Research Article: 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

Date Published: April 5, 2018

Publisher: BioMed Central

Author(s): Terence Fullerton, Brendon Binneman, William David, Marielle Delnomdedieu, James Kupiec, Peter Lockwood, Jessica Mancuso, Jeffrey Miceli, Joanne Bell.


Symptomatic 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.

This 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.

At 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).

SAM-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., NCT01712074. Registered 19 October 2012.

The online version of this article (10.1186/s13195-018-0368-9) contains supplementary material, which is available to authorized users.

Partial Text

Alzheimer’s disease (AD) is the most common form of dementia, affecting up to 5% of the population over the age of 65 years and 30% of those over the age of 80 years [1]. The pathology of AD is characterized by the presence of large numbers of amyloid plaques in the brain, neurons containing neurofibrillary tangles, and neurodegeneration [2]. Cognitive dysfunction, behavioral and mood disorders, and progressive memory loss represent the hallmark clinical features.

The trial was terminated after the interim analysis was conducted when 163 subjects had completed the week 12 posttreatment visit (visit 5); the analysis revealed the criteria for futility had been met. The Bayesian predictive probability for success on the ADAS-cog13 endpoint at study end was shown to be less than 1%, meaning that even if the trial had been continued to completion (n = 342) there was essentially no chance to demonstrate a benefit of SAM-760 over placebo on the primary endpoint. As the trial recruitment was paused for the interim analysis and no subjects were ongoing during the conduct of the interim analysis, the results below describe the final analysis of the trial.

In this study, administration of SAM-760 30 mg QD for 12 weeks to subjects with mild to moderate AD with existing neuropsychiatric symptoms and receiving a stable daily dose of donepezil was generally safe and well tolerated. Despite a human positron emission tomography (PET) study indicating saturation of the 5-HT6 receptor at the 30-mg QD dose [13], there was no significant difference compared with placebo for the primary endpoint (ADAS-cog13). Similarly, there was no significant difference for the key secondary endpoint of NPI total score, or for any of the exploratory efficacy parameters (MMSE, ADAS-cog11, CDSS, CGI, and ADCS-ADL). In fact, in all cases except the CSDD, numerical differences were in favor of placebo, indicating no trends for any treatment benefits in this study. The predictive probability of a successful outcome (i.e., P(ΔΔADAS-cog13 > 0) > 0.9) in favor of SAM-760 had the study been continued to completion (with 342 subjects) was less than 1%. This prediction, together with the consistency of inferences about treatment effect reported above and for the per-protocol analysis, strongly suggest that the inference regarding treatment effectiveness was not likely impacted by suboptimal power. Results of the per-protocol analysis on ADAS-cog and NPI also did not change the inferences regarding treatment effect. Plasma concentrations of SAM-760 were consistent with expectations and reached steady-state exposure after 2 weeks. Similarly, plasma donepezil concentrations were consistent with previous reports in the literature [16]. These findings support the notion that subjects were generally compliant with the dosing schedule of study drug and donepezil during the trial.

While our study failed to demonstrate a treatment effect of 5-HT6 antagonism with SAM-760, this work contributes to the growing body of literature with this approach. When interpreted in light of the recent Phase 3 results of other 5-HT6 antagonists, it would appear that this mechanism has been sufficiently tested to conclude a clear lack of utility in AD.




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