Lowering of Amyloid Plaque Through Monoclonal Antibodies Correlated With Better Clinical Benefit, Meta-Analysis Suggests

Findings from a large-scale meta-analysis of 9 trials assessing antiamyloid monoclonal antibodies for the treatment of Alzheimer disease (AD) revealed that achieving greater amyloid negativity and lowering amyloid plaque level at an early time point was correlated with better patient outcomes on Clinical Dementia Rating-sum of boxes (CDR-SB) scale, a standard measurement of cognitive function.¹

Presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, the analysis looked at data from studies that assessed antiamyloid therapies aducanumab (Aduhelm; Biogen), lecanemab (Leqembi; Eisai), donanemab (Eli Lilly), gantenerumab, and crenezumab. The goal of the analysis was to answer whether the amount of amyloid reduction over a certain period, or the absolute amyloid reduction at a certain time point, is most important in the relationship between amyloid PET and clinical end points.

Senior investigator Marzia Antonella Scelsi, senior statistical scientist at Roche, and colleagues extracted multiple PET and CDR-SB metrics from 12 dose arms across the 9 studies, with changes on a Centiloid scale to compare results. Study-level PET summaries were extracted both at an “early” time point, approximately 12 months before end-of-study, and at end-of-study. These summaries included baseline Centiloid, absolute Centiloid value in treated arm at timepoints specified, change from baseline in Centiloid in treated arm, difference treated-placebo in Centiloid change from baseline, and proportion of patients below amyloid positivity threshold at early and late time points.

READ MORE: Anti-Amyloid-ß Oligomer Antibody ACU193 Reduces Amyloid Plaques in Dose-Dependent Manner

At the conclusion of the analysis, results showed that the relative reduction (RR) in CDR-SB at end-of-study was moderately correlated with difference between treated and placebo in Centiloid change from baseline (Spearman’s rho = 0.55; 95% CI, ­–0.85 to 0.04; P = .071). Similar correlations were found when considering the absolute Centiloid at end-of-study (rho = –0.59; 95% CI, –0.87 to –0.02; P = .049) or the percentage below threshold at end-of-study (rho = 0.56; 95% CI, ­–0.02 to 0.85; P = .06).

To gain the maximal potential of AD therapeutics, clinicians have aimed to treat patients as early as possible. When the early time point was considered for all PET metrics, the correlation numerically increased, with the greatest differences observed for early absolute Centiloid (rho = –0.68; 95% CI, –0.90 to –0.17; P = .019) and early proportion below positivity threshold (rho = 0.65; 95% CI, 0.12-0.89; P = .023). investigators also noted that the lowest difference between the predicted and observed value of the CDR-SB RR in a leave-one-out prediction model was achieved using either Centiloid value or early proportion below positivity threshold as the predictor.

The Aß cascade hypothesis of AD was originally proposed by the theory that the accumulation of Aß, in particular Aß1-42, is the initial trigger for neurodegeneration; however, the chemical nature and the precise biological roles of Aß in AD pathogenesis have been elusive. The clearance of Aß from the brain can be accomplished by several mechanisms which include nonenzymatic and enzymatic pathways. In addition, through research, the role of amyloid precursor protein processing and resulting Aß production in disease development was established from the genetic analysis of familial forms of AD.²

Although the connection between Aß reduction and better outcomes has been previously reported, a widely cited meta-analysis published in 2022 concluded that Aß reduction does not substantially improve cognition. Pooling data from 16 randomized trials demonstrated that each 0.1-unit decrease in PET Aß standard uptake ratio was association with a reduction by 0.09 (95% CI, 0.034-0.15), 0.33 (95% CI, 0.12-0.55), and 0.13 (95% CI, 0.017-0.24) point in the average change of the CDR-SB, the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively.³

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REFERENCES
1. Scelsi MA, Jackson J, Tonietto M, et al. An exploration of amyloid removal measures in relation to clinical benefit: a review and meta-regression of anti-amyloid trials in AD. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 24-27, 2023; Boston, MA. POSTER LB15
2. Yoon S, Jo SA. Mechanisms of amyloid-ß peptide clearance: potential therapeutic targets for Alzheimer’s disease. Biomol Ther. 2012;20(3):245-255. doi:10.4062/biomolther.2012.20.3.245.
3. Pang M, Zhu L, Gabelle A, et al. Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: an instrumental variable meta-analysis. Alzheim Dement. 2023;19(4):1292-1299. doi:10.1002/alz.12768