Newron's ENIGMA-TRS 2 US enrolment hold stays as ex-US sites expand
Newron Pharmaceuticals has confirmed that the US Food and Drug Administration will maintain its hold on new patient enrolment at American sites in the Phase 3 ENIGMA-TRS 2 study of evenamide, a glutamate modulator under investigation for treatment-resistant schizophrenia (TRS). The Italian-listed biopharmaceutical company said it expects to receive written communication from the agency outlining its rationale and any protocol changes required to lift the restriction.
The hold was first disclosed on 29 April 2026, after Newron notified the FDA of the sudden unexpected death of a trial participant at a non-US site. The site investigator assessed the death as unrelated to study treatment, and the independent international safety monitoring board subsequently reviewed the event and recommended that both ENIGMA studies continue as designed. Notably, no US patients had been dosed with evenamide at the time the hold was imposed, as all US participants were still in the 42-day screening window.
Enrolment strategy shifts outside the US
With the US sites frozen, Newron is broadening the geographic footprint of ENIGMA-TRS 2, initiating expansion across clinical centres in Europe, Asia and Latin America. Approximately 80 patients have entered screening to date. The study is designed to enrol at least 400 patients in a 12-week, randomised, double-blind, placebo-controlled design evaluating the 15 mg twice-daily dose of evenamide against placebo.
Its companion study, ENIGMA-TRS 1, is running in parallel across 20 countries and is designed to assess both 15 mg and 30 mg twice-daily doses. The primary efficacy endpoint for ENIGMA-TRS 1 is the change from baseline in Positive and Negative Syndrome Scale scores at 12 weeks, with topline results from that assessment expected in the first quarter of 2027. The company said enrolment in ENIGMA-TRS 1 was on track to reach at least 600 patients by mid-October 2026.
"Newron is highly confident in the significant body of clinical and preclinical safety data for evenamide, and we will continue to work constructively with the FDA to address the clinical hold," said Ravi Anand, Chief Medical Officer at Newron.
Competitive and regulatory context
TRS is a high-unmet-need indication. Current treatment options are limited; clozapine remains the only agent with a specific label for TRS, yet its use is constrained by the need for mandatory haematological monitoring due to the risk of agranulocytosis. A well-tolerated add-on therapy addressing glutamate dysregulation would occupy a distinct mechanistic niche, and Newron is positioning evenamide as potentially the first approved add-on in this population.
The FDA's clinical hold process under 21 CFR Part 312 can be a significant development hurdle, particularly for CNS programmes where safety signals are difficult to attribute in complex, polypharmacy patient populations. The agency's written response, which Newron anticipates receiving, will be a critical document for investors and clinical partners alike: the specificity of any protocol amendments requested will indicate how close the programme is to resuming US enrolment.
Newron has secured regional commercialisation partnerships with EA Pharma, a subsidiary of Eisai, for Japan and selected Asian territories, and with Myung In Pharm for South Korea, providing some commercial infrastructure should the ENIGMA programme succeed. The Q1 2027 topline readout from ENIGMA-TRS 1 will be the next major inflection point for the asset and the company.