Regeneron and Sanofi announced that the U.S. Phase 3 clinical trial of Kevzara® (sarilumab) 400 mg in COVID-19 patients requiring mechanical ventilation failed to meet its primary and key secondary endpoints when the drug was added to best supportive care compared to best supportive care alone (placebo). 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 included multi-organ dysfunction syndrome (6% Kevzara, 5% placebo) and hypotension (4% Kevzara and 3% placebo). The industry sponsors have halted this U.S.-based clinical trial, including a second cohort of patients who received a higher dose of Kevzara (800 mg), based on these findings. Both Regeneron and Sanofi have commented in a press release to submit detailed peer-reviewed disclosure of what happened in this partially publicly financed clinical trial. There are several other Kevzara studies ongoing involving COVID-19 patients: what are the implications of the results from those studies? What about the 43 Actemra (tocilizumab) clinical trials associated with COVID-19 patients and the failed Italian tocilizumab (Actemra) study? Is their growing evidence that pharma company’s pursuit of repurposing IL-6 inhibitors against COVID-19 is a failed strategy? After all, clinical trials are expensive and, as is the case in this U.S., study public funds can be involved. How can these funds be best utilized to protect patients?
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.
The primary analysis group included 194 patients who were critically ill with COVID-19 and were receiving mechanical ventilation at the time of enrollment. 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 1) death; 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. Some minor positive trends were observed but based on the totality of findings and the termination of this study those interested in click through to the source for more details.
U.S. Public Funding Supported this Trial
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; and Biomedical Advanced Research and Development Authority (BARDA), under OT number: HHSO100201700020C.
The BARDA funding was announced on March 21, 2020 when BARDA Director Rick A. Bright, PhD, commented, “By repurposing a currently approved product, we may be able to expedite development and make treatments available quickly.”
Another Trial Ongoing
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. and has recommended that the trial outside of the U.S. continue. The companies expect to report results of the trial outside of the U.S. in Q3 2020.
Upon a search of Clincaltrials.gov, TrialSite News found 10 clinical trials disclosed involving Kevzara. What are the implications for these studies? According to a search in the governmental clinical trials database, Roche has 43 Actemra trials associated with COVID-19 patients. Are there any implications for these studies?
Impact Other Drugs?
Back in April, Regeneron CEO George D. Yancopoulos commented, “When you try everything under the kitchen sink most of the time it’s not going to deliver the results that you want, no matter what the small 20-patient or 30-patient studies say.”
Reporting on the emerging data back in April, STAT’s Matthew Herper suggested that the emerging data points from the Sanofi/Regeneron study could possibly impact similar drugs that are in use off-label in at least some hospitals. An example would be Roche’s Actemra. Does this findings reduce the probability that other repurposed medicines used against autoimmune diseases such as rheumatoid arthritis can possibly help severe to critical COVID-19 patients requiring mechanical ventilation?
In an Italian clinical trial evaluating the use of Roche’s Actemra in patient patients with early-state COVID-19 pneumonia the investigators found that the anti-inflammatory didn’t improve patients’ severe respiratory symptoms, reduce ICU visits or cut mortality rates better than standard of care. The Italian regulatory AIFA, reported that this study was the first such randomized test in the world involving Roche’s Actemra in COVID-19 patients. The study results evaluate the hypothesis that IL-6 inhibitors such as Actemra and Regeneron, help patients with COVID-19.
Call to Action: Do these results potentially implicate other repurposed IL-6 inhibitor drugs for autoimmune disorders as a possible treatment for severe to critical COVID-19 patients in need of mechanical ventilation? What about the failed tocilizumab (Actemra) trial in Italy?