Four Deaths Prompt FDA Safety Concerns About Novel Schizophrenia Drug

The FDA flagged a potential safety signal after four deaths were reported among patients with treatment-resistant schizophrenia who received investigational evenamide in clinical trials, Newron Pharmaceuticals said Thursday.

The notice follows an announcement in April that the agency halted patient enrollment in the phase III ENIGMA-TRS 2 trial after the sudden death of a participant in an evenamide clinical trial. That hold remains in place at U.S. study centers but enrollment continues in other countries, and additional clinical sites are being added.

“Our team is working with high commitment to complete a thorough review of the FDA’s feedback and the available data, and to submit our response upon its completion,” Newron Chief Medical Officer Ravi Anand, MD, said in a news release. “Our assessment is supported by the substantial body of preclinical and clinical safety data generated with evenamide.”

The FDA’s concern relates to the risk that some sodium channel blockers may trigger arrhythmias that can lead to serious cardiovascular events or seizures, the company stated.

Evenamide is a glutamate modulator that selectively inhibits voltage-gated sodium channels in the brain. It is being studied as an adjunctive therapy for people with treatment-resistant schizophrenia.

The FDA noted four deaths among evenamide-treated participants in clinical trials to date, compared with one death among participants who received placebo. Of the four deaths, three were considered unrelated to evenamide by the study investigators; one was considered “possibly related” because two autopsies could not identify a definitive cause of death.

“The four deaths have been characterized by the FDA as a potential safety signal based on the possibility of a fatal arrhythmic mechanism, which cannot be definitively excluded through post hoc adjudication,” Newron said.

Evenamide can lead to small shortening of the QTc interval on an electrocardiogram (ECG), the company explained. “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,” it added.

The phase III ENIGMA-TRS development program includes the ENIGMA-TRS 1 trial — an ongoing study evaluating evenamide in Europe, Asia, Latin America, and Canada — and the ENIGMA-TRS 2 trial in the U.S. and other countries.

U.S. patients entered the screening phase in ENIGMA-TRS 2, but no U.S. participants have been dosed with evenamide, Newron said.

The company expects to announce results from the 12-week primary endpoint assessment of ENIGMA-TRS 1 early next year.