Newron Pharmaceuticals S.p.A. has received the FDA's written communication regarding the clinical hold at U.S. study centers in its Phase 3 ENIGMA-TRS 2 study of evenamide, an experimental add-on treatment for treatment-resistant schizophrenia. The company is now reviewing the agency's feedback and preparing its formal response. The hold, originally reported on April 29, 2026, remains in place at U.S. sites, although no U.S. patients have been dosed with evenamide in the study. The FDA's concern centers on the known risk that certain sodium channel blockers can trigger arrhythmias, which may lead to serious cardiovascular events or seizures. Evenamide is a selective voltage-gated sodium channel blocker that modulates glutamate. In its written communication, the FDA noted four deaths among patients treated with evenamide across all clinical studies to date, compared with one death among patients receiving placebo. Three of the four deaths were considered unrelated to evenamide by study investigators, while one was deemed possibly related because two autopsies could not determine a definitive cause. The FDA characterized the four deaths as a potential safety signal based on the possibility of a fatal arrhythmic mechanism that cannot be definitively excluded through post hoc adjudication. Evenamide is also associated with a very small shortening of the QTc interval on an electrocardiogram, a finding for which no established risk or intervention threshold exists, and standard screening ECG does not reliably exclude latent sodium-channel disorders in asymptomatic patients. Newron is reviewing the full body of safety data from the evenamide program, which includes more than 10,000 ECGs from approximately 700 evenamide-treated subjects and input from independent cardiac electrophysiologists. The company said it has not observed a pattern of cardiac abnormalities or arrhythmias in the preclinical and clinical safety data generated to date, including a thorough QT study and more than 5,000 ECGs from over 700 patients with schizophrenia. Ravi Anand, MD, Chief Medical Officer of Newron, stated that the company remains confident in the ENIGMA-TRS studies and encouraged by the program's progress. He emphasized that patient safety is the utmost priority and that the team is working with high commitment to complete a thorough review of the FDA's feedback and available data. Anand noted that the four deaths among evenamide-treated patients represent an incidence of 0.56%, compared with one death and an incidence of 0.27% among patients receiving placebo, and that when adjusted for duration of treatment, the mortality rate was 1.31 per 100 patient-years for evenamide compared with 1.81 per 100 patient-years for placebo.
The development program continues outside the United States. ENIGMA-TRS 1 enrollment is expected to be completed by mid-October 2026, with topline 12-week data anticipated in the first quarter of 2027. That study is a 52-week, randomized, double-blind, placebo-controlled Phase 3 trial evaluating 15 mg and 30 mg twice-daily doses of evenamide in at least 600 patients with treatment-resistant schizophrenia across 20 countries. ENIGMA-TRS 2 enrollment is ongoing outside the U.S., and additional clinical sites are being added as planned; that study will include at least 400 patients in a 12-week trial of the 15 mg twice-daily dose. Newron is also evaluating additional cardiac screening and monitoring measures for ENIGMA-TRS 2 as part of its response to the FDA. The clinical hold has significant implications for patients with treatment-resistant schizophrenia, a severe form of the disease that reduces life expectancy by about 20 years, according to Professor Dr. Peter Falkai of LMU University of Munich. Falkai noted that schizophrenia itself reduces life expectancy by about 10 years and that available antipsychotic medications carry debilitating cardiac, hormonal, metabolic and motor side effects. Evenamide, if approved, could become the first add-on therapy for treatment-resistant schizophrenia, a population that currently does not respond to any medication. Newron's shares trade on the SIX Swiss Exchange and XETRA under the symbols NWRN and NP5. The company has development and commercialization agreements for evenamide with EA Pharma in Japan and other Asian territories, and with Myung In Pharm for South Korea. Newron's first marketed product, Xadago/safinamide, is approved for Parkinson's disease in multiple regions. The company's handling of the FDA clinical hold and the safety review will be closely watched by investors and the medical community. For more information, visit https://www.newron.com and connect on LinkedIn. The original release is available on www.newmediawire.com.
