Newron Pharmaceuticals S.p.A. announced that it has received written communication from the U.S. Food and Drug Administration (FDA) regarding the clinical hold at U.S. study centers in its Phase 3 ENIGMA-TRS 2 study with evenamide. The company is conducting a thorough review of the FDA feedback and the available data and intends to submit its response upon completion. The clinical hold remains in place at U.S. sites, but enrollment in ENIGMA-TRS 2 continues outside the United States, with additional clinical sites being added as planned.
The FDA's concern relates to the known risk that certain sodium channel blockers may trigger arrhythmias, which can lead to serious cardiovascular events or seizures. Evenamide is a glutamate modulator that acts as 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 to date, compared with one death among patients receiving placebo. Of the four deaths among patients receiving evenamide, three were considered unrelated to evenamide by study investigators, while one was considered "possibly related" because two autopsies could not identify a definitive cause of death. The FDA characterized the four deaths 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 result in a very small shortening of the QTc interval on an electrocardiogram. 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. Newron is reviewing the FDA's feedback and the full body of safety data generated across the evenamide development program, which includes more than 10,000 ECGs from approximately 700 evenamide-treated subjects and input from independent cardiac electrophysiologists. Newron has not observed a pattern of cardiac abnormalities or arrhythmias in the preclinical and clinical safety data generated with evenamide 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 also 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. Our assessment is supported by the substantial body of preclinical and clinical safety data generated with evenamide. To date, we have not observed a pattern of cardiac abnormalities or arrhythmias. The four deaths among patients treated with evenamide represent an incidence of 0.56%, compared with one death and an incidence of 0.27% among patients receiving placebo. 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."
Professor Dr. Peter Falkai, Chair Department of Psychiatry and Psychotherapy at LMU University of Munich, stated: "Schizophrenia is a tragic disease that affects patients in the teenage (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 that makes them suffer from cardiac, hormonal, metabolic and motor disorders. 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."
Newron continues to advance the Phase 3 ENIGMA-TRS development program. ENIGMA-TRS 1 enrollment is expected to be completed by mid-October, with topline 12-week data expected in Q1 2027. ENIGMA-TRS 1 is an ongoing, international, 52-week, randomized, double-blind, placebo-controlled Phase 3 study evaluating the efficacy, tolerability, and safety of the 15mg BID and 30mg BID therapeutic doses of evenamide compared to placebo. The study is expected to have enrolled at least 600 patients by mid-October 2026 at study centers in 20 countries in Europe, Asia, Latin America, and Canada. The primary efficacy endpoint of the trial will be the change from baseline in the Positive and Negative Syndrome Scale (PANSS) scores at 12 weeks.
ENIGMA-TRS 2 is taking place at centers in the U.S. and selected additional countries with the same screening procedure as the ENIGMA-TRS 1 trial. It will include at least 400 patients in a 12-week, randomized, double-blind, placebo-controlled Phase 3 study, designed to evaluate the efficacy, tolerability, and safety of the 15mg BID dose of evenamide compared to placebo. In December 2025, ENIGMA-TRS 2 was initiated in the U.S. following approvals from the FDA and the Institutional Review Board. On April 29, 2026, Newron reported a hold by the FDA on the enrollment of new patients in the U.S. sites of the study. While U.S. patients entered screening, no U.S. patients have been dosed with evenamide in the study. Management will provide a brief update on the FDA clinical hold and ENIGMA-TRS development program on a conference call today at 3.30 pm CEST. The call will be recorded and access details are available here. The original release can be viewed on www.newmediawire.com.
