Clarity AD: Asian regional analysis of a phase III trial of lecanemab in early Alzheimer's disease.

Abstract

Background: Across Asia, Alzheimer's disease prevalence is expected to rise dramatically due to, among other factors, rapidly aging populations. Alzheimer's disease pathology is triggered by the accumulation of soluble and insoluble aggregated Aβ peptides (oligomers, protofibrils, and fibrils). Lecanemab is a recently approved humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils), with activity at insoluble fibrils. In the recent 18-month phase 3 Clarity AD study, lecanemab demonstrated a consistent slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer's disease. Lecanemab was well tolerated in Clarity AD, with an increase in incidence of infusion related reactions and amyloid-related imaging abnormalities (ARIA) versus placebo.

Objectives: The objective of this manuscript is to present the results for the Asian region population of Clarity AD.

Design: The core Clarity AD study was an 18-month, multicenter, double-blind, placebo-controlled, parallel-group study.

Setting: Academic and clinical centers in Asia PARTICIPANTS: A total of 294 individuals with early Alzheimer's disease (i.e., mild cognitive impairment or mild Alzheimer's disease).

Intervention: Eligible patients were randomized across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly) according to a fixed 1:1 schedule.

Measurements: The primary efficacy endpoint in the core study was change in the Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) from baseline at 18 months. Key secondary endpoints included change from baseline at 18 months in amyloid PET Centiloids (in patients participating in the amyloid PET sub-study), AD COMposite Score (ADCOMS) and AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14). Safety was monitored throughout the study in a blinded manner by the sponsor and in an unblinded manner by an independent data safety monitoring committee.

Results: Of the total of 1795 subjects randomized in Clarity AD, 294 subjects were in the Asian region (Japan:152; Korea:129; Singapore:13). The efficacy of lecanemab was consistent with the overall population. For the primary endpoint, there was a slowing of decline with lecanemab in the CDR-SB at 18 months compared to placebo in the Asian region (adjusted mean difference: -0.349; 95 % confidence intervals: -0.773, 0.076; 24 % slowing of decline). Results for the secondary efficacy endpoints also favored lecanemab versus placebo in Asians. Lecanemab was well tolerated in Asian subjects, with a safety profile in Asian subjects similar to the overall Clarity AD population. The most common adverse events of special interest were ARIA-H (lecanemab:14.4 %; placebo:16.2 %), ARIA-E (lecanemab:6.2 %; placebo:1.4 %), and infusion-related reactions (lecanemab:12.3 %; placebo:1.4 %). Incidence of adverse events leading to study drug dose interruption or withdrawal, infusion-related reactions, ARIA-E and ARIA-H was lower for the lecanemab treated group in the Asian region relative to the overall Clarity AD population. Results from quality of life and biomarker assessments in the Asia region were also generally similar to the overall Clarity AD population.

Conclusion: In the Clarity AD Asian region cohort, the overall efficacy, biomarker changes and safety profile of lecanemab were consistent with the overall population, with a favorable risk-benefit profile and manageable risks. ARIA events and infusion-related reactions occurred less commonly with lecanemab in the Asian region subgroup than the overall population.