Neumora Therapeutics (NASDAQ:NMRA) reported top-line results from a Phase IB signal-seeking study of NMRA-511 in agitation associated with dementia due to Alzheimer’s disease, with management highlighting what it described as a clinically meaningful reduction in agitation scores and a favorable tolerability profile that the company believes supports further development and dose exploration.
Agitation in Alzheimer’s disease and Neumora’s positioning
Management framed Alzheimer’s disease (AD) agitation as a large and underserved condition, stating that agitation affects over 70% of individuals living with Alzheimer’s disease dementia and is among the most disruptive symptoms for patients and caregivers. President Josh Pinto said behavioral symptoms like agitation are associated with caregiver stress, earlier placement in long-term care facilities, and increased morbidity and mortality.
Mechanism rationale: V1a antagonism and anxiety
Chief Scientific Officer Nick Brandon reviewed the company’s rationale linking vasopressin biology to anxiety, describing a body of preclinical and clinical literature supporting a role for V1a receptors in anxiety-related behaviors. He cited human studies in which intranasal vasopressin increased autonomic responsiveness to threat stimuli and increased anxiety, and referenced published work involving a V1a antagonist, SRX246, including reported suppression of anxiety in a human anxiety model and reduced aggressive behaviors in a subgroup of patients with Huntington’s disease.
Brandon also highlighted Neumora’s own preclinical work with NMRA-511 in a “human threat test” in marmosets, in which animals exposed to an unfamiliar human displayed high levels of anxiety and those receiving NMRA-511 showed reduced anxiety behaviors without reduced locomotor activity. He said these data were previously presented at ACNP in 2022 and helped motivate a pre-specified analysis of patients with elevated anxiety in the Phase IB trial.
Phase IB study design and efficacy readouts
Chief Operating and Development Officer Bill Aurora said the Phase IB program was a two-part, randomized, double-blind, placebo-controlled signal-seeking study that was not powered for statistical significance and was intended to estimate effect size to inform future development. Part A evaluated safety, tolerability, pharmacokinetics, and “cardiodynamics” in healthy elderly participants over two weeks. The company focused the call on Part B, an eight-week, multi-center parallel-group cohort in adults with agitation associated with dementia due to Alzheimer’s disease.
Aurora said Part B enrolled 80 patients randomized to NMRA-511 20 mg twice daily or placebo. The primary endpoint was change from baseline to week eight in the Cohen-Mansfield Agitation Inventory (CMAI) total score. The study also included a pre-specified analysis of patients with elevated baseline anxiety, assessed using the Rating of Anxiety in Dementia (RAID) scale, with a threshold of 12 or greater.
- Modified analysis set (71 patients): Aurora reported an absolute reduction of 15.7 points in CMAI total score at week eight with NMRA-511, with a Cohen’s d effect size range of 0.2–0.23.
- Elevated anxiety subgroup (RAID ≥12; 36 patients): Aurora said NMRA-511 showed a 20.1-point absolute reduction in CMAI total score at week eight, with a Cohen’s d effect size range of 0.51–0.64.
Aurora also highlighted results on CMAI subscores, emphasizing the aggression subscore as particularly meaningful for caregiver and patient safety. In the modified analysis set, he said NMRA-511 produced a 5.3-point reduction in the aggression subscore. In the elevated anxiety subgroup, he said the aggression subscore also showed “robust results.”
During Q&A, the company was asked whether it would enrich future studies for baseline anxiety. Aurora said Neumora was “in a position where we could enrich,” but did not view enrichment as “critically necessary” to see benefit, adding that details of the next study design would follow. Pinto noted anxiety prevalence in AD is about 70% and argued the overlap between AD anxiety and AD agitation suggests a large addressable population regardless of whether the trial formally enriches.
Safety/tolerability, dose plans, and development next steps
Aurora said NMRA-511 was “safe and well tolerated” in Part B, with treatment-emergent adverse events typically mild to moderate and a 2.5% discontinuation rate due to adverse events. He also said the study did not show sedation or somnolence—effects he noted have been associated with other treatments for AD agitation and may be problematic in the elderly.
Management repeatedly pointed to the safety profile as enabling exploration of higher doses. Pinto said Neumora selected 20 mg twice daily to maintain exposure (AUC) and avoid higher peak concentrations (Cmax). He noted a prior multiple ascending dose (MAD) study dosed up to 40 mg once daily and said the company believes it can dose higher, adding that in neuropsychiatric conditions dosing toward a maximum tolerated dose can matter for efficacy. He said receptor occupancy estimates are based on modeling because “for V1a, there is not a receptor occupancy ligand.”
The company outlined several planned steps for NMRA-511:
- MAD extension cohort: Aurora said Neumora plans to initiate and complete a MAD extension cohort in 2026, while Pinto later added the company is planning to initiate a MAD extension study testing higher doses “this year” and aims to complete it by year-end to support moving into a Phase II/III program thereafter. The company did not provide a specific start date.
- Formulation change: Aurora said Neumora plans to move from a twice-daily formulation to a once-daily extended-release formulation in 2026, which it believes would be more favorable for patients and caregivers.
- Future pivotal development: Aurora said, after these steps, Neumora plans to initiate a Phase II/III study in AD agitation.
Aurora also said the extended-release formulation is expected to expand intellectual property, adding four years of exclusivity to the company’s current expectations. He said Neumora expects to be able to exclusively market NMRA-511 into 2046 based on composition-of-matter patent expectations.
In closing remarks, CEO Paul Berns said the company was “quite pleased” with what it called an “unsurpassed clinical effect size” in the pre-specified elevated anxiety population and cited precedent for trial enrichment strategies used by other sponsors. Berns said the results support moving into dose-ranging work and inform how Neumora might “index into a population” to improve risk-adjusted probabilities of success in subsequent studies.
Other pipeline update: navacaprant enrollment expansion
In response to an analyst question, Pinto also discussed navacaprant and said Neumora plans to increase enrollment by up to 25% in its KOASTAL-2 and KOASTAL-3 studies under existing protocol allowances. He attributed the decision to operational changes implemented after a prior pause, including SAFER and VCT measures intended to improve patient selection, which he said have led to higher screen-fail rates and what the company believes is a higher-quality enrolled population.
Pinto said the company expects a combined readout in the second quarter, including top-line results for KOASTAL-2 and KOASTAL-3 and additional data focused on the “post-pause pooled population,” which he said should exceed 400 patients.
About Neumora Therapeutics (NASDAQ:NMRA)
Neumora Therapeutics, headquartered in Cambridge, Massachusetts, is a clinical-stage biopharmaceutical company focused on developing precision therapies for disorders of the central nervous system. The company applies an integrated approach that combines advanced biological insights, single-cell genomics and machine learning to accelerate the discovery and development of novel treatments for neurological and psychiatric diseases.
Neumora’s product pipeline spans small molecules, biologics and gene-based modalities targeting areas of high unmet need such as neurodegenerative conditions, mood and anxiety disorders, neuropathic pain and movement disorders.
