The U.S. Food and Drug Administration placed a partial clinical hold on U.S. enrollment in Newron’s Phase III ENIGMA-TRS 2 trials of evenamide after a reported sudden death, while global studies continue.
Written By: Nikita Jha, BPharm
Reviewed By: Pharmacally Editorial Team
Newron Pharmaceuticals S.p.A. announced that the U.S. Food and Drug Administration has placed a partial clinical hold on U.S. enrollment in the Phase III ENIGMA-TRS 2 study evaluating evenamide in treatment-resistant schizophrenia (TRS).
The decision follows the company’s report of a sudden death in a trial participant at a non-U.S. study site. While the site investigator assessed the event as unrelated to evenamide, the FDA has initiated a review of the case, consistent with standard regulatory practice for unexpected serious adverse events in late-stage trials.
Evenamide is a novel oral agent designed to reduce excessive glutamate release, a pathway implicated in treatment-resistant schizophrenia.
Newron stated that the independent international data and safety monitoring board (DSMB) for the ENIGMA-TRS program reviewed the case and recommended that studies continue as planned. The company added that, to date, no increased mortality risk has been observed between evenamide and placebo-treated patients across the development program.
“Patient safety remains our highest priority,” said Ravi Anand, Chief Medical Officer of Newron. “All participants are carefully evaluated, and the independent safety monitoring board has reviewed this event and advised continuation of the studies as designed.”
ENIGMA-TRS 1 continues to enroll globally across 21 countries, with more than 400 patients recruited to date. The study is a 52-week, randomized, double-blind, placebo-controlled trial evaluating 15 mg and 30 mg twice-daily doses of evenamide as add-on therapy to second-generation antipsychotics, including clozapine. The primary endpoint is change in Positive and Negative Syndrome Scale (PANSS) scores at 12 weeks, with topline results expected in the fourth quarter of 2026.
ENIGMA-TRS 2 is a 12-week, randomized, double-blind, placebo-controlled study evaluating 15 mg twice-daily evenamide in at least 400 patients. While U.S. enrollment is currently paused, the trial has received approvals in Argentina and India and is awaiting final regulatory clearance in Colombia and Malaysia.
Schizophrenia is associated with a significantly elevated baseline mortality risk, with life expectancy reduced by approximately 10–25 years compared with the general population. Sudden unexpected death accounts for an estimated 20% of mortality in this population.
Newron said it is working closely with the FDA to provide the requested information and resolve the hold.
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About the Writer
Nikita Jha, BPharm a pharmacy graduate specializing in medical writing, with a strong ability to interpret complex medical and regulatory information and translate it into clear, accurate, and evidence-based healthcare content. Known for her attention to detail and precision, she focuses on delivering high-quality scientific communication that supports drug safety and informed decision-making.