Objective: To evaluate the effects of bapineuzumab on brain b-amyloid (Ab) burden using 11 C-Pittsburgh compound B ( 11 C-PiB)-PET.Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE e4 carriers and noncarriers,were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Ab monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Ab over 71 weeks using an 11 C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Bapineuzumab, a humanized monoclonal antibody targeting the N-terminus of b-amyloid (Ab), was recently evaluated in phase 3 trials for the treatment of mild to moderate Alzheimer disease (AD) dementia. As part of those investigations, brain volumetric MRI, brain amyloid PET imaging, and CSF sampling were performed in biomarker substudies. The primary aim of the substudies was to assess the pharmacologic effects of bapineuzumab on AD CNS biomarkers. The PET substudy used 11 C-Pittsburgh compound B ( 11 C-PiB)-PET as a measure of brain fibrillar Ab.1 Differences in the incidence of amyloid-related imaging abnormalities (ARIA) and potential efficacy signals had been seen between participants treated with bapineuzumab who were APOE e4 carriers and noncarriers in phase 2 studies 2-4 ; therefore, separate clinical trials for APOE e4 carriers (Study 302) and noncarriers (Study 301) were conducted in phase 3. The primary clinical and biomarker endpoint results of these trials were recently All authors contributed equally to this work.

In rodents 5-hydroxytryptamine type 7 (5-HT 7 ) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT 7 receptor antagonist, (3-(4-chlorophenyl)-1, 4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo [3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT 7 blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drugdrug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) Ͻ ϭ 12] and from sites with no placebo response (MADRS Ͼ ϭ 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.

ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.

Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.