Masupirdine (SUVN‐502): A promising clinical candidate for the management of agitation in Alzheimer’s dementia

Background Masupirdine is a potent and selective 5‐HT6 receptor antagonist and has completed Phase‐2 clinical proof of concept studies in patients with Alzheimer’s type dementia. 5‐HT6 receptors are G‐protein coupled receptors mainly localized in the brain regions primarily involved in cognition and behavior i.e., cortex, dorsal hippocampus and striatum. Evidence from the studies in animal models suggests that 5‐HT6 receptor antagonists may have a potential role in controlling neuropsychiatric behavior such as agitation. Method Masupirdine has been evaluated in a phase‐2a proof‐of‐concept, 26‐week, randomized, double‐blind, placebo‐controlled, multicenter, parallel groups in United States under active US IND. Sub group analyses has been carried out to evaluate the effects of masupirdine on domains related to agitation/ aggression using Neuropsychiatric Inventory (NPI‐12) scale. Masupirdine was also tested in resident intruder task to evaluate its effects on animal model relevant to aggression. Additionally, masupirdine has been evaluated using microdialysis technique to assess its effect on the modulation of monoaminergic neurotransmitters. Result In Phase‐2 clinical study subgroup analyses, masupirdine showed robust efficacy in agitation/aggression scores in subjects who had baseline symptoms of agitation/aggression. The effect observed was greater than the minimum difference observed to be clinically important. Similar beneficial effects were observed on extended composite NPI‐12 score related to agitation/ aggression (agitation/ aggression + aberrant motor behavior + sleep and nighttime behavior disorder). Masupirdine was found to be safe and well tolerated in this study. In preclinical animal models, masupirdine reduced the aggressive behaviour in resident intruder task and increased neurotransmitters with role in modulation of agitation and aggression. Conclusion Masupirdine showed clinically meaningful improvement in the neuropsychiatric symptoms associated with agitation/aggression in patients with AD and reduced aggression in animal models. Masupirdine could be a differentiated novel therapeutic option for the management of agitation/ aggression in Alzheimer’s patients.