July 2, 2020: “Sanofi and Regeneron Pharmaceuticals announced that the U.S. Phase 3 trial of Kevzara® (sarilumab) 400 mg in COVID-19 patients requiring mechanical ventilation did not meet its primary and key secondary endpoints when Kevzara was added to best supportive care compared to best supportive care alone (placebo).
Minor positive trends were observed in the primary pre-specified analysis group (critical patients on Kevzara 400 mg who were mechanically ventilated at baseline) that did not reach statistical significance and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline.
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In the primary analysis group, adverse events were experienced by 80% of Kevzara patients and 77% of placebo patients. Serious adverse events that occurred in at least 3% of patients and more frequently among Kevzara patients were multi-organ dysfunction syndrome (6% Kevzara, 5% placebo) and hypotension (4% Kevzara, 3% placebo).
Based on the results, the U.S.-based trial has been stopped, including in a second cohort of patients who received a higher dose of Kevzara (800 mg). Detailed results will be submitted to a peer-reviewed publication later this year.
The primary analysis group included 194 patients who were critically ill with COVID-19 and receiving mechanical ventilation at the time of enrolment.
The primary endpoint assessed the percentage of patients who achieved at least a 1-point change from baseline on a 7-point scale, which consisted of
2) hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);
3) hospitalized, requiring non-invasive ventilation or high flow oxygen devices;
4) hospitalized, requiring supplemental oxygen;
5) hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (COVID-19 related or otherwise);
6) hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care;
7) discharged from hospital. A second cohort, which was partially recruited (n=27), compared Kevzara 800 mg versus placebo.
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.
The Phase 3 Kevzara trial was designed to evaluate this hypothesis in a large, placebo-controlled trial. The trial has been funded in part with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under OT number: HHSO100201700020C.
A separate Sanofi-led trial outside of the U.S. in hospitalized patients with severe and critical COVID-19 using a different dosing regimen is ongoing.
The same Independent Data Monitoring Committee (IDMC) is overseeing both the Regeneron-led U.S. trial and the Sanofi-led trial outside of U.S., which has recommended that the trial outside of the U.S. continue. The companies expect to report results in Q3 2020.
1: Endpoints that showed positive trends in patients on mechanical ventilation at baseline, and were countered by negative trends in patients who were not mechanically ventilated at baseline included: the proportion of patients with a 1-point improvement on day 22 (primary endpoint for mechanical ventilation group); the proportion of patients who died by day 29; and proportion of patients who recovered by day 22.
Kevzara® (sarilumab) Injection
Kevzara is currently approved in multiple countries to treat adults with moderately to severely active rheumatoid arthritis who have not responded to or tolerated previous therapy.
Kevzara binds specifically to the IL-6 receptor and has been shown to inhibit IL-6-mediated signaling. IL-6 is an immune system protein produced in increased quantities in patients with rheumatoid arthritis and has been associated with disease activity, joint destruction and other systemic problems.
Kevzara is being investigated for its ability to reduce the overactive inflammatory immune response associated with COVID-19 based on evidence of markedly elevated levels of IL-6 in critically ill patients infected with coronaviruses.
Regeneron Pharmaceuticals, Inc.
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases.
Founded and led for over 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to seven FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories.
Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, infectious diseases and rare diseases.
Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune which uses unique genetically-humanized mice to produce optimized fully-human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.”