Neumora Initiates Phase 1b Trial for Alzheimer's-Related Agitation Treatment
Neumora Therapeutics, Inc. (Neumora), a clinical-stage biopharmaceutical company with a therapeutics pipeline consisting of seven clinical and pre-clinical brain disease programs, today announced the initiation of a Phase 1b study evaluating NMRA-511 for the treatment of agitation associated with dementia due to Alzheimer's disease (AD). NMRA-511 is an oral, highly potent and selective antagonist of the vasopressin 1a receptor (V1aR) and is highly brain penetrant. Modulation of the V1aR is known to play a role in the regulation of aggression, stress and anxiety responses.
"We believe there is a strong rationale to evaluate the potential benefits of NMRA-511 for the treatment of agitation associated with dementia due to AD given the preclinical and clinical data supporting the role that the V1aR plays in regulating key agitation-related processes in the brain," said Robert Lenz, M.D., Ph.D., executive vice president and head of research and development, Neumora. "Millions of people in the U.S. are impacted by AD, and agitation is one of the most disruptive and burdensome symptoms for individuals and their families as it is associated with greater caregiver stress, increased morbidity and mortality, and earlier placement in long-term care facilities. Despite the significant impact of agitation in AD, there is currently only one approved product available, which carries a black-box warning for mortality in elderly people. We believe that patients deserve added treatment options and are eager to further elucidate the potential of NMRA-511 in this indication."
The Phase 1b study will investigate NMRA-511 initially in healthy elderly adult participants and then people with agitation associated with dementia due to AD. Part A of the Phase 1b study will be a randomized, double-blind, placebo-controlled cohort designed to evaluate the safety, tolerability and pharmacokinetics of NMRA-511 in approximately 8 healthy elderly participants. Part B of the Phase 1b study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group cohort designed to evaluate the safety, tolerability, and efficacy of NMRA-511 20 mg twice-daily (BID) in approximately 88 people with agitation associated with dementia due to AD. The primary endpoint of this signal-seeking study is change from baseline to Week 8 on the Cohen-Mansfield Agitation Inventory total score. Neumora expects to report topline data from this Phase 1b study in the second half of 2025.
Several lines of evidence indicate that V1aR antagonists have therapeutic potential for reducing symptoms of agitation. Pre-clinically, multiple models have demonstrated that activating the vasopressin system with the endogenous agonist AVP modulates social-emotional, anxiety and threat-related behaviors across species. In rodents, the selective breeding of strains for aggressive or anxiety traits show dysregulated vasopressin release and hypothalamic-pituitary-adrenal axis functioning. Additionally, vasopressin-deficient rodents displayed impaired responses to threat stimuli, reduced anxiety and depressive-like behaviors, and impaired aggression toward intruders. Clinically, in healthy volunteers, exogenously administered vasopressin increased autonomic responsiveness to threat stimuli and increased anxiety. Conversely, V1aR antagonist administration suppressed anxiety induced by unpredictable threats. This finding is in line with data showing that concentrations of vasopressin in cerebrospinal fluid were positively correlated with levels of aggression in individuals with personality disorders. Together, these data support the development of a V1aR antagonist for the treatment of symptoms of agitation, aggression, and anxiety.
Neumora recently completed a Phase 1a Single Ascending Dose (SAD) / Multiple Ascending Dose (MAD) study that evaluated 5,10, 15, 20 and 40 mg doses of NMRA-511 in 92 healthy adult participants. NMRA-511 was generally well tolerated across doses in the study, with no serious adverse events observed at any dose level. The Company looks forward to sharing additional data from the SAD / MAD study with NMRA-511 at future medical meetings.