The protocol for a clinical trial of a drug for autoimmune disorders in patients with Covid-19 is being amended so that it will only enroll critically ill patients, after a review of available data indicated that it did not appear effective in patients with severe disease.
Tarrytown, New York-based Regeneron Pharmaceuticals and Paris-based Sanofi said Monday that they would amend the 600-patient Phase III portion of their Phase II/III study of Kevzara (sarilumab) so that it would only enroll patients critically ill with Covid-19 and exclude severely ill patients. The decision was based on a recommendation following a review of available Phase II and Phase III data by the trial’s independent data monitoring committee, showing that while there was a positive trend in favor of the drug among critically ill patients, the trend among severely ill patients was negative. The Phase III portion is also being amended to randomized patients only to Kevzara at 400mg or placebo, while discontinuing the 200mg dose.
“Even in a pandemic setting, it’s both crucial and possible to obtain controlled data in adequately sized trials to provide the evidence needed to inform optimal medical care,” Regeneron President George Yancopoulos said in a statement. “Emerging evidence with Kevzara and other repurposed drugs in the Covid-19 crisis highlight the challenges of making decisions about existing medicines for new threats using small, uncontrolled studies.”
A preliminary analysis of the Phase II data showed that an important market of inflammation, C-reactive protein (CRP), was rapidly lowered, meaning that portion of the study met its primary endpoint. Levels of IL-6 – the inflammatory cytokine that Kevzara targets – were higher in critical patients than in severe patients.
Overall, patients in the placebo arm saw a 21% reduction in CRP from baseline, compared with 77% in the 200mg Kevzara group and 79% in the 400mg group. In terms of deaths, 27% of critical patients on placebo died, compared with 36% of those receiving the 200mg dose and 23% receiving the 400mg dose. Critically ill patients, comprising 49% of the 457 in the Phase II study, were defined as those requiring mechanical ventilation, high-flow oxygenation or ICU treatment, while the 28% of those in the severely ill population were defined as requiring oxygen. The remaining 23% were defined as having multi-system organ dysfunction.
In a note to investors, Baird analyst Brian Skorney called the initial data “surprisingly disappointing,” but praised the companies’ handling of the findings.
“These results demonstrate why it is so important to run randomized, double-blind, placebo-controlled clinical studies,” he wrote. “The use of IL-6 antibodies in the setting of [Covid-19] has been widespread and these results challenge this medical practice and indicate, in some patients, it could be making things worse. So kudos to Regeneron for not going the route of abandoning evidence-based medicine, as so many others have, even if it doesn’t give everyone the answer we all want.”
Roche’s Actemra (tocilizumab) is another monoclonal antibody targeting IL-6 under development for Covid-19. Other drugs meant to target the inflammation that causes the disease’s most severe symptoms include various small molecules and other monoclonal antibodies.
Another analyst, RBC Capital Markets’ Kennen MacKay, wrote, “Initial Kevzara data leaves door open for limited benefit in some subgroups, but randomized data doesn’t live up to hope built up for the IL-6 class based on uncontrolled trial data,” referring to the 21-patient Chinese study that served as a rationale for the larger, company-sponsored trial.
Photo: Kaikoro, Getty Images