The Food and Drug Administration has flagged four deaths among patients treated with an experimental schizophrenia drug as a potential safety signal, in written feedback explaining why a clinical hold on the drug’s U.S. trial sites remains in place.
The drug, evenamide, is being developed by Italy-based Newron Pharmaceuticals for people with treatment-resistant schizophrenia, a severe form of the illness that responds poorly to existing medications. According to the company, the agency noted four deaths across all of the drug’s studies, compared with one among patients receiving placebo, and said a fatal irregular-heartbeat mechanism could not be definitively excluded — a known concern with some drugs in evenamide’s class, the sodium channel blockers. Newron’s shares fell 5.7 percent after the disclosure.
The company disputes the implication. Investigators judged three of the four deaths unrelated to the drug, with one considered possibly related because autopsies did not establish a cause. Newron says it has reviewed more than 10,000 electrocardiograms from about 700 treated subjects without finding a pattern of cardiac abnormalities, and that adjusted for treatment duration, mortality rates were actually lower on evenamide than on placebo. The firm is preparing a response to the agency and evaluating additional cardiac screening.
The hold, first imposed on new U.S. enrollment in April, does not affect the trial outside the United States, where enrollment continues. A sister study is expected to complete enrollment by mid-October, with first results due in early 2027. No American patients have received the drug in the halted trial.
What a clinical hold does, and what it does not do
A clinical hold is a regulatory order that pauses some or all of an investigational drug study for safety or other specified reasons. It can apply to a proposed trial that has not started, to enrollment of new participants, or to dosing in an ongoing study, depending on the concern. A hold is not a final finding that a drug caused an adverse outcome, and it is not the same as rejecting a marketing application. It is a mechanism for requiring additional information, protocol changes or safeguards before exposure continues in the affected population.
Resolving a hold usually requires a complete response that addresses each issue raised by regulators. That can include additional analyses of existing data, independent adjudication of serious events, more intensive monitoring, exclusion of higher risk participants, changes to dose or stopping rules, or new studies designed to test a specific safety question. The process can take longer when the concern involves events that are uncommon, difficult to attribute, or also occur in the underlying illness being treated.
How cardiac safety signals are evaluated
Electrocardiograms measure the electrical activity of the heart, including intervals that can indicate a risk of abnormal rhythm when prolonged or otherwise disturbed. In a development program, reviewers look not only at average changes but at outliers, dose relationships, timing after dosing, interacting medicines and whether a pattern appears consistently across studies. A small number of deaths requires especially careful case by case review because people with severe psychiatric illness may have other medical conditions and may receive multiple medicines that complicate attribution.
Exposure adjustment is another tool in that evaluation. If one group is followed or treated for substantially longer than a comparison group, a simple count of events can mislead, so analysts may compare rates over person time as well as total numbers. That adjustment does not settle causality, but it helps determine whether an imbalance is larger than would be expected from the observation period alone. For evenamide, the central issues to watch are the content of the sponsor response, whether regulators accept additional cardiac screening as sufficient or require further data, and whether the non U.S. program generates evidence that can be reconciled with the concerns identified in the U.S. review. Treatment resistant schizophrenia remains an area of substantial unmet need, which raises the value of an effective new option but does not lower the safety evidence required to test and ultimately approve one.
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