Usmarapride (SUVN-D4010), a 5-HT4 receptor partial agonist for the potential treatment of Alzheimer's disease: Behavioural, neurochemical and pharmacological profiling.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which affects cognitive functions with negative impact on day to day activities and an ultimate loss of independent living. Current standard of care (SOC) for AD, viz. donepezil, rivastigmine, galantamine, memantine etc. either alone or in combination show modest efficacy without changing the course of the disease. On prolonged treatment, side effects are more common with an eventual loss of efficacy. Aducanumab, a monoclonal antibody is a disease modifying therapeutic agent targeting the toxic amyloid beta (Aß) proteins for its clearance. However, it is found to have only modest efficacy in AD patients and its approval by FDA is controversial. Alternate, effective and safe therapeutics are need of the hour, as AD cases are expected to be doubled by 2050. Recently, 5-HT4 receptors have been envisioned as target for alleviating AD associated cognitive impairment with potential disease modifying ability impacting disease progression. Usmarapride is a 5-HT4 receptor partial agonist, being developed for the possible treatment of AD with symptomatic and disease modifying potential. Usmarapride demonstrated promising effects in ameliorating cognitive deficits in diverse animal models of episodic, working, social, and emotional memories. Usmarapride produced elevation in cortical acetylcholine levels in rats. Furthermore, usmarapride increased levels of soluble amyloid precursor protein alpha, a potential mechanism to reverse toxic Aß peptide pathology. Usmarapride also potentiated the pharmacological effects of donepezil in animal models. To conclude, usmarapride may be a promising intervention for alleviating the cognitive dysfunction in AD patients with disease modifying potential.

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.

Potential beneficial effects of masupirdine (SUVN-502) on agitation/aggression and psychosis in patients with moderate Alzheimer's disease: Exploratory post hoc analyses.

OBJECTIVES: The effects of masupirdine on the neuropsychiatric symptoms were explored. METHODS: Masupirdine (SUVN-502) was evaluated for its effects on cognition in patients with moderate AD. The prespecified primary outcome showed no drug-placebo difference. Post hoc analyses of domains of the 12-item neuropsychiatric inventory scale were carried out. RESULTS: In a subgroup of patients (placebo, n = 57; masupirdine 50 mg, n = 53; masupirdine 100 mg, n = 48) with baseline agitation/aggression symptoms ≥1, a statistically significant reduction in agitation/aggression scores was observed in masupirdine 50 mg (95% confidence interval (CI), -1.9 to -0.5, p < 0.001) and masupirdine 100 mg (95% CI, -1.7 to -0.3, p = 0.007) treated arms at Week 13 in comparison to placebo and the effect was sustained for trial duration of 26 weeks in the masupirdine 50 mg treatment arm (95% CI, -2.3 to -0.8, p < 0.001). Similar observations were noted in the subgroup of patients (placebo, n = 29; masupirdine 50 mg, n = 30; masupirdine 100 mg, n = 21) with baseline agitation/aggression symptoms ≥3. In the subgroup of patients (placebo, n = 28; masupirdine 50 mg, n = 28; masupirdine 100 mg, n = 28) who had baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores was observed in the masupirdine 50 mg (Week 4: 95% CI, -2.8 to -1.4, p < 0.001; Week 13: 95% CI, -3.3 to -1.3, p < 0.001) and masupirdine 100 mg (Week 4: 95% CI, -1.4 to 0, p = 0.046; Week 13: 95% CI, -1.9 to 0.1, p = 0.073) treatment arms in comparison to placebo. CONCLUSION: Further research is warranted to explore the potential beneficial effects of masupirdine on NPS.