Regeneron Pharmaceuticals and Sanofi announced the preliminary results from the Phase 2 portion of an ongoing Phase 2/3 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 2 and Phase 3 data, the trial will be immediately amended so that only "critical" patients continue to be enrolled to receive Kevzara 400 mg or placebo.
The randomized Phase 2 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 2 portion of the trial demonstrated that Kevzara rapidly lowered C-reactive protein (CRP), a key marker of inflammation, meeting the primary endpoint (see table below). 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 signals were observed with the use of Kevzara in COVID-19 patients.
Analysis of clinical outcomes in the Phase 2 trial was exploratory and pre-specified to focus on the "severe" and "critical" groups. In the preliminary Phase 2 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 (see table below). Subsequent to the IDMC review, Regeneron and Sanofi reviewed the discontinued "severe" group data, which revealed that the negative trends in the Phase 2 trial (n=126) were not reproduced in Phase 3 trial (n=276), and that clinical outcomes were balanced across the Kevzara and placebo treatment arms. Outcomes for the "severe" group were better than expected based on prior reports, regardless of treatment assignment: for example, in the Phase 2 portion, approximately 80% were discharged, 10% of patients died and 10% remain hospitalized.
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"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," said George D. Yancopoulos, M.D., Ph.D., Regeneron Co-Founder, President and Chief Scientific Officer. "Emerging evidence with Kevzara and other repurposed drugs in the COVID-19 crisis highlight the challenges of making decisions about existing medicines for new viral threats using small, uncontrolled studies. We await results of the ongoing Phase 3 trial to learn more about COVID-19, and better understand whether some patients may benefit from Kevzara treatment. In addition, there is an acute need for tailored approaches that specifically target this virus. To that end, Regeneron is rapidly advancing our targeted anti-SARS-CoV-2 antibody cocktail and we plan to initiate clinical trials in June."
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 found elevated IL-6 levels and suggested that inhibiting this pathway with the IL-6 blocker 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 2/3 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 Food and Drug Administration (FDA) and hospitals across the country.