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 first-in-class glutamate modulator for treatment-resistant schizophrenia. The company is conducting a thorough review of the FDA’s feedback and the available data and intends to submit its response upon completion, according to a press release distributed via NEWMEDIAWIRE.
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. 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, three were considered unrelated to evenamide by study investigators, while one was considered “possibly related” because two autopsies could not identify a definitive cause. The FDA characterized these 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 known to cause a very small shortening of the QTc interval on an electrocardiogram, and unlike QTc prolongation, there is no established risk threshold for QTc shortening.
Newron is reviewing the FDA’s feedback alongside 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 the preclinical and clinical data generated 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.” He 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 placebo patients. 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 clinical hold remains in place at U.S. study centers, but Newron continues to advance the broader Phase 3 ENIGMA-TRS development program. 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. Professor Dr. Peter Falkai of LMU University of Munich emphasized the urgent need for new treatments, stating that schizophrenia reduces life expectancy by about 10 years, and treatment-resistant schizophrenia reduces it by about 20 years. The company will host an investor update conference call today at 3:30 pm CEST. For more information, visit https://www.newron.com. The original release is available at www.newmediawire.com.
