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

Abstract

BackgroundSymptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.ResultsAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).ConclusionsSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists.Trial registrationClinicaltrials.gov, NCT01712074. Registered 19 October 2012.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0368-9) contains supplementary material, which is available to authorized users.

Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

“…Of the 56 AD dementia articles, we were able to identify a complete published protocol with a statistical analysis plan for only 17 (30.4%) 28,37,40,41,44,45,47,52,54,55,[63][64][65][66]68,70,71 ; of these, only 8 (47.1%) 40,41,54,55,63,65,68,70 included a sex-specific data analysis in the protocol. Of the 56 total articles, 8 (14.3%) 27,49,[54][55][56]64,67,68 incorporated sex-specific data analysis in the methods section.…”

Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase 2 Randomized Placebo-Controlled Study

“…Masupirdine, a 5-HT 6 receptor antagonist, was evaluated in participants with moderate AD [12][13][14][15][16][17][18][19][20]. In this phase 2 study, based on the potential beneficial effects of coadministration of masupirdine with donepezil and memantine on cognition observed in animal models, and the common use of memantine along with acetylcholinesterase inhibitors (AChEIs) in this population, patients on stable background therapy of donepezil and memantine were recruited.…”

“…Similarly, preliminary signs of efficacy for idalopirdine were not confirmed in phase 3 trials [ 15 ]. A phase 2 clinical trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in patients with AD on a stable regimen of donepezil 5 to 10 mg QD was terminated before planned completion, as the study met the futility criteria [ 16 ]. The potential utility of 5-HT 6 receptor antagonists in the treatment of AD has been evaluated either as monotherapy or as an add-on therapy to donepezil.…”

Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

“…Other largely unsuccessful attempts to improve cognitive decline by enhancing neurotransmission are shown in Table 2 [60–71]. Despite encouraging preclinical and Phase II clinical results, the number of agents thought to improve cognitive decline by enhancing cholinergic neurotransmission, using serotonin 6 (5-HT6) receptor antagonists, Intepirdine [60], Idalopirdine [61], and PF-05212377 [62], failed to reach efficacy endpoints. Similarly, previous attempts to enhance acetylcholine response using H3 receptor antagonists, ABT-288, GSK239512, and S 38093, did not show sufficient cognitive improvement [64–66].…”