Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.

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IntroductionThe safety, pharmacokinetics, and effect on peripheral and central amyloid β (Aβ) of multiple doses of ponezumab, an anti-Aβ monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year.MethodsSubjects were aged ≥50 years with Mini–Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively.ResultsPonezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aβ increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected.ConclusionsBoth ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.

IntroductionMultiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD).MethodsIn part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter.ResultsPonezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ1–x and Aβ1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume.ConclusionsMultiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

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.