptor agonists showed no clear benefit on either disease progression or survival in COVID-19 patients was because they included less severely ill patients, and started treatment at different stages in the disease course.
“A crucial difference may be that in our study, critically ill patients were enrolled within 24 hours of starting organ support,” Gordon said. “This highlights a potential early window for treatment where the sickest patients may gain the most benefit from immune modulation treatment.”
Coinciding with publication of the data, the U.K. government said it is updating its guidance and recommending the use of Actemra in patients admitted to ICUs, effective immediately.
“This is a significant step forward for increasing survival of patients in intensive care with COVID-19,” said England’s deputy chief medical officer, Jonathan Van-Tam. “The data shows that tocilizumab, and likely sarilumab, speed up and improve the odds of recovery in intensive care.”
Actemra is being tested in the larger U.K. recovery trial, which is assessing a number of different drugs in a centrally randomized open-label study involving all acute care hospitals in the country. As a result, supplies of the drug are already available.
The Department of Health said it is working closely with Roche to maintain supplies. The government also put Actemra and Kevzara on the list of priority drugs than cannot be exported from the U.K.
Recovery and Remap-Cap
In June, the large scale U.K. Recovery trial made the first major breakthrough in therapeutics for COVID-19 infection, showing that corticosteroids have a statistically significant impact on mortality in the most seriously ill patients, with a one-third reduction in deaths in patients on ventilators, while in those receiving oxygen therapy, there was a 15% reduction in 28-day mortality.
Remap-Cap shows IL-6 inhibitors have an added effect, noted Peter Horby, professor of emerging infectious diseases at Oxford University, who is co-lead of Recovery. “The findings of a benefit are in addition to corticosteroids, which were taken by 93% of the participants. This means we now have two drugs, which combined have a greater effect,” he said commenting on the Remap-Cap data.
Remap-Cap stopped recruiting patients to the standard-of-care arm in November, after the data safety monitoring board recognized the survival benefits of IL-6 inhibitor therapy. The preprint published on Jan. 7 discusses the subsequent analysis of the data.
The Recovery trial also is testing Actemra and has continued to enroll patients to that arm of the study, which has recruited more than 2,800 of an intended to 4,000 participants. Patients who have low oxygen saturations or need ventilation and have evidence of significant inflammation are eligible – a broader category than patients recruited to Remap-Cap.
Following the DSMB’s recommendation to stop standard of care in Remap-Cap, Horby and his co-lead Martin Landray wrote to Recovery trial investigators in 176 hospitals asking them to keep recruiting to the Actemra study, saying despite the Remap-Cap findings, “both the nature and size of the apparent benefit remain unknown both overall and in particular types of patients.”
Commenting on the analysis of the Remap-Cap data as the preprint was published, Landray, who is professor of medicine and epidemiology at Oxford University, welcomed the news. “It shows that tocilizumab reduces length of time that critically ill patients require mechanical ventilators and other forms of organ support. In contrast to previous trials, Remap-Cap also reports lower mortality among patients given tocilizumab.”
But, Landray said, there remain unanswered questions. “For example, exactly how well does tocilizumab work in different types of patients? And if given earlier, might it reduce the need for patients to require mechanical ventilation in the first place?"
Recovery has the numbers to help fill those gaps. “We don’t yet know the answers. But, Remap-Cap has injected that bit of optimism we all need,” said Landray.
Similarly, Horby said, “This result is for critically ill patients and we hope to soon have results from Recovery on the effect of tocilizumab in less severely ill patients in hospital.”
While IL-6 inhibitors should theoretically help to damp down the cytokine storm seen in fatal COVID-19, previous studies have shown no clear survival benefit, noted Robin Ferner, honorary professor of clinical pharmacology at Birmingham University. “If the published data from Remap-Cap are supported by further studies, this suggests that two IL-6 receptor antagonists can reduce the death rate in the most severely ill patients.
“But they are no magic cure: of 401 patients given the drugs, 109 died. With standard treatment, 144 out of 402 died,” Ferner said.