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, a potential treatment for treatment-resistant schizophrenia. The company is reviewing the FDA's feedback and preparing a response, while continuing to advance the broader ENIGMA-TRS development program.
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. 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 is also known to cause a very small shortening of the QTc interval on an ECG, for which there is no established risk threshold.
Newron is reviewing the FDA's feedback and the full body of safety data from the evenamide development program, 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.
"We remain confident in the ENIGMA-TRS studies and encouraged by the program's progress. Our belief in the potential of evenamide and its novel mechanism for patients with treatment-resistant schizophrenia remains strong," said Ravi Anand, MD, Chief Medical Officer of Newron. "Patient safety is our utmost priority. Our team is working with high commitment to complete a thorough review of the FDA's feedback and the available data, and to submit our response upon its completion."
Professor Dr. Peter Falkai, Chair of the Department of Psychiatry and Psychotherapy at LMU University of Munich, highlighted the urgent need for new treatments: "Schizophrenia is a tragic disease that affects patients in their teenage years (males) and early twenties (females) and has a devastating effect on their lives. In addition to multiple episodes of psychosis and hospitalization, patients need to take antipsychotic medication with debilitating side-effects. Furthermore, schizophrenia reduces life-expectancy by about 10 years. TRS, a more severe form of the disease in which patients do not respond to any medication, reduces longevity by about 20 years."
Despite the clinical hold at U.S. sites, Newron continues to advance the ENIGMA-TRS program. ENIGMA-TRS 1 enrollment is expected to be completed by mid-October 2026, with topline 12-week data expected in Q1 2027. The study is expected to enroll at least 600 patients across 20 countries in Europe, Asia, Latin America, and Canada. ENIGMA-TRS 2 enrollment continues outside the U.S., with additional clinical sites being added as planned. That study will include at least 400 patients in a 12-week, randomized, double-blind, placebo-controlled Phase 3 study evaluating the 15mg BID dose of evenamide. No U.S. patients have been dosed in the study.
Newron also noted that the mortality rate, adjusted for duration of treatment, was 1.31 per 100 patient-years for evenamide compared with 1.81 per 100 patient-years for placebo. The company will host an investor update call today at 3.30 pm CEST to discuss the FDA clinical hold and ENIGMA-TRS development program. Access details are available here. For more information, visit https://www.newron.com and connect on LinkedIn. The original release is available on www.newmediawire.com.
