Two randomized controlled trials of SB742457 in mild‐to‐moderate Alzheimer's disease

Abstract

BackgroundTwo previous studies of SB742457, a 5-hydroxytryptamine (5-HT6) receptor antagonist, suggested the efficacy of improvements in cognition and global outcome in Alzheimer's disease (AD).MethodsTwo randomized, placebo-controlled trials investigated SB742457 15 and 35 mg daily in subjects with mild-to-moderate AD (Mini-Mental Health State Examination [MMSE] 10–26). Study 1 (n = 576) investigated SB742457 and donepezil (5–10 mg daily) as monotherapy for 6 months. Study 2 (n = 684) investigated SB742457 in subjects who were maintained on donepezil. Coprimary endpoints at 24 weeks assessed cognition (AD Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global outcome (Study 1: Clinician Interview-Based Impression of Change Plus Caregiver Input [CIBIC+]; Study 2: Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Safety was assessed throughout.ResultsBoth studies failed to achieve formal statistical significance for their primary objectives. Study 1: SB742457 monotherapy was not statistically significantly different from placebo on any endpoint. Donepezil improved CIBIC+ but not ADAS-Cog. Study 2: SB742457 35 mg showed statistically significant differences relative to placebo for ADAS-cog (weeks 12, 24, and 48, but not week 36), ADCS-ADL (weeks 12–36, but not week 48), and CDR-SB (week 12 only).ConclusionNeither study met the overall criteria for success, but as an adjunct to donepezil, SB742457 was associated with sustained improvements for up to 48 weeks in cognition and ADL, compared with donepezil alone.Clinical Trial Registration: Clinicaltrials.gov: Study 1 NCT00708552; Study 2 NCT00710684.

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

“…The negative results from the phase 3 MINDSET study run counter to the phase 2 results with intepirdine that had suggested a potential benefit in Alzheimer disease. 11…”

“…5,6 Even though clinical trials did not support 5-HT 6 antagonist monotherapy among patients with Alzheimer disease, 8,9 2 phase 2 trials suggested that administration of 5-HT 6 antagonists added to cholinesterase inhibitor therapy may improve cognition in Alzheimer disease. 10,11 In one of the phase 2 studies, 10 90 mg/d of idalopirdine (30 mg taken 3 times per day) added to a stable dose of donepezil provided significant improvement in cognitive performance relative to donepezil monotherapy among patients with moderate Alzheimer disease dementia. Therefore, 3 randomized clinical trials (STARSHINE [study 1], STARBEAM [study 2], and STARBRIGHT [study 3]) were conducted to assess the efficacy of idalopirdine when added to donepezil or another cholinesterase inhibitor therapy for the treatment of mild to moderate Alzheimer disease.…”

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…Further, the results of different studies were inconsistent. For instance, one study found a significant change in global function but not cognition [89], while another report failed to find any significant improvements [90,91].…”

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

“…The potential for therapeutic use of 5-HT 6 antagonists in the treatment of AD has been investigated in prior clinical trials that have demonstrated mixed results with respect to clinical efficacy. In clinical trials of SB-742457 (now known as intepirdine), administered as monotherapy to individuals with mild to moderate AD, there was no significant benefit of treatment versus placebo on measures of cognition or global impression of change, although some favorable trends were noted [ 8 , 9 ]. In contrast, studies where 5-HT 6 antagonists were added to existing stable regimens of cholinesterase inhibitors have produced more favorable results, with significant effects observed on measures of cognition and activities of daily living [ 10 , 11 ].…”