Newron Pharmaceuticals SpA has received written communication from the US Food and Drug Administration (FDA) regarding the clinical hold at US study centres in its Phase 3 ENIGMA-TRS 2 trial evaluating evenamide for treatment-resistant schizophrenia. The company is reviewing the regulator’s feedback and the available safety data and plans to submit a response after completing its assessment.

The FDA’s concerns relate to the potential risk of arrhythmias associated with certain sodium channel blockers, which may lead to serious cardiovascular events or seizures. Evenamide is a glutamate modulator that acts as a selective voltage-gated sodium channel blocker.

In its communication, the FDA noted four deaths among patients treated with evenamide across its clinical development programme, compared with one death among patients receiving placebo. Investigators considered three of the four deaths in the evenamide group unrelated to treatment. The fourth was considered possibly related because two autopsies did not establish a definitive cause of death. The FDA has identified these cases as a potential safety signal, noting that a fatal arrhythmic mechanism cannot be definitively excluded through retrospective assessment.

Evenamide has also been associated with a small shortening of the QTc interval, an electrocardiogram measure of the heart’s electrical activity. According to the company, unlike QTc prolongation, QTc shortening has no established risk or intervention threshold, and a standard screening electrocardiogram may not reliably identify underlying sodium channel disorders in asymptomatic individuals.

Newron is reviewing safety data generated throughout the evenamide development programme, including more than 10,000 electrocardiograms 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 data available to date. These data include a thorough QT study and more than 5,000 electrocardiograms from over 700 patients with schizophrenia. Newron is also evaluating additional cardiac screening and monitoring measures for the ENIGMA-TRS 2 trial as part of its planned response to the FDA.

The company reported that deaths occurred in 0.56 percent of patients treated with evenamide, compared with 0.27 percent among placebo recipients. After adjustment for treatment duration, the mortality rates were 1.31 per 100 patient-years for evenamide and 1.81 per 100 patient-years for placebo, according to Newron. The company continues to assess these findings alongside the FDA’s concerns and the broader safety dataset.

Despite the clinical hold at US study centres, Newron continues to advance its Phase 3 ENIGMA-TRS programme. Recruitment for ENIGMA-TRS 1 is expected to be completed by mid-October 2026, with topline 12-week results anticipated in the first quarter of 2027. Recruitment for ENIGMA-TRS 2 is continuing at sites outside the US, with additional clinical sites being added as planned.

The FDA clinical hold remains in place at US study centres in ENIGMA-TRS 2 while Newron evaluates the regulator’s feedback. The next steps will depend on the company’s assessment and its response to the identified safety concerns.