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Summer 2020 - Vaccines

Study of Kevzara from Severe to Critical COVID-19 Patients

Following a review by the Independent Data Monitoring Committee (IDMC) of 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, the trial was amended so only critical patients continue to be enrolled to receive Kevzara 400 mg or placebo.

The randomized Phase II portion of the trial assessed intravenously administered Kevzara higher dose (400 mg), Kevzara lower dose (200 mg) and placebo in 457 hospitalized patients who were categorized at baseline as having either severe illness (28 percent), critical illness (49 percent) or multi-system organ dysfunction (MSOD) (23 percent). 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. Results demonstrated Kevzara rapidly lowered C-reactive protein (CRP), 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 signals were observed with the use of Kevzara in COVID-19 patients.

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 reviewed the discontinued severe group data, which revealed the negative trends in the Phase II trial (n=126) were not reproduced in the Phase III trial (n=276), and 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 II portion, approximately 80 percent of patients were discharged, 10 percent of patients died and 10 percent remain hospitalized.

“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, MD, PhD, 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 III 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.” Regeneron has rapidly advanced its targeted anti-SARSCoV-2 antibody cocktail, and it initiated clinical trials in June.

The Kevzara trial was designed after a small, single-arm study in China that found elevated IL-6 levels among mostly severe, febrile hospitalized COVID-19 patients, which suggested 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.

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.

References

Regeneron and Sanofi Provide Update on U.S. Phase 2/3 AdaptiveDesigned Trial of Kevzara® (sarilumab) in Hospitalized COVID-19 Patients. Regeneron Pharmaceuticals press release, April 27, 2020. Accessed at www.prnewswire.com/news-releases/regeneron-andsanofi-provide-update-on-us-phase-23-adaptive-designed-trial-ofkevzara-sarilumab-in-hospitalized-covid-19-patients-301047326.html.

BSTQ Staff
BioSupply Trends Quarterly [BSTQ] is the definitive source for industry trends, news and information for the biopharmaceuticals marketplace. With timely and critical information, each themed issue covers topics ranging from product breakthroughs, industry insights and innovations, up-to-the-minute news on the latest clinical trials, accessibility, and service and safety concerns.