Regeneron & Sanofi Amend Phase II/III Kevzara COVID-19 Clinical Trial—Only Focus on Critical Patients

Apr 28, 2020 | ARDS, Coronavirus, COVID-19, IL-6 pathway, Kevzara, Regeneron, Sanofi

Regeneron & Sanofi Amend Phase IIIII Kevzara COVID-19 Clinical Trial—Only Focus on Critical Patients

An Independent Data Monitoring Committee (IDMC) suggested that Regeneron and Sanofi only continue the ongoing Phase II/III clinical trial for Kevzara in the more advanced “critical” group with higher-dose versus placebo while they discontinue the less advanced group. Now the sponsors will only enroll “critical” patients at the 400 mg dose while they discontinue lower-dose Kevzara (200 mg).

The premise behind the use of Kevzara as an investigational product to address SARS-CoV-2 centers on data from Chinese clinical trials revealing data points that the IL-6 pathway may play an important role in the overactive inflammatory response in the lungs of COVID-19 afflicted patients. Hence, an initial driver for Regeneron and Sanofi to seek to leverage similar experimental product in a properly designed and randomized trial to produce more evidence as to the safety and effectiveness of this approach in severe to critical COVID-19 cases. The use of Kevzara to treat the symptoms of COVID-19 is investigational and has not been fully evaluated by any regulatory authority.

The Study Ongoing

The preliminary results from the Phase II portion of the 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 IDMC reviewed all available Phase II and III data and recommended the trial be amended to proceed only with “critical” patients (require oxygen supplementation and ventilator).

Analysis

The IDMC reviewed 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).

The preliminary analysis of the Phase II segment of the trial does reveal that the investigational drug 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.

The 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.” Hence, subsequent to IDMC review, Regeneron and Sanofi reviewed the discontinued “severe” group data, which revealed that the negative trends in the Phase II trial (n = 126) were not reproduced in Phase III trial (n =276), and that clinical outcomes were balanced across the Kevzara and placebo treatment arms.

CEO Acknowledges Regeneron Investigating

CEO George D. Yancopoulos, MD, PhD, Regeneron Co-Founder, President and Chief Scientific Officer, commented that “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.” The CEO furthered, “Emerging evidence with Kevzara and other repurposed drugs in the COVID-19 crisis highlight the challenges of making decision 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 form 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.”

Other Trials

The companies are conducting a second trial in countries outside of the United States. 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. Results from this study are expected in Q3 2020. The recent IDMC-based findings (and amendment) will be shared with and considered by the trials outside of the U.S.

The Drug

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 severely ill patients infected with coronaviruses

Funding

The U.S. Kevzara 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; and BARDA.

Call to Action: Interested in more details from the IDMC finding—see link to underlying source.

Source: Regeneron

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