FDA Halts Neumora's Schizophrenia Drug Trials Over Preclinical Safety Concerns

The FDA has placed a clinical hold on Neumora Therapeutics' schizophrenia drug due to safety concerns identified in preclinical studies. The drug - a highly selective positive allosteric modulator of the M4 muscarinic receptor - was put on clinical hold to further investigate the safety signals that emerged during the preclinical phase, indicating potential risks that need to be addressed before continuing with human trials.

The following article originally appeared in BioSpace.

Neumora Therapeutics on Monday announced that the FDA has slapped a clinical hold on the Phase I trial of its schizophrenia candidate NMRA-266 after recently available preclinical data showed that the investigational drug triggered convulsions in rabbits.

Currently, around 30 patients have been enrolled and dosed in the Phase I ascending dose study of NMRA-266, none of whom have shown signs of convulsions, according to Neumora. The biopharma said it will work with the FDA to find a way to best resolve the clinical hold.

Neumora’s shares dropped 26% in premarket trading on Monday in response to the news, according to Seeking Alpha.

NMRA-266 is a highly selective positive allosteric modulator of the M4 muscarinic receptor, which when activated suppresses the release of the neurotransmitter acetylcholine in the brain. In schizophrenia, the circuits that these M4 receptors modulate are disrupted, giving rise to the signature positive, negative and cognitive symptoms of the condition.

In its fourth-quarter and full-year 2023 results last month, Neumora said it planned to report Phase I data for NMRA-266 by mid-2024. The company was also looking forward to launching a Phase Ib trial of the candidate in the second half of this year, with an initial readout expected in 2025. However, following Monday’s clinical hold, Neumora’s prior guidance is no longer applicable.

CEO Henry Gosebruch in a statement Monday said that the company is “disappointed with the unanticipated safety findings in rabbits.” Neumora will provide an update on NMRA-266’s development program once available.

In the meantime, Neumora will focus on the development of its other pipeline assets including lead program navacaprant, a highly selective kappa opioid receptor blocker that is currently in Phase III development as a monotherapy for major depressive disorder. According to Neumora’s website, navacaprant is designed to be orally available and modulate the dopamine and reward brain pathways, which in turn allows it to affect the regulation of mood, cognition and behavior.

“We anticipate several important milestones including Phase III data in major depressive disorder and the initiation of a Phase II study in bipolar depression with navacaprant,” Gosebruch said in a statement, adding that Neumora is also set to start a Phase Ib Alzheimer’s disease study for NMRA-511, its investigational vasopressin 1a receptor antagonist.

Monday’s clinical hold comes one week after Bristol Myers Squibb scored a big late-stage schizophrenia win for investigational antipsychotic KarXT, which in the Phase III EMERGENT-4 study led to at least a 30% symptomatic improvement in more than 75% of treated patients at 52 weeks of follow-up. KarXT was originally developed by Karuna Therapeutics, which BMS bought in December 2023 for $14 billion.

Also targeting the market is Boehringer Ingelheim, which last month pledged up to $732 million in a deal with Sosei Heptares for the option to license the latter’s potentially first-in-class GRP52 agonists for all symptoms of schizophrenia.

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