Sanofi and Regeneron provide update on U.S. Phase II/III adaptive-designed trial in hospitalized COVID-19 patients.

Sanofi and Regeneron Pharmaceuticals, Inc., announced the preliminary results from the Phase II portion of an ongoing Phase II/III trial evaluating Kevzara (sarilumab) , an interleukin-6 (IL-6) receptor antibody, in hospitalized patients with “severe” or “critical” respiratory illness caused by COVID-19. Following a review by the Independent Data Monitoring Committee (IDMC) of all available Phase II and Phase III data, the trial will be immediately amended so that only “critical” patients continue to be enrolled to receive Kevzara 400 mg or placebo.

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The randomized Phase II portion of the trial compared intravenously-administered Kevzara higher dose (400 mg), Kevzara lower dose (200 mg) and placebo. It assessed 457 hospitalized patients, who were categorized at baseline as having either “severe” illness (28% of patients), “critical” illness (49% of patients) or “multi-system organ dysfunction” (MSOD) (23% of patients). Patients were classified as “severe” if they required oxygen supplementation without mechanical or high-flow oxygenation; or “critical” if they required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit. Preliminary analysis of the Phase II portion of the trial demonstrated that Kevzara rapidly lowered C-reactive protein, a key marker of inflammation, meeting the primary endpoint.

< Baseline levels of IL-6 were elevated across all treatment arms, with higher levels observed in “critical” patients compared to “severe” patients. Additionally, no new safety findings were observed with the use of Kevzara in COVID-19 patients.

Analysis of clinical outcomes in the Phase II trial were exploratory and pre-specified to focus on the “severe” and “critical” groups . In the preliminary Phase II analysis, Kevzara had no notable benefit on clinical outcomes when combining the “severe” and “critical” groups, versus placebo. However, there were negative trends for most outcomes in the “severe” group, while there were positive trends for all outcomes in the “critical” group . Subsequent to the IDMC review, Regeneron and Sanofi conducted a review of the discontinued “severe” group that revealed the negative trends in the Phase II (n=126) were not reproduced in Phase III (n=276), and that clinical outcomes were balanced across all treatment arms. Outcomes for the “severe” group were better than expected based on prior reports, regardless of treatment assignment: for example, in the Phase II portion, approximately 80% were discharged, 10% of patients died and 10% remain hospitalized.

The Kevzara trial was designed after a small (n=21), single-arm study in China (Xu et al) among mostly severe, febrile hospitalized COVID-19 patients, which found elevated IL-6 levels, and suggested that inhibiting this pathway with the IL-6 inhibitor tocilizumab rapidly reduced fever and improved oxygenation in severe patients, allowing for successful hospital discharge. These uncontrolled findings require confirmation in adequately-sized and well-controlled trials.

Last month, Regeneron and Sanofi moved rapidly to evaluate Kevzara in a prospective, randomized, placebo-controlled adaptively-designed U.S. Phase II/III trial in collaboration with U.S. groups including the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, the FDA, and hospitals across the country.

The ongoing portion of the Phase III trial, which is continuing to enroll, currently includes more than 600 patients in the “critical” group. Regeneron and Sanofi remain blinded to the ongoing portion of the Phase III trial and expect to report results by June.

In addition, the companies are also conducting a second trial in countries outside of the U.S. The Phase III trial of Kevzara in approximately 400 patients hospitalized with COVID-19 infection is currently enrolling in Italy, Spain, Germany, France, Canada, Russia, Israel and Japan. Initial results from this second trial are expected in the third-quarter. The findings from the U.S. trial will be shared immediately with the IDMC and similar amendments to the trial outside the U.S. will be considered..