The US Food and Drug Administration's (FDA) clinical hold on US enrollment in a phase 3 trial of evenamide for treatment-resistant schizophrenia remains in place following identification of a potential cardiac safety signal involving deaths among patients receiving the investigational drug.
Newron Pharmaceuticals announced October 8 that it had received written FDA feedback concerning the hold on US study sites in ENIGMA-TRS 2. The agency identified a potential risk of fatal arrhythmias associated with evenamide, a selective voltage-gated sodium channel blocker being investigated as adjunctive treatment for treatment-resistant schizophrenia.
According to Newron's account of the FDA communication, 4 deaths occurred among evenamide-treated patients across clinical studies, compared with 1 among placebo recipients. Investigators classified 3 deaths as unrelated to treatment, while 1 was considered possibly related because 2 autopsy findings did not establish a definitive cause.
The FDA characterized the deaths as a potential safety signal because a fatal arrhythmic mechanism could not be definitively excluded. The concern relates to the recognized potential for certain sodium channel blockers to trigger arrhythmias associated with serious cardiovascular events or seizures.
Evenamide has also been associated with slight shortening of the corrected QT (QTc) interval. Unlike QTc prolongation, QTc shortening has no established risk or intervention threshold, and a standard screening electrocardiogram (ECG) cannot reliably exclude latent sodium-channel disorders in asymptomatic patients.
Newron reported incidence rates of 0.56% with evenamide and 0.27% with placebo. When adjusted for treatment exposure, mortality rates were 1.31 and 1.81 deaths per 100 patient-years, respectively. The company stated that its safety database, including more than 10,000 ECGs from approximately 700 evenamide-treated participants, has not demonstrated a consistent pattern of cardiac abnormalities or arrhythmias.
The clinical hold, initially imposed in April 2026 following a sudden death at a study site outside the US, applies to enrollment at US centers in ENIGMA-TRS 2. No US participants have received evenamide in that study.
ENIGMA-TRS 2 is a randomized, double-blind, placebo-controlled trial designed to enroll at least 400 patients and evaluate evenamide 15 mg twice daily against placebo over 12 weeks. Enrollment continues outside the US.
The separate ENIGMA-TRS 1 trial is evaluating 15 mg and 30 mg twice-daily doses in at least 600 patients. Its primary efficacy end point is change in Positive and Negative Syndrome Scale scores at 12 weeks, with topline results expected in the first quarter of 2027.
Newron is reviewing the FDA's feedback and considering additional cardiac screening and monitoring measures before submitting its response. The company has not announced when US enrollment might resume.
Sources
Newron Pharmaceuticals. Newron provides update on FDA clinical hold and phase 3 ENIGMA-TRS development program. Published October 8, 2026. Newron announcement
Newron Pharmaceuticals. Newron reports a pause in enrollment of new study participants in US centers of ENIGMA-TRS 2 study. Published April 29, 2026. Newron announcement
