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Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

ABSTRACT: Introduction:Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid ? (A?)1-40 and A?1-42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free A? isoforms and their relationship with solanezumab exposure. Methods:CSF A? isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3. Results:Solanezumab produced statistically significant increases in CSF total A? isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free A? isoforms were observed. Solanezumab penetration into the central nervous system was low. Discussion:Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total A? concentrations.

SUBMITTER: Willis BA

PROVIDER: S-EPMC6258891 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

Willis Brian A BA Sundell Karen K Lachno D Richard DR Ferguson-Sells Lisa R LR Case Michael G MG Holdridge Karen K DeMattos Ronald B RB Raskin Joel J Siemers Eric R ER Dean Robert A RA

Alzheimer's & dementia (New York, N. Y.) 20181109

<h4>Introduction</h4>Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)<sub>1-40</sub> and Aβ<sub>1-42</sub> in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.<h ...[more]

PMID: 30511011

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Project description:BackgroundTrials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results.MethodsWe tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks.ResultsA total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group.ConclusionsSolanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

Dataset Information

Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

Publications

Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

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