Newron Pharmaceuticals S.p.A. announced on October 8, 2026, that it has received written communication from the U.S. Food and Drug Administration regarding the clinical hold at U.S. study centers in its Phase 3 ENIGMA-TRS 2 study with evenamide. The company is reviewing the FDA's feedback and preparing its response. The hold, initially reported on April 29, 2026, prevents enrollment of new patients at U.S. sites, but no U.S. patients have been dosed. The news matters because it clarifies the FDA's specific safety concerns and outlines Newron's next steps, which could affect the timeline for a potential new treatment for treatment-resistant schizophrenia.
The FDA's concern relates to the known risk that certain sodium channel blockers may trigger arrhythmias, leading to serious cardiovascular events or seizures. Evenamide is a selective voltage-gated sodium channel blocker. In its written communication, the FDA noted four deaths among patients treated with evenamide across all clinical studies, compared with one death among patients receiving placebo. Three of the four deaths were considered unrelated to evenamide by investigators, while one was considered possibly related because two autopsies could not identify a definitive cause. The FDA characterized these as a potential safety signal based on the possibility of a fatal arrhythmic mechanism, which cannot be definitively excluded through post hoc adjudication. Evenamide also causes a very small shortening of the QTc interval on an ECG, for which there is no established risk threshold.
Newron is reviewing the full body of safety data, which includes more than 10,000 ECGs from approximately 700 evenamide-treated subjects and input from independent cardiac electrophysiologists. The company has not observed a pattern of cardiac abnormalities or arrhythmias in preclinical and clinical data to date, including a thorough QT study and more than 5,000 ECGs from over 700 patients with schizophrenia. As part of its response, Newron is evaluating additional cardiac screening and monitoring measures for ENIGMA-TRS 2. According to Ravi Anand, MD, Chief Medical Officer, the four deaths represent an incidence of 0.56% compared with 0.27% for placebo, and when adjusted for treatment duration, the mortality rate was 1.31 per 100 patient-years for evenamide versus 1.81 per 100 patient-years for placebo.
Despite the hold, the Phase 3 ENIGMA-TRS development program continues to advance. ENIGMA-TRS 1 enrollment is expected to be completed by mid-October 2026, with topline 12-week data expected in the first quarter of 2027. ENIGMA-TRS 2 enrollment continues outside the U.S., and additional clinical sites are being added as planned. The program's progress is critical for patients with treatment-resistant schizophrenia, a severe form of the disease that reduces life expectancy by about 20 years, as noted by Professor Dr. Peter Falkai of LMU University of Munich. Evenamide has the potential to be the first add-on therapy for this population. Newron's management provided an update on the clinical hold and program during a conference call today. For more details, see the original release. The company's ongoing review and planned response to the FDA will determine whether U.S. enrollment can resume, making this a pivotal moment for the program and for patients awaiting new options.
