Sanofi and Regeneron Pharmaceuticals announced Thursday that a Phase III trial of their rheumatoid arthritis drug Kevzara (sarilumab) 400 mg in COVID-19 patients requiring mechanical ventilation did not meet its primary and key secondary endpoints when the IL-6 receptor antibody was added to best supportive care, versus best supportive care alone. Following on the results, the US-based trial has been stopped, including in a second cohort of patients who received the higher 800-mg dose.
The news comes after Sanofi and Regeneron reported in April that the Phase II portion of the trial testing Kevzara at the 200-mg and 400-mg doses showed it had "no notable benefit" on clinical outcomes versus placebo in hospitalised coronavirus patients with severe or critical respiratory illness. At the time, the companies indicated that based on those results, the study would be amended so that only critical patients continued to be enrolled, and that these would receive the 400-mg dose or placebo.
The new analysis focused on a group of 194 critically ill COVID-19 patients on mechanical ventilation at the time of enrolment. The primary endpoint assessed the percentage of those who achieved at least a 1-point change from baseline on a 7-point patient-status scale that ranged from death to discharge from hospital. A second cohort, which was partially recruited with 27 subjects, compared Kevzara 800 mg versus placebo.
Minor positive trends
Sanofi and Regeneron said that while "minor positive trends" were seen in the primary analysis group receiving the 400-mg dose, these did not reach statistical significance and were "countered by negative trends" in a subgroup of critical patients who were not intubated at baseline. Further, adverse events were experienced by 80% of Kevzara patients and 77% of placebo patients. Among the serious adverse events that occurred more frequently among Kevzara-treated patients were multi-organ dysfunction syndrome, which occurred at rates of 6% for Kevzara versus 5% for placebo, and hypotension, which occurred at rates of 4% and 3%, respectively. Detailed findings will be submitted to a peer-reviewed publication later this year.
Meanwhile, a separate Sanofi-led trial outside the US in hospitalised patients with severe and critical COVID-19 using a different dosing regimen is ongoing on the recommendation of the same independent data monitoring committee overseeing the Regeneron-led US trial. The companies expect to report results in the third quarter.
Inhibiting IL-6 pathway
Sanofi and Regeneron explained that the Kevzara trial was designed after a small single-arm study in China of mostly severe, febrile hospitalised COVID-19 patients found elevated IL-6 levels and suggested that inhibiting this pathway with Roche's anti-IL-6 receptor biologic Actemra/RoActemra (tocilizumab) rapidly reduced fever and improved oxygenation in severe cases.
In March, Roche launched the Phase III COVACTA trial testing Actemra/RoActemra plus standard of care in hospitalised adults with severe COVID-19 pneumonia, compared to placebo plus standard of care. It later announced a collaboration with Gilead Sciences to evaluate combining Actemra/RoActemra with remdesivir in the REMDACTA study.
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