Neumora Therapeutics has launched a Phase 1 clinical trial of NMRA-861, a novel positive allosteric modulator targeting the M4 muscarinic receptor for schizophrenia treatment. The single-ascending dose/multiple-ascending dose study will evaluate the investigational drug in healthy adult participants and adults with stable schizophrenia, with data expected in the first quarter of 2026.
Novel Mechanism Addresses Treatment Limitations
NMRA-861 represents a departure from conventional antipsychotic approaches by targeting the M4 muscarinic receptor rather than blocking D2 dopamine receptors. This mechanism aims to deliver antipsychotic effects while avoiding the side effects associated with first- and second-generation antipsychotics.
"NMRA-861 has potential as a differentiated treatment option across multiple indications and may offer an improved therapeutic profile relative to current antipsychotics and other non-selective muscarinic agonists," said Nick Brandon, Ph.D., chief scientific officer at Neumora.
The drug demonstrated robust activity in preclinical efficacy models and was safe and well-tolerated in preclinical toxicology studies. Notably, no convulsions were observed in studies conducted in rabbits, dogs, and rats.
Addressing Critical Unmet Medical Need
Schizophrenia affects approximately 3 million adults in the United States and is characterized by positive symptoms such as delusions and hallucinations, negative symptoms including diminished emotional expression, and cognitive symptoms involving memory deficits. Current treatment options face significant limitations, with a National Institute of Mental Health study finding that approximately 75 percent of people with schizophrenia discontinue medication within 18 months due to inefficacy or intolerable side effects.
"Although antipsychotic agents are the cornerstone of treatment for schizophrenia, their effectiveness is limited, leaving many patients symptomatic despite ongoing antipsychotic therapy. Additionally, medication-related side effects and non-adherence remain key obstacles in treating patients," said Dr. Christoph Correll, Clinical Professor of Psychiatry at Zucker School of Medicine at Hofstra/Northwell and Professor of Child and Adolescent Psychiatry at Charité University Medicine, Berlin.
Best-in-Class Pharmacological Profile
NMRA-861 has demonstrated potential best-in-class pharmacology that may enable a more favorable therapeutic profile. The compound's selectivity for the M4 receptor through allosteric binding allows for greater specificity, potentially leading to improved tolerability and once-daily dosing capabilities.
M4 muscarinic receptor-targeting compounds have shown robust antipsychotic activity in multiple placebo-controlled clinical trials, validating this approach for schizophrenia treatment. The potential for M4 positive allosteric modulators to modulate cholinergic and dopamine signaling without traditional antipsychotic side effects represents a promising therapeutic avenue.
Intellectual Property and Development Timeline
Neumora exclusively licensed intellectual property rights related to NMRA-861 from the Warren Center for Neuroscience Drug Discovery at Vanderbilt University, including a composition of matter patent extending to 2044. The preclinical studies demonstrating NMRA-861's best-in-class profile were completed at the Warren Center.
The Phase 1 study will provide crucial safety and tolerability data, along with human pharmacokinetic information confirming the potential for once-daily dosing and central nervous system penetration. This milestone represents an important step for Neumora's M4 franchise as the company advances its pipeline of seven neuroscience programs targeting novel mechanisms for neuropsychiatric disorders and neurodegenerative diseases.
