PARIS & TARRYTOWN, N.Y.—At the end of April, Sanofi S.A. and Regeneron Pharmaceuticals Inc. announced 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.
The randomized Phase 2 portion of the trial compared intravenously administered 200 mg of Kevzara, 400 mg of Kevzara and placebo. The trial assessed 457 hospitalized patients who were categorized at baseline as having either severe illness (28 percent), critical illness (49 percent) or multi-system organ dysfunction (23 percent). Patients were classified as severe if they required oxygen supplementation without mechanical or high-flow oxygenation, or were classified critical if they required mechanical ventilation, high-flow oxygenation or ICU treatment.
Preliminary analysis of the Phase 2 portion of the trial demonstrated that Kevzara rapidly lowered C-reactive protein—a key marker of inflammation—and met the primary endpoint. Baseline levels of IL-6 were elevated across all treatment arms, with higher levels observed in critical patients. No new safety findings were observed.
“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. 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,” said Dr. George D. Yancopoulos, co-founder, president and chief scientific officer of Regeneron. “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.”
Analysis of clinical outcomes in the Phase 2 trial was exploratory, and focused on the severe and critical groups. In the preliminary analysis, Kevzara had no notable benefit on clinical outcomes when combining severe and critical groups versus placebo. However, there were negative trends for most outcomes in the severe group and positive trends for all outcomes in the critical group. Following a review by an 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.
“Targeting the correct patient population and severity group is vital when conducting any study. However, testing a variety of severity groups in this trial allowed a process of elimination to help understand the relationship between the cytokine response in COVID-19 patients, and more importantly, when to treat with IL-6 inhibitors (or in this case, when not to treat),” points out Angad Lotay, an infectious diseases analyst at GlobalData. “In order to draw more conclusive evidence, Sanofi and Regeneron are proceeding with [the] Phase 3 portion of the Phase 2/3 trial, specifically targeting critically ill patients at a dose of 400 mg. This will provide a more accurate demonstration as to whether there is a relationship between the use of IL-6 modulators and the most severe COVID-19 patients.”
“Although it is known that IL-6 is a key cytokine mediator in CRS [cytokine release syndrome], its onset and peak timing can vary in different diseases. It is important to evaluate the relationship between the peak level and time of serum cytokines to ultimately optimize treatment timing. Sanofi and Regeneron now have some data on that, and the results of the Phase 3 Kevzara trial will provide a better understanding of this pattern in COVID-19 patients,” Lotay adds.
After the IDMC review, Regeneron and Sanofi conducted a review of the discontinued severe group that revealed the negative trends in Phase 2 (n=126) were not reproduced in Phase 3 (n=276). Clinical outcomes were balanced across all treatment arms, and outcomes for the severe group were better than expected based on prior reports, regardless of treatment assignment; e.g., in the Phase 2 portion approximately 80 percent were discharged, 10 percent died and 10 percent remain hospitalized.
“As we quickly follow the science to better understand this disease and explore how best to treat patients, these initial results from the randomized clinical trial setting provide physicians much-needed insights and information regarding Kevzara for patients with COVID-19,” noted Dr. John Reed, global head of Research and Development at Sanofi.
The Kevzara trial was designed after a small, single-arm study in China (Xu et al.) among mostly severe, febrile hospitalized COVID-19 patients. The study 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.
Regeneron and Sanofi began evaluating Kevzara for COVID-19 in March, in collaboration with the Biomedical Advanced Research and Development Authority, the U.S. Food and Drug Administration, and hospitals across the country. The Phase 2/3 trial has an adaptive design with two parts and expects to enroll up to 400 patients. The first part recruited patients with severe COVID-19 infection across approximately 16 U.S. sites, and evaluated the impact of Kevzara on fever and patients’ need for supplemental oxygen. The second, larger part of the trial will evaluate the improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and/or hospitalization.