Neumora's NMRA-511 Shows Clinically Meaningful Results in Phase 1b Alzheimer's Agitation Study
核心洞察
Neumora Therapeutics announced positive Phase 1b results for NMRA-511, an oral vasopressin 1a receptor (搜索) antagonist, demonstrating clinically meaningful effect sizes in treating Alzheimer's disease (搜索) agitation (搜索).
The drug showed particularly strong efficacy in patients with elevated anxiety (搜索), achieving placebo-adjusted CMAI score reductions of -7.6 and -5.6 at weeks 6 and 8 respectively.
NMRA-511 demonstrated a favorable safety profile with no reports of somnolence or sedation and only 2.5% treatment discontinuation due to adverse events.
Neumora Therapeutics announced positive results from its Phase 1b signal-seeking study of NMRA-511, an investigational vasopressin 1a receptor (搜索) (V1aR (搜索)) antagonist for treating agitation (搜索) in Alzheimer's disease (搜索) patients. The oral, brain-penetrant drug demonstrated clinically meaningful effect sizes while maintaining a favorable safety profile with no reports of somnolence or sedation.
Study Design and Patient Population
The Phase 1b study consisted of two parts: Part A evaluated safety and pharmacokinetics in healthy elderly participants, while Part B was a multicenter, randomized, double-blind, placebo-controlled study in 80 people with AD agitation (搜索). The efficacy analysis included 71 patients in the modified analysis set, with 36 patients comprising a pre-specified subpopulation with elevated anxiety (搜索) at baseline.
Primary Efficacy Results
In the overall patient population, NMRA-511 20 mg twice-daily demonstrated placebo-adjusted changes from baseline on the Cohen-Mansfield Agitation (搜索) Inventory (CMAI) total score of -2.6 and -2.1 at weeks 6 and 8 respectively. These results represent Cohen's d effect sizes ranging from 0.20 to 0.23, indicating clinically meaningful improvements in agitation symptoms.
The CMAI is a clinically validated scale measuring the frequency of 29 agitated behaviors and serves as a standard assessment tool for agitation (搜索) in dementia (搜索) patients.
Enhanced Efficacy in Elevated Anxiety Population
Particularly compelling results emerged in patients with elevated anxiety (搜索) at baseline, defined as those with Rating Anxiety in Dementia (搜索) scores ≥12. This subgroup demonstrated substantially greater improvements, with placebo-adjusted CMAI score reductions of -7.6 and -5.6 at weeks 6 and 8 respectively, representing Cohen's d effect sizes of 0.51-0.64.
"The results of treatment with NMRA-511 are particularly encouraging, as they demonstrated clinically meaningful effects in agitation (搜索) symptoms among people with AD agitation, and even more profound results among those with elevated anxiety (搜索) – representing a significant number of treated patients," said Anton P. Porsteinsson, M.D., Director of the Alzheimer's Disease (搜索) Care, Research and Education Program at University of Rochester School of Medicine and Dentistry (搜索).
Safety and Tolerability Profile
NMRA-511 demonstrated a favorable safety profile throughout the study period. Treatment-emergent adverse events were typically mild to moderate in severity, with low treatment discontinuation rates due to adverse events at 2.5%. The most common adverse effects occurring in more than 5% of patients in either treatment group included nasopharyngitis, urinary tract infection, anemia, arthralgia, diarrhea, dizziness, headache, hyponatremia, myalgia, nausea, vomiting, and abdominal pain.
Notably, the study reported no instances of somnolence or sedation, addressing key tolerability concerns associated with existing treatments for AD agitation (搜索).
Mechanism of Action and Clinical Rationale
NMRA-511 is a highly potent and selective antagonist of the vasopressin 1a receptor (搜索), exhibiting greater than 3,000-fold selectivity over V1b and V2 receptors and approximately 300-fold selectivity over the oxytocin receptor (搜索) in preclinical studies. The V1aR (搜索) plays a crucial role in regulating aggression, affiliation, stress, and anxiety (搜索) responses, providing a mechanistic rationale for its therapeutic potential in agitation (搜索) disorders.
"Anxiety (搜索) is often an underlying symptom that is present early in the AD agitation (搜索) disease course, and there is an unmet need for tolerable therapies that can reduce agitation and anxiety symptoms," explained Bill Aurora, Pharm.D., chief operating and development officer at Neumora.
Development Timeline and Next Steps
Neumora has outlined a comprehensive development plan for NMRA-511, including three key initiatives planned for 2026. The company will initiate a multiple ascending dose extension study to investigate higher doses, develop an extended-release formulation to enable once-daily dosing, and launch a Phase 2/3 dose-ranging study.
The advancement comes as the company also announced plans to increase enrollment in its KOASTAL studies of navacaprant in major depressive disorder (搜索), targeting up to 25% enrollment beyond the original target of 332 patients, with joint topline data readout expected in the second quarter of 2026.
Clinical Context and Unmet Need
AD agitation (搜索) represents a significant clinical challenge, affecting a substantial portion of Alzheimer's patients and creating distress for both patients and caregivers. According to Dr. Porsteinsson, the condition is associated with increased morbidity and mortality and earlier placement in long-term care facilities. Current treatment options are often limited by modest efficacy and tolerability concerns, creating substantial unmet medical need for effective, well-tolerated therapies.