Clinical Scorecard: FDA flags potential cardiac risk with evenamide

At a Glance

Key Highlights

• The FDA clinical hold on US enrollment in ENIGMA-TRS 2 remains in place after the agency identified a potential fatal-arrhythmia safety signal.
• Across clinical studies, 4 deaths occurred among evenamide-treated patients and 1 among placebo recipients; investigators classified 3 deaths as unrelated to treatment and 1 as possibly related.
• Reported incidence rates were 0.56% with evenamide and 0.27% with placebo; exposure-adjusted mortality rates were 1.31 and 1.81 deaths per 100 patient-years, respectively.
• Newron reported more than 10,000 ECGs from approximately 700 evenamide-treated participants, without a consistent pattern of cardiac abnormalities or arrhythmias.
• Newron is reviewing FDA feedback and considering additional cardiac screening and monitoring measures; no date for resuming US enrollment has been announced.

Guideline-Based Recommendations

Diagnosis

• The FDA stated that a standard screening ECG cannot reliably exclude latent sodium-channel disorders in asymptomatic patients.

Management

• The FDA clinical hold applies to enrollment at US centers in ENIGMA-TRS 2; enrollment continues outside the US.
• Newron is considering additional cardiac screening and monitoring measures before responding to the FDA.

Monitoring & Follow-up

• The FDA identified potential fatal arrhythmias as a safety concern; the source does not specify a monitoring protocol.
• Evenamide has been associated with slight QTc shortening, for which the source reports no established risk or intervention threshold.

Risks

• The FDA said a fatal arrhythmic mechanism could not be definitively excluded in one death considered possibly related to treatment.
• Certain sodium channel blockers can trigger arrhythmias associated with serious cardiovascular events or seizures.

Patient & Prescribing Data

Investigational adjunctive treatment for treatment-resistant schizophrenia; no US participants in ENIGMA-TRS 2 have received evenamide.

ENIGMA-TRS 2 evaluates evenamide 15 mg twice daily versus placebo for 12 weeks. ENIGMA-TRS 1 evaluates 15 mg and 30 mg twice-daily doses. Evenamide remains investigational.

Clinical Best Practices

• Do not treat a standard screening ECG as reliably excluding latent sodium-channel disorders in asymptomatic patients, as stated in the FDA feedback.
• Distinguish the reported crude incidence rates from exposure-adjusted mortality rates when describing the safety data.
• The source reports no established risk or intervention threshold for QTc shortening.

Related Resources & Content

• Newron Pharmaceuticals. Newron provides update on FDA clinical hold and phase 3 ENIGMA-TRS development program. October 8, 2026.
• Newron Pharmaceuticals. Newron reports a pause in enrollment of new study participants in US centers of ENIGMA-TRS 2 study. April 29, 2026.