The FDA has flagged a potential safety signal for evenamide, an investigational adjunctive treatment for treatment-resistant schizophrenia, after four deaths occurred among patients who received the drug in clinical trials. Newron Pharmaceuticals disclosed the agency's concern on Thursday. The deaths compare with one death in the placebo group.
Investigators judged three of the four deaths as unrelated to evenamide; one was deemed possibly related because autopsies could not establish a definitive cause. The FDA said the signal is based on the possibility of a fatal arrhythmic mechanism that cannot be ruled out through post hoc adjudication. The agency is concerned that some sodium channel blockers may trigger arrhythmias leading to serious cardiovascular events or seizures.
The U.S. hold on enrollment in the phase III ENIGMA-TRS 2 trial, first announced in April after a sudden death, remains in place. No U.S. participants had been dosed with evenamide, though some had entered screening. Enrollment continues in other countries, and Newron says it is adding sites. The company's chief medical officer, Ravi Anand, said the team is working to complete a thorough review of the FDA's feedback and data and to submit a response, adding that the assessment is supported by a substantial body of preclinical and clinical safety data.
Newron noted that evenamide can cause small shortening of the QTc interval on an electrocardiogram. Unlike QTc prolongation, there is no established risk or intervention threshold for QTc shortening, and a standard screening ECG does not reliably exclude latent sodium-channel disorders in asymptomatic patients. Results from the ongoing ENIGMA-TRS 1 trial are expected early next year.