Background

NMRA-511 is an oral, selective, brain-penetrant antagonist of the vasopressin 1a receptor (V1aR). The V1aR is expressed in multiple areas of the brain, and plays a role in social behaviors, anxiety, and threat processing.

Nonselective vasopressin receptor antagonists are marketed as diuretics that act on V1 and V2 receptors in the kidney to increase urine production. They are mainly prescribed to correct low blood sodium, particularly in people with congestive heart failure. Several lines of evidence argue for using selective V1aR antagonists to treat Alzheimer’s agitation. Concentrations of vasopressin in cerebrospinal fluid positively correlated with levels of aggression in people with personality disorders (Coccaro et al., 1998). In healthy adults, the V1aR antagonist SRX246 suppressed anxiety induced by unpredictable electric shocks (Lago et al., 2021). It also reduced aggressive behavior in people with Huntington disease and irritability (Maibach et al., 2022).

However, people with Alzheimer’s disease are reported to have deficits of vasopressin in CSF and brain tissue (Raskind, et al., 1986; Mazurek et al., 1986). In the APP/PS1 mouse model of AD, intranasal application of a vasopressin derivative [AVP-(4-8)] improved memory (Zhang et al., 2020).

No preclinical work on NMRA-511 is published. In data shown at meetings, the company claims that the compound is highly selective over closely related receptors, showing a 3,000-fold preference for V1a over the V1b and V2 receptors, and 300-fold preference over the oxytocin receptor. NMRA-511 reduced anxiety-related behaviors in response to a perceived threat in marmosets, and altered EEG spectra in marmosets and people (Wallace et al., 2022).

Findings

According to information on the company web site, Neumora completed a Phase 1a single- and multiple-ascending-dose study in 92 healthy adults. Doses of 5, 10, 15, 20, and 40 mg were well tolerated, with no serious adverse events observed.

In July 2024, Phase 1b began. Part A is evaluating the safety, tolerability, and pharmacokinetics of two weeks of 20 mg NMRA-511 twice a day, or placebo, in eight healthy elderly participants. Part B will compare the safety and efficacy of eight weeks of 20 mg twice daily to placebo in 88 patients with mild to severe AD dementia and agitation. The primary endpoint is change from baseline on the Cohen-Mansfield Agitation Inventory total score. Neumora expects to report top-line data at the end of 2025.

For information on this study, see clinicaltrials.gov.