A 5-HT6 Antagonist as Adjunctive Therapy to Cholinesterase Inhibitors in Patients with Mild-to-Moderate Alzheimer’s Disease: Idalopirdine in Phase III (PL02.006)

Objective: To assess the efficacy and safety of idalopirdine as adjunctive therapy to cholinesterase inhibitors in patients with mild-to-moderate Alzheimer’s disease (AD).Background: 5-HT6 receptor antagonists offer a new approach to the symptomatic treatment of AD. 5-HT6 receptors are almost exclusively expressed within the CNS, in areas critical to memory and executive function. Preclinical data support that idalopirdine (Lu AE58054), a selective 5-HT6 receptor antagonist, when added to the cholinesterase-inhibitor donepezil, may potentiate cholinergic and glutamatergic transmission and neural oscillations in the hippocampus and frontal lobes, and reverse working memory deficits.Methods: A Phase II study explored the efficacy/safety of 90 mg/day of idalopirdine as add-on to donepezil background therapy in 278 individuals with moderate AD (MMSE 12-19) using a double-blind, placebo-controlled, parallel-group design. Based on Phase II results, a global Phase III program was launched to elucidate the efficacy and safety of idalopirdine (10-60 mg/day) in individuals aged ≥50 years with mild and moderate AD (MMSE 12-22) on stable background cholinesterase-inhibitor therapy. The program consists of three 24-week, double-blind, placebo-controlled studies involving ~2500 patients worldwide, and a 6-12 month, open-label extension study in ~1700 patients.Results: Positive Phase II results were observed with idalopirdine add-on treatment which included statistically significant benefits on the primary endpoint of cognition; supportive data consistent with potential benefits on function and clinical global impression instruments; and possible amelioration of anxiety and hallucinations while overall behavioral effect not significant. Idalopirdine add-on treatment was generally safe and well-tolerated. Transient elevations in transaminases (ALT/AST) were observed; these were asymptomatic and normalized whether affected individuals continued on treatment or were withdrawn.A large Phase III program aims to validate and extend promising Phase II results for idalopirdine add-on treatment to donepezil/other cholinesterase inhibitors in a broader population of individuals with mild and moderate AD. Recruitment is ongoing. Disclosure: Dr. Atri has received personal compensation for activities with Lundbeck. Dr. Tong has received personal compensation for activities with Lundbeck LLC as an employee. Dr. Isojarvi has received personal compensation fro activities with Lundbeck LLC. Dr. Odergren has received personal compensation for activities with Lundeck as an employee.