Newron FDA Clinical Hold Continues: Evenamide Safety Flag

The Newron FDA clinical hold on the US arm of a pivotal schizophrenia trial is staying in place, and the regulator has now explained why. In a company update dated 8 October 2026, Newron Pharmaceuticals said the US Food and Drug Administration (FDA) has cited a possible cardiac safety signal for its drug evenamide, based on four deaths among treated patients across all studies, compared with one in the placebo group. The hold stops new US enrolment in the Phase 3 ENIGMA-TRS 2 trial. Trials outside the US continue.

Evenamide is being developed as an add-on treatment for treatment-resistant schizophrenia, a group of patients who do not respond adequately to standard antipsychotics. The hold is a setback for the US portion of the programme, but not a halt of the whole programme, and Newron says it remains confident in the studies.

What the FDA has flagged

According to the company’s account of the FDA’s written feedback, the agency’s concern rests on three points:

• Mechanism: evenamide is a selective voltage-gated sodium channel blocker, and some drugs in that broad class are known to trigger irregular heart rhythms (arrhythmias), which can lead to serious cardiovascular events or seizures.
• Deaths: four deaths among evenamide-treated patients across all studies, versus one in the placebo group. The FDA regards this as a potential signal of a fatal arrhythmic mechanism that review after the fact cannot rule out.
• ECG limits: evenamide slightly shortens the QTc interval on an electrocardiogram. There is no established risk threshold for QTc shortening, and a standard screening ECG may not reliably detect latent sodium-channel disorders.

These points are Newron’s description of the FDA’s position. The FDA’s letter itself has not been published, and regulators do not usually release such correspondence.

The deaths: what is known and what is not

Newron says study investigators judged three of the four deaths in evenamide-treated patients to be unrelated to the drug. The fourth was assessed as “possibly related”, because two autopsies did not identify a definitive cause. That uncertainty is exactly what the FDA is pointing to.

The company reports an incidence of 0.56% for evenamide (four deaths) against 0.27% for placebo (one death). When it adjusts for how long patients were treated, it reports 1.31 deaths per 100 patient-years on evenamide against 1.81 on placebo. Both sets of figures are company-reported. They look reassuring or concerning depending on which is used, and with so few events, small changes in the count would move the percentages a great deal. In our assessment, the numbers are too small to prove or disprove a drug effect, which is why the regulator is asking for more cardiac safety work rather than drawing a conclusion.

A note on the numbers: some headlines refer to five deaths in the programme. That is the four evenamide deaths plus the one placebo death, not five on the drug.

How the hold began

The hold was first reported on 29 April 2026. At that time it followed a single death at a site outside the US, which Newron said was unrelated to evenamide. The hold barred new patients from enrolling at US sites. Some US patients entered screening, but according to the company none has been dosed with evenamide. ENIGMA-TRS 2 began enrolling in the US in December 2025 after FDA and ethics board approvals.

Newron’s response

Newron says it is reviewing the FDA feedback alongside its full safety dataset. It cites more than 10,000 ECGs from about 700 evenamide-treated subjects, a thorough QT study, and input from independent cardiac electrophysiologists, and says it has seen no pattern of cardiac abnormalities or arrhythmias. It is also evaluating additional cardiac screening and monitoring for ENIGMA-TRS 2. Chief Medical Officer Ravi Anand said the company remains confident in the studies and that patient safety is its top priority. The company will respond to the FDA after completing its review.

We note one inconsistency in the public record: an April update cited more than 5,000 ECGs from over 700 patients, while the October update cites more than 10,000 ECGs from about 700 subjects. The later figure presumably reflects a larger or more complete dataset, but the company has not explained the difference in the material we reviewed.

What the two Phase 3 trials involve

• ENIGMA-TRS 1: a 52-week, randomised, double-blind, placebo-controlled trial of 15 mg and 30 mg twice-daily doses. Enrolment was expected to reach at least 600 patients across 20 countries in Europe, Asia, Latin America and Canada by mid-October 2026. The primary endpoint is the change in PANSS score from baseline at 12 weeks. Topline results are expected in the first quarter of 2027.
• ENIGMA-TRS 2: a 12-week, randomised, double-blind, placebo-controlled study of at least 400 patients on the 15 mg twice-daily dose. The US sites are on hold; enrolment continues elsewhere and more sites are being added.

ENIGMA-TRS 1 is not affected by the US hold, so the first-quarter 2027 timeline for its topline data has not changed in the company’s update.

Why this matters

For patients, treatment-resistant schizophrenia has few options, which is why new mechanisms attract attention. For investors, a US clinical hold can delay a US filing, since regulators generally need US-relevant data and a resolved safety question. For the field, the case is a reminder that a new mechanism, even one with a clean early record, is judged on rare, serious events as well as efficacy. Related regulatory stories on our site include the FDA’s extended mifepristone safety review, and you can browse more pharmaceutical news.

What to watch next

• Newron’s formal response to the FDA, and whether the hold is lifted.
• Any new cardiac monitoring added to the ENIGMA-TRS 2 protocol.
• Completion of ENIGMA-TRS 1 enrolment and the first-quarter 2027 topline readout.

Frequently asked questions

Why is the FDA holding the Newron schizophrenia trial?

The agency cited a possible cardiac safety signal. The company says the FDA noted four deaths among evenamide-treated patients across all studies, versus one on placebo, and a known arrhythmia risk with some sodium channel blockers.

Does the clinical hold stop all evenamide trials?

No. It applies to US sites in ENIGMA-TRS 2. ENIGMA-TRS 1 and non-US enrolment continue.

Were the deaths caused by evenamide?

Investigators judged three unrelated. One was assessed as possibly related, with no definitive cause after two autopsies.

What is evenamide?

A first-in-class glutamate modulator that acts as a selective voltage-gated sodium channel blocker, being developed as an add-on therapy for treatment-resistant schizophrenia.

When will ENIGMA-TRS 1 report results?

Topline results are expected in the first quarter of 2027, according to the company.

How we reported this: we relied on the company’s announcement of 8 October 2026 and its website. Claims about the FDA’s position and the safety data are company-reported; we could not see the FDA letter. Last updated: 9 October 2026. This article is news reporting and not medical or investment advice.