IDALOPIRDINE, A 5-HT6 ANTAGONIST, AS ADJUNCTIVE THERAPY TO ACETYLCHOLINESTERASE INHIBITORS IN PATIENTS WITH MILD-MODERATE ALZHEIMER’S DISEASE: KEY OUTCOMES FROM THE STAR PHASE III PROGRAM

Abstract

Idalopirdine is a novel, selective, 5-HT6 receptor antagonist tested as adjunctive to acetylcholinesterase-inhibitors (AChEIs) for the treatment of mild-moderate Alzheimer's disease (AD). In a Phase II study in patients with moderate AD (MMSE 12–19), idalopirdine 90mg/day (30mg TID) added to stable donepezil treatment produced significant improvement in cognitive performance relative to donepezil monotherapy (Lancet Neurol. 2014;13:1092–9). Here, we present data from a large phase III program designed to establish the efficacy and safety of idalopirdine 10–60mg/day adjunctive to AChEI in mild-moderate AD. The phase III program consisted of three 24-week, double-blind, parallel group, placebo-controlled, multi-national, multi-center, fixed-dose (10, 30, and 60mg QD) studies of idalopirdine as adjunctive to AChEIs in patients aged ≥50 years with mild-moderate AD (MMSE 12–22) (NCT01955161; NCT02006641; NCT02006654). The primary endpoint in all studies was change from Baseline to Week-24 in ADAS-cog total score; key secondary endpoints were change from Baseline to Week-24 in ADCS-ADL23 total and ADCS-CGIC scores. Endpoints were analyzed using an MMRM approach. Dose-group efficacy required a significant benefit over placebo for the primary endpoint and at least one key secondary endpoint. 2525 patients (n=933, 858, 734) (mean age 74 years; mean Baseline ADAS-cog score 26; 62–65% female) were randomized across three studies. None of the doses met the prespecified efficacy criteria in the studies. A priori defined strata analyses suggested some indication of efficacy for 60mg/day in the moderate MMSE stratum (MMSE 12–18, ∼60% of patients); although these were not replicated by endpoints across studies. The proportion of patients reporting treatment-emergent adverse events was comparable between idalopirdine and placebo groups across studies. Transient, dose-dependent increases in liver enzymes and vomiting were infrequently observed (<5%). Study completion rates were high (89–91%), as was roll-over to the ongoing open-label extension study (NCT02079246; 90–92%). The 24-week efficacy of 10–60mg/day idalopirdine as adjunctive to AChEI in mild-moderate AD was not demonstrated in a large phase III program. Idalopirdine 10–60mg/day was safe and well-tolerated. The phase III program did not replicate phase II efficacy results performed in a moderate stage population with idalopirdine 90 mg (30mg TID) dose.