Sanofi and Regeneron Pharmaceuticals said today they will narrow the Phase III portion of their trial assessing the marketed arthritis drug Kevzara® (sarilumab) as a COVID-19 treatment after preliminary analysis showed a benefit from the drug only in patients with more advanced “critical” respiratory illness caused by the disease.
At the recommendation of the study’s Independent Data Monitoring Committee (IDMC), the companies said, they will enroll only critical patients in the Phase III study portion (NCT04315298) and end the portion of the study assessing the drug in less advanced “severe” respiratory illness caused by COVID-19.
The Phase III study will also be amended to end treatment with Kevzara at the lower dose of 200 mg, with all new patients receiving either higher-dose Kevzara (400 mg) or placebo.
The trial’s randomized Phase II portion assessed 457 hospitalized patients, who were categorized as “severe” (28% of patients), “critical” (49%) or “multi-system organ dysfunction” (MSOD; 23%). 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.
While Kevzara rapidly lowered C-reactive protein, a key marker of inflammation, meeting the primary endpoint in a preliminary analysis of data from the Phase II portion of the trial, Kevzara “had no notable benefit on clinical outcomes when combining the ‘severe’ and ‘critical’ groups, versus placebo,” Sanofi and Regeneron acknowledged.
Kevzara is among 18 candidates designated as “Front Runners” among 160+ COVID-19 therapeutics under study in GEN’s updated A-List published April 13, “Vanquishing the Virus: 160+ COVID-19 Drug and Vaccine Candidates in Development.”
Negative, positive trends
Sanofi and Regeneron also acknowledged unspecified “negative trends” for most of the outcomes recorded for the severe patient group, as well as positive trends for all outcomes in the critical patients group, which Sanofi and Regeneron detailed in their announcement:
- The number of patients who died dropped with increased Kevzara dosage, to 20 of 88 (23%) at 400 mg from 34 of 94 (36%) at 200 mg, and 12 of 44 (27%) among placebo patients.
- The number of patients “on a ventilator” also dropped with increased Kevzara dosage, to 8 of 88 (9%) at 400 mg from 9 of 94 (10%) at 200 mg, and 12 of 44 (27%) among placebo patients.
- Patients showing a 2 point improvement on a 7-point scale (from 1 = death to 7 = discharge from hospital) improved slightly with higher dosage, to 52 of 88 patients (59%) at 400 mg, from 48 of 94 (51%) at 200 mg, and 18 of 44 (41%) among placebo patients.
- Patients off oxygenation also improved with higher dosage, to 51 of 88 patients (58%) at 400 mg, from 40 of 94 (43%) at 200 mg, and 18 of 44 (41%) among placebo patients.
- The number of patients discharged increased with higher dosage, to 51 of 88 patients (58%) at 400 mg from 40 of 94 (43%) at 200 mg, and 18 of 44 (41%) among placebo patients.
Following the IDMC review, Regeneron and Sanofi conducted their own analysis of the discontinued “severe” group, finding that the negative trends in the 126-patient Phase II portion were not reproduced in the 276-patient Phase III portion, and that clinical outcomes were balanced across all treatment arms.
Outcomes for the “severe” group were better than expected based on earlier reports, regardless of treatment assignment; in the Phase 2 portion, approximately 80% of patients were discharged, 10% of patients died and 10% remain hospitalized, the companies disclosed.
600 “Critical” patients
The ongoing portion of the Phase I trial, which continues to enroll patients, currently includes more than 600 participants in the “critical” group. Regeneron and Sanofi said they remain blinded to the ongoing portion of the Phase III trial and expect to report results by June.
The companies are also conducting a second trial in countries outside of the U.S. 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. Initial results from this second trial are expected in the third-quarter.
Findings from the U.S. trial will be shared immediately with the IDMC and similar amendments to the trial outside the U.S. will be considered, the companies said.
Sanofi and Regeneron launched their Phase II/III trial last month.
Kevzara is an interleukin-6 (IL-6) receptor antagonist approved by the FDA in 2017 to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
Regeneron and Sanofi reason that IL-6 may play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19.
Preliminary chinese data
The companies noted that a potential role of IL-6 is supported by preliminary data from a single-arm, 21-patient trial in China using another IL-6 receptor antibody, tocilizumab, which is under study by several companies for effectiveness against SARS-CoV-2—and is marketed in the U.S. as Actemra® by Genentech, a member of the Roche Group.
The non-peer reviewed results from the Chinese study showed that 15 of 20 COVID-19 patients treated with tocilizumab reduced their need for supplemental oxygen within days of receiving that treatment, and showed rapidly reduced fever. Based on these results, China recently updated its COVID-19 treatment guidelines, approving the use of tocilizumab to treat patients with severe or critical disease.
The U.S. Kevzara trial has been funded in part with Federal funds from the U.S. Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; and the Biomedical Advanced Research and Development Authority (BARDA), under OT number: HHSO100201700020C.
“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,” John Reed, MD, PhD, Sanofi’s Global Head of Research and Development, said in a statement.
He said Sanofi is pursuing multiple initiatives to fight COVID-19, including researching other potential treatment options, developing vaccine candidates that can be manufactured at large-scale, and a potential collaboration for an innovative SARS-CoV-2 smartphone-based self-testing solution.
“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,” added George D. Yancopoulos, MD, PhD, Regeneron co-founder, president and chief scientific officer.
Yancopoulos said Regeneron plans to initiate a clinical trial in June for its targeted anti-SARS-CoV-2 “antibody cocktail” combination of neutralizing monoclonal antibodies leveraging Regeneron’s monoclonal antibody discovery platform called VelocImmune®, part of the company’s VelociSuite technologies. He added: “There is an acute need for tailored approaches that specifically target this virus.”