The FDA has flagged four deaths among patients receiving Newron Pharmaceuticals’ investigational schizophrenia drug evenamide as a potential safety signal, in its written explanation of a clinical hold on U.S. sites in a Phase 3 trial. The four deaths occurred across all clinical studies of evenamide, compared with one death among patients receiving placebo, according to an October 8 release from the company. Investigators considered three deaths unrelated to evenamide and one possibly related. The FDA cited the possibility of a fatal arrhythmic mechanism that could not be definitively excluded, a concern that stems from the known risk that some sodium channel blockers, the drug class evenamide belongs to, can trigger arrhythmias.
The clinical hold, first placed on new enrollment at U.S. sites in April after the sudden death of a participant, remains in place at U.S. study centers in the Phase 3 ENIGMA-TRS 2 trial, though enrollment continues outside the U.S. and no U.S. patients have received evenamide in the study. Newron reported a mortality incidence of 0.56 percent among evenamide-treated patients versus 0.27 percent on placebo, but said that when adjusted for treatment duration the rates were 1.31 and 1.81 per 100 patient-years respectively. The company said it has not observed a pattern of cardiac abnormalities or arrhythmias in safety data including more than 10,000 electrocardiograms from about 700 evenamide-treated subjects, and is reviewing the FDA’s feedback while evaluating additional cardiac screening and monitoring.
Shares of the Switzerland-listed company fell 5.7 percent in afternoon trading Thursday. Enrollment in the separate ENIGMA-TRS 1 trial is expected to finish by mid-October, with topline 12-week results expected in the first quarter of 2027. Evenamide is being developed as an add-on therapy for treatment-resistant schizophrenia, a population with few options, so the FDA’s cardiac concern puts the program’s U.S. path on hold while the rest of the world continues enrolling.