Newron plans heart tests to lift schizophrenia trial hold

Why it matters: Roughly a third of people with schizophrenia are treatment-resistant, and only about 40% of them respond to clozapine, the most effective antipsychotic used for this condition. Evenamide, Newron’s lead drug, is in two Phase 3 trials as an add-on for this group, and the company says it could become the first such treatment.

• Evenamide tests whether calming overactive brain circuits can help patients who remain ill despite antipsychotics, potentially addressing symptoms that dopamine-blocking drugs often leave untreated. Researchers argue the approach could extend beyond psychosis.
• In a four-week trial of 291 patients doing poorly on a second-generation antipsychotic, including clozapine, adding evenamide cut symptom scores by 10.2 points, against 7.6 for placebo, meeting the trial’s main goal. In a one-year study of treatment-resistant patients not on clozapine, with no placebo group, a quarter reached remission, a result the company hailed at the time (January 2024) as “never before seen.”
• Newron said on an Oct. 8 investor call that it would update the timeline of the affected trial, ENIGMA-TRS 2, once it had a clearer picture, but expected little delay.

Backstory: The FDA halted U.S. enrollment in the ENIGMA-TRS 2 trial in April, after Newron reported a single sudden death at a site outside the U.S., and kept the hold in September. Four of the five deaths were among patients on evenamide, one on placebo.

• The agency’s concern, CEO Stefan Weber said, is a possible link between sodium-channel blockers such as evenamide and arrhythmias that may lead to sudden death.
• Investigators judged three of the four deaths unrelated to evenamide and one possibly related.
• Per 100 patient-years on treatment, Newron puts deaths at 1.31 on evenamide and 1.81 on placebo, though the placebo rate reflects one death and the evenamide rate includes studies without a placebo group.

What they’re saying: Ravi Anand, the company’s chief medical officer, said none of the four had heart symptoms or electrocardiogram (ECG) abnormalities, and that one choked while trying to swallow three pieces of bread at once, months after a similar episode. The agency’s suspicion persists, he said, because “the FDA can’t find any reason [for the deaths] and we can’t find any other reason.”

Zoom in: Still, Newron will propose testing every ENIGMA-TRS 2 patient for Brugada syndrome, an inherited heart-rhythm disorder that can cause sudden death, and other sodium-channel disorders, Anand said.

• Evenamide slightly shortens the heart-rate-corrected QT interval, the heart’s recharge time between beats, and the FDA noted there is no established risk threshold for such shortening. The trial would exclude patients whose QT is already short.
• Enrollment would narrow to patients who are not improving on any treatment, to strengthen the risk-benefit case.
• Anand expected to file the amendment in 10 to 12 days. The FDA must reply with a complete response within 30 days.

Reality check: A normal ECG or a negative genetic test cannot reliably rule out Brugada syndrome. The FDA says a standard screening ECG does not reliably exclude hidden sodium-channel disorders in patients without symptoms, and the genetic cause is unknown in most families with the syndrome, according to the rare-disease database Orphanet.

• Anand said the FDA has not specified the criteria it wants, leaving Newron to propose them.

What’s next: ENIGMA-TRS 1, a separate Phase 3 trial of at least 600 patients in Europe, Asia, Latin America and Canada, is unaffected by the hold and due to report its main 12-week results in the first quarter of 2027.

• In Europe, neither Britain’s MHRA nor Germany’s health authority, which reviewed the trial protocols, has asked anything further since receiving Newron’s answers, Anand said.
• Newron now hopes to enroll 60 to 80 of ENIGMA-TRS 2’s at least 400 patients in the U.S., down from about 100, and is adding cheaper sites elsewhere, which Anand said would probably keep the trial’s total cost roughly unchanged.
• If the hold lasts, he said, Newron could seek U.S. approval on data from abroad. He put Europe’s share of patients across the two trials at 30% to 40%.
• Weber said Newron is funded through most of 2027, past both trials’ expected first results. In February, it secured up to €38 million, €12 million of it contingent on positive trial results.

Bottom line: Evenamide could mark a rare break from more than half a century of schizophrenia drugs built on blocking dopamine, but Newron must demonstrate a clinical benefit in Phase 3 and persuade the FDA that the drug’s potential cardiac risks can be managed.