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The FDA has flagged four deaths among participants who received investigational schizophrenia drug evenamide as a potential safety signal, Newron Pharmaceuticals said. Three deaths were judged unrelated by study investigators; one was considered possibly related, though autopsies did not establish a definitive cause. U.S. enrollment in one phase III trial remains on hold, while studies continue in other countries.
The FDA has flagged four deaths among participants in clinical trials of investigational schizophrenia drug evenamide as a potential safety signal, Newron Pharmaceuticals said Thursday. The agency’s concern has kept U.S. enrollment in one phase III trial on hold, although studies are continuing at sites in other countries.
Newron said the FDA noted four deaths among people who received evenamide in trials, compared with one death in placebo groups. Study investigators considered three of the four deaths unrelated to the drug. One was classified as “possibly related”; autopsies in two cases did not establish a definitive cause of death. The company said the FDA viewed the deaths as a potential signal because a fatal heart rhythm problem could not be ruled out after the fact.
The FDA’s concern, as described by Newron, involves the possibility that some sodium channel blockers can cause arrhythmias that may lead to serious cardiovascular events or seizures. Evenamide is described by the company as a glutamate modulator that selectively inhibits voltage-gated sodium channels in the brain. It is being tested as an add-on treatment for people with treatment-resistant schizophrenia.
The U.S. hold applies to enrollment in the phase III ENIGMA-TRS 2 study. Newron said U.S. participants had entered screening but none had received evenamide. Enrollment continues in other countries, and the company said it is adding clinical sites. Newron Chief Medical Officer Ravi Anand said the company was reviewing the FDA’s feedback and available data before submitting a response.
U.S. Trial Enrollment Remains Paused
The safety review affects the pace of testing for a drug being studied in a group with treatment-resistant schizophrenia, for whom the company is investigating evenamide as an additional therapy. The continued U.S. hold means people at those study centers cannot newly enroll while the agency and company address the concern. Trials outside the United States are still underway, so the development is a pause in one part of the program rather than a reported end to all research.
The deaths also underline the limits of what the available case reviews establish. Three were judged unrelated by investigators, while one was considered possibly related; the FDA’s signal reflects the possibility of a fatal arrhythmic mechanism that could not be definitively excluded. It is a safety concern under review, not a finding that evenamide caused the deaths.
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Two Trials Make Up the Phase III Program
The phase III program includes ENIGMA-TRS 1, an ongoing study in Europe, Asia, Latin America and Canada, and ENIGMA-TRS 2, which includes U.S. sites and other countries. Newron said the U.S. hold followed an earlier agency action in April, after a participant in an evenamide clinical trial died suddenly. The current safety feedback refers to four deaths among evenamide-treated participants across trials to date, according to the company.
Newron also said evenamide may cause small shortening of the QTc interval on an electrocardiogram. The company stated that, unlike QTc prolongation, there is no established risk or intervention threshold for QTc shortening, and a standard screening ECG does not reliably rule out latent sodium-channel disorders in people without symptoms. These are the company’s descriptions of the issue; the supplied report does not detail the FDA’s full analysis or the cases behind each 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 Pharmaceuticals
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Cause of Deaths Still Unresolved
The available report does not identify the participants, provide the circumstances or timing of each death, or explain the evidence behind the investigators’ classifications. It also does not describe the FDA’s complete feedback, the specific data the agency requested, or whether the agency has concluded that evenamide caused any death. The company said two autopsies did not establish a definitive cause, leaving a possible arrhythmic cause unexcluded rather than confirmed.
It is also unclear when the FDA will complete its review or what conditions might allow U.S. enrollment to resume. Newron’s statement that studies continue abroad does not, by itself, establish that the FDA has cleared the drug’s safety concern.
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Company Response and Trial Results Ahead
Newron said it is reviewing the agency’s feedback and available data and plans to submit a response when that review is complete. The U.S. ENIGMA-TRS 2 enrollment hold remains in place for now; the company has not provided a date for a decision on lifting it.
Meanwhile, ENIGMA-TRS 1 continues outside the United States. Newron expects to report results from that study’s 12-week primary endpoint assessment early next year, according to the report. Those results and any further FDA direction may clarify the program’s next steps, but the timing and outcome of the agency’s safety review remain unknown.
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Key Questions
What did the FDA flag about evenamide?
Newron said the FDA identified four deaths among evenamide-treated trial participants as a potential safety signal, citing the possibility of a fatal heart rhythm problem that could not be definitively ruled out.
Were the deaths confirmed to be caused by evenamide?
No. Investigators considered three deaths unrelated to the drug and one possibly related. Newron said autopsies in two cases did not identify a definitive cause. The report does not establish that evenamide caused any of the deaths.
Has the U.S. trial been stopped?
Enrollment in the U.S. phase III ENIGMA-TRS 2 trial remains on hold. Newron said U.S. participants had entered screening, but none had received evenamide. Trials continue in other countries.
What happens next for evenamide?
Newron is reviewing the FDA’s feedback and plans to submit a response after completing its review. The company expects results from the 12-week primary endpoint assessment of ENIGMA-TRS 1 early next year; no date has been given for a decision on U.S. enrollment.
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