Newron Pharmaceuticals S.p.A. 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, according to a company update. The company is conducting a thorough review of the FDA's feedback and the available data and intends to submit its response upon completion. The hold, which was initially reported on April 29, 2026, 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, with topline 12-week data anticipated in the first quarter of 2027. ENIGMA-TRS 2 enrollment is continuing outside the U.S., and additional clinical sites are 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 evenamide-treated patients, 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. The company 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.
Ravi Anand, MD, Chief Medical Officer of Newron, said, "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." He added 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 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.
The implications for Newron are significant. The clinical hold delays U.S. enrollment in ENIGMA-TRS 2, one of two pivotal Phase 3 trials intended to support regulatory approval of evenamide for treatment-resistant schizophrenia. However, the continuation of ENIGMA-TRS 1 and ex-U.S. enrollment in ENIGMA-TRS 2 may allow the company to maintain momentum. The safety review will be critical in determining whether U.S. activities can resume. Evenamide has the potential to be the first add-on therapy for treatment-resistant schizophrenia, a severe form of the disease in which patients do not respond to other medications. Professor Dr. Peter Falkai of LMU University of Munich noted that schizophrenia reduces life expectancy by about 10 years, and treatment-resistant schizophrenia reduces it by about 20 years. Newron is listed on the SIX Swiss Exchange and XETRA. The company's lead compound, evenamide, is also being developed for poorly responding patients with schizophrenia. For more information, visit https://www.newron.com and connect with the company on LinkedIn. The original release is available on www.newmediawire.com.
