Newron reviews FDA feedback on clinical hold for Phase 3 ENIGMA-TRS 2
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 an ongoing clinical hold at U.S. study centers for its Phase 3 ENIGMA-TRS 2 study of evenamide, according to the company. The biopharmaceutical company, headquartered in Milan, Italy, stated that it is conducting a thorough review of the feedback and available data before submitting a formal response. The announcement follows an earlier press release issued by the company on September 25, 2026. Management also scheduled a call for 3:30 pm CEST on the day of the announcement.
- The FDA placed a clinical hold on U.S. study centers for the Phase 3 ENIGMA-TRS 2 trial evaluating evenamide in treatment-resistant schizophrenia.
- Regulators noted four deaths among evenamide-treated patients across all clinical studies to date compared to one in the placebo group, identifying a potential safety signal regarding fatal arrhythmias.
- Newron reports that ENIGMA-TRS 1 enrollment is nearing completion with mid-October targets, while ENIGMA-TRS 2 continues outside the U.S.
FDA Cites Patient Deaths Linked to Sodium Channel Blockers
The regulatory review centers on the known pharmacological profile of sodium channel blockers, a class of medications that can occasionally trigger cardiac arrhythmias leading to serious cardiovascular events or seizures. Evenamide acts as a glutamate modulator via its function as a selective voltage-gated sodium channel blocker. In its communication, the FDA cited four patient deaths associated with evenamide across clinical trials, versus one death in the placebo cohort. Study investigators deemed three of those four deaths unrelated to the drug, while classifying one as “possibly related” because post-mortem autopsies could not establish a definitive cause of death.
Evenamide administration is known to cause a very small shortening of the QTc interval on electrocardiograms. Unlike QTc prolongation, science currently lacks an established risk or intervention threshold for QTc shortening, and standard screening ECGs fail to reliably identify latent sodium-channel disorders in asymptomatic individuals. Newron is currently reviewing these findings alongside a safety dataset comprising more than 10,000 ECGs from approximately 700 subjects treated with evenamide, drawing on guidance from independent cardiac electrophysiologists.
Newron Denies Consistent Patterns of Cardiac Abnormalities
Newron maintains that its preclinical and clinical safety evaluations have not detected any consistent pattern of cardiac abnormalities or arrhythmias. This safety evaluation encompasses a thorough QT study alongside more than 5,000 ECGs gathered from over 700 patients diagnosed with schizophrenia. Ravi Anand, Chief Medical Officer at Newron, stated that patient safety remains the utmost priority while the company evaluates additional cardiac screening and monitoring measures for the ENIGMA-TRS 2 protocol.
While the clinical hold remains active across U.S. sites—where no patients have yet been dosed with the drug candidate—development is proceeding across international locations. ENIGMA-TRS 1 enrollment is projected to finish by mid-October 2026, with topline 12-week data expected during the first quarter of 2027. Meanwhile, ENIGMA-TRS 2 enrollment continues outside the U.S., with additional clinical sites being integrated into the trial network as originally planned.
Global Regulatory Approval Context
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