Neumora Begins Phase 1b Study of NMRA-511 for Alzheimer's Agitation

Neumora Therapeutics, Inc., based in Watertown, Mass., has initiated a Phase 1b clinical trial to evaluate NMRA-511, a drug candidate for treating agitation associated with Alzheimer's disease (AD). NMRA-511 is a highly potent and selective antagonist of the vasopressin 1a receptor (V1aR), which is involved in regulating aggression, stress, and anxiety. The drug has shown promising results in preclinical studies and a Phase 1a trial, where it was well-tolerated across various doses without any serious adverse events.

Alzheimer’s disease affects approximately 7 million people in the United States, and the number is expected to rise to over 13 million by 2050. Agitation is a common and disruptive symptom in AD patients, leading to increased caregiver stress, greater morbidity and mortality, and earlier placement in long-term care facilities. Despite its prevalence, there is only one approved treatment for agitation in AD, which carries significant risks for elderly patients. This highlights the urgent need for new therapeutic options.

NMRA-511, an oral medication, stands out due to its high brain penetration and its role in modulating aggression, stress, and anxiety through the V1aR. Robert Lenz, M.D., Ph.D., Neumora's Executive Vice President and Head of Research and Development, emphasized the strong rationale for exploring NMRA-511’s potential benefits. He noted that agitation in Alzheimer's disease is a significant burden, not just for patients but also for their families.

The Phase 1b study of NMRA-511 will consist of two parts. Part A will involve about eight healthy elderly participants in a randomized, double-blind, placebo-controlled cohort to evaluate safety, tolerability, and pharmacokinetics. Part B will include roughly 88 participants with AD-related agitation in a multicenter, double-blind, placebo-controlled, parallel-group cohort to assess the drug's safety, tolerability, and efficacy. The primary endpoint will be the change from baseline to Week 8 on the Cohen-Mansfield Agitation Inventory total score. The topline data from this study are expected in the second half of 2025.

Preclinical and clinical evidence suggests that V1aR antagonists like NMRA-511 could effectively reduce symptoms of agitation. Studies have shown that activation of the vasopressin system influences social-emotional, anxiety, and threat-related behaviors. Rodent models have indicated that V1aR antagonism can reduce anxiety and aggression. Clinical trials have also demonstrated that administering V1aR antagonists can suppress anxiety induced by unpredictable threats.

Neumora completed a Phase 1a Single Ascending Dose (SAD) / Multiple Ascending Dose (MAD) study with 92 healthy adult participants, evaluating doses ranging from 5 mg to 40 mg. The drug was generally well-tolerated, and no serious adverse events were reported at any dose level. The company plans to share additional data from this study at future medical meetings.

NMRA-511 shows over 3,000-fold selectivity for V1aR over V1b and V2 receptors and about 300-fold selectivity over the oxytocin receptor. This selectivity, combined with the drug's ability to penetrate the brain effectively, makes it a promising candidate for treating neuropsychiatric and neurodegenerative disorders related to anxiety, aggression, and stress.

Neumora's mission is to transform brain disease treatment through innovative therapies. Their pipeline includes seven clinical and preclinical programs focusing on various neuropsychiatric and neurodegenerative diseases. The company aims to improve treatment outcomes and quality of life for patients suffering from brain diseases through precision medicine approaches supported by translational, clinical, and computational tools.