FDA Cites 4 Deaths, Potential Cardiac Risk in Evenamide Trial

FDA has cited four deaths among patients treated with Newron Pharmaceuticals’ investigational schizophrenia drug evenamide as a potential cardiac safety signal, according to new details disclosed by the company concerning the agency's continuing clinical hold on its Phase 3 ENIGMA-TRS 2 study in the U.S.

A Newron update says it received a written communication from FDA explaining its concerns and is reviewing the agency's feedback before submitting a response. The hold remains in place at U.S. study centers, while enrollment continues outside the country.

According to Newron, FDA identified four deaths among evenamide-treated patients across the drug's clinical development program, compared with one death among placebo recipients. Investigators considered three of the four deaths unrelated to treatment, while one was classified as possibly related because autopsies could not establish a definitive cause of death.

FDA characterized the deaths as a potential safety signal because a fatal arrhythmic mechanism could not be definitively excluded through retrospective assessment, Newron notes.

The agency's concerns center on the known potential for certain sodium-channel blockers to trigger cardiac arrhythmias that can lead to serious cardiovascular events or seizures. “Evenamide is also known to result in a very small shortening of the QTc interval on an electrocardiogram (ECG),” the company says. “Unlike QTc prolongation, there is no established risk or intervention threshold for QTc shortening, and a standard screening ECG does not reliably exclude latent sodium-channel disorders in asymptomatic patients.”

The clinical hold was initially imposed in April after Newron reported the sudden, unexpected death of a study participant outside the U.S. The investigator assessed that death as unrelated to treatment, and an independent safety monitoring board subsequently recommended continuing the ENIGMA-TRS studies as designed.

FDA reaffirmed the hold in September, preventing enrollment of new U.S. patients in ENIGMA-TRS 2.

Newron disputes the suggestion of a broader cardiac safety problem, saying its development program includes more than 10,000 ECGs from approximately 700 evenamide-treated subjects and assessments by independent cardiac electrophysiologists. The company said it has not identified a pattern of cardiac abnormalities or arrhythmias.

Chief Medical Officer Ravi Anand said the four deaths represented an incidence of 0.56% among evenamide recipients, compared with 0.27% among placebo recipients. When adjusted for treatment exposure, mortality rates were 1.31 and 1.81 per 100 patient-years, respectively.

The company is evaluating additional cardiac screening and monitoring measures as part of its response to FDA.