Neumora Therapeutics announced the initiation of a Phase 1 single-ascending dose/multiple-ascending dose (SAD/MAD) study of NMRA-898, marking the second M4 muscarinic receptor positive allosteric modulator (PAM) to enter clinical development within the company's neuropsychiatric franchise. The Watertown, Massachusetts-based clinical-stage biopharmaceutical company previously launched a Phase 1 study with NMRA-861 in July 2025.
Novel Mechanism Targets Unmet Medical Need
NMRA-898 represents an investigational positive allosteric modulator of the M4 muscarinic receptor subtype, offering a fundamentally different approach to treating schizophrenia compared to current standard of care. While most approved antipsychotics work primarily by blocking D2 dopamine receptors, growing evidence supports targeting the M4 muscarinic receptor to elicit antipsychotic effects without the side effects associated with first- and second-generation antipsychotics.
The compound has demonstrated a best-in-class preclinical profile in studies completed at the Warren Center for Neuroscience Drug Discovery at Vanderbilt University, from which Neumora exclusively licensed certain intellectual property rights. Notably, no convulsions were observed in preclinical studies conducted across multiple species, including rabbits.
Strategic Portfolio Expansion
"With both NMRA-898 and NMRA-861 now in the clinic, we are positioned with exceptional strategic flexibility as we advance two potentially best-in-class M4 PAMs," said Bill Aurora, Pharm.D., chief operating and development officer at Neumora. "These structurally distinct M4 compounds each demonstrate potential best-in-class pharmacology, giving us the optionality to pursue one or both assets as we advance development."
Both Phase 1 studies will evaluate safety, tolerability, and human pharmacokinetic data for each compound, confirming the potential for once-daily dosing and central nervous system exposure. Neumora plans to evaluate its M4 franchise strategy based on these data, potentially advancing development of one or both programs. The company expects to provide a comprehensive franchise update by mid-2026.
Addressing Treatment Discontinuation Crisis
The clinical development addresses a significant unmet medical need in schizophrenia treatment. The neuropsychiatric disorder 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 substantial challenges, with a National Institute of Mental Health study finding that approximately 75 percent of people with schizophrenia discontinue medication within 18 months due in part to inefficacy or intolerable side effects. Many approved therapies are associated with serious adverse effects, including extrapyramidal symptoms and cardiometabolic effects.
Intellectual Property and Development Timeline
Neumora's exclusive license from Vanderbilt University includes a composition of matter patent for NMRA-898 extending to 2044, excluding any patent term adjustment or extension. M4 muscarinic receptor-targeting compounds have demonstrated robust antipsychotic activity in multiple placebo-controlled clinical trials, supporting the therapeutic approach for schizophrenia treatment.
The company's therapeutic pipeline currently consists of seven programs targeting novel mechanisms of action for underserved, prevalent diseases. Neumora's mission focuses on redefining neuroscience drug development by advancing next-generation therapies that offer improved treatment outcomes and quality of life for patients with brain diseases.
