Newron Evenamide Faces FDA Clinical Hold in ENIGMA-TRS 2 Trial

Newron Pharmaceuticals has provided an update on the U.S. Food and Drug Administration (FDA) clinical hold affecting U.S. study centers participating in the Phase 3 ENIGMA-TRS 2 trial of evenamide for treatment-resistant schizophrenia (TRS). The company has received the FDA’s written communication and is reviewing the agency’s feedback while preparing a formal response.

The FDA’s concerns center on a potential cardiac safety signal involving four deaths reported among patients treated with evenamide across the clinical development program. Despite the U.S. clinical hold, Newron reported continued progress in the global ENIGMA-TRS Phase 3 program.

FDA Reviews Potential Cardiac Safety Signal

According to Newron, the FDA’s concern relates to the established risk that some sodium channel blockers may cause cardiac arrhythmias, potentially resulting in serious cardiovascular events or seizures. Evenamide is being developed as a first-in-class glutamate modulator that acts through selective voltage-gated sodium channel blockade.

The FDA highlighted four deaths among patients treated with evenamide across clinical studies conducted to date, compared with one death among placebo-treated patients. Investigators considered three of the four deaths in the evenamide group unrelated to treatment. The fourth was classified as possibly related because autopsies could not establish a definitive cause of death.

The FDA considered the deaths a potential safety signal because a fatal arrhythmic mechanism could not be conclusively excluded.

The agency also noted that evenamide is associated with a very small shortening of the QTc interval on electrocardiography. Unlike QTc prolongation, there is currently no established risk threshold or intervention guideline for QTc shortening. Newron also noted that routine ECG screening may not reliably identify latent sodium-channel disorders in asymptomatic individuals.

Newron Reviews Safety Database

Newron is reviewing the complete safety database generated during the evenamide development program, including more than 10,000 ECG recordings from approximately 700 treated subjects and assessments by independent cardiac electrophysiology experts.

The company reported that no consistent pattern of cardiac abnormalities or arrhythmias has been identified in preclinical or clinical studies to date. The available dataset includes a thorough QT study and more than 5,000 ECG assessments from more than 700 patients with schizophrenia.

As part of its response to the FDA, Newron is also evaluating additional cardiac screening and monitoring measures for ENIGMA-TRS 2.

The four deaths among evenamide-treated patients represented an incidence of 0.56%, compared with 0.27% among placebo-treated patients. When adjusted for treatment duration, reported mortality rates were 1.31 per 100 patient-years for evenamide and 1.81 per 100 patient-years for placebo. These exposure-adjusted figures provide additional context to the raw death counts but do not establish a mortality benefit for either treatment.

ENIGMA-TRS Phase 3 Program Continues

ENIGMA-TRS 1 is an international, randomized, double-blind, placebo-controlled Phase 3 study evaluating evenamide at 15 mg twice daily and 30 mg twice daily as an add-on treatment in patients with treatment-resistant schizophrenia receiving second-generation antipsychotics, including clozapine.

The study is expected to enroll at least 600 patients across approximately 20 countries in Europe, Asia, Latin America, and Canada. Its primary efficacy endpoint is the change from baseline in Positive and Negative Syndrome Scale (PANSS) scores at Week 12. Treatment continues under double-blind, placebo-controlled conditions through Weeks 26 and 52. Enrollment is expected to be completed by mid-October 2026, with topline Week 12 efficacy and safety results anticipated in the first quarter of 2027.

ENIGMA-TRS 2 is a randomized, double-blind, placebo-controlled Phase 3 study evaluating evenamide 15 mg twice daily versus placebo in at least 400 patients with treatment-resistant schizophrenia.

The study was initiated in the United States in December 2025 following FDA and Institutional Review Board approvals. Although screening began at U.S. sites, no U.S. participants have been dosed with evenamide in the study following the FDA’s hold on new patient enrollment announced in April 2026. Enrollment in ENIGMA-TRS 2 continues outside the United States, with additional international sites being activated.

Regulatory Review Remains Ongoing

The current FDA review follows the U.S. enrollment hold initiated in April 2026. Newron is now assessing the agency’s written concerns alongside its broader cardiac safety database and preparing a formal response.

The company’s next major clinical readout is expected from ENIGMA-TRS 1 in the first quarter of 2027. Meanwhile, the continuation of international enrollment in ENIGMA-TRS 2 means that the global Phase 3 development program remains active while the FDA’s safety review of the U.S. component continues.

Evenamide remains an investigational therapy and has not been approved for the treatment of schizophrenia.

Reference

Newron Provides Update on FDA Clinical Hold and Phase 3 ENIGMA-TRS Development Program, Newron, 08 October 2026

Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects with Documented Treatment-Resistant Schizophrenia (ENIGMA-TRS 2), ClinicalTrials.gov ID NCT07184619