How do anti‑amyloid antibodies like lecanemab and donanemab differ in trial design, efficacy and safety outcomes for early AD?
Executive summary
Lecanemab and donanemab are two recently approved anti‑amyloid monoclonal antibodies tested in large, randomized trials in early Alzheimer’s disease that both produced substantial amyloid PET clearance and statistically significant but modest slowing of clinical decline over ~18 months [1] [2]. Their trial designs, primary endpoints, measured effect sizes and safety profiles differ in ways that matter for clinicians and patients: lecanemab emphasized protofibril binding and clinical change on CDR‑SB in CLARITY‑AD, while donanemab trials focused on plaque removal and used distinct endpoints and tau‑stratified analyses [1] [3].
1. Trial design: populations, targets, and endpoints diverged
Lecanemab’s pivotal CLARITY‑AD was a large, double‑blind randomized trial in early symptomatic AD targeting soluble Aβ protofibrils with biweekly infusions and used clinical scales like the CDR‑SB and ADCOMS as primary clinical endpoints with blinded raters [1] [4]. Donanemab’s TRAILBLAZER program targeted N‑terminal pyroglutamate‑modified Aβ in plaques and emphasized amyloid plaque clearance as a key outcome—including a coprimary outcome in TRAILBLAZER‑ALZ 4 comparing plaque clearance versus aducanumab by florbetapir PET at 6 months—and stratified analyses by tau burden to define subgroups more likely to benefit [3] [5]. Meta‑analytic re‑evaluations pooled trials of both drugs but note differences in inclusion criteria, duration (~72 weeks in pooled analyses), and outcome measures that complicate direct head‑to‑head comparisons [6] [7].
2. Efficacy: both clear amyloid but clinical benefits are modest
Both antibodies produced dramatic reductions in brain amyloid PET burden in their 18‑month randomized trials while showing highly statistically significant but modest slowing of cognitive decline on composite and global scales [2] [4]. Meta‑analysis found that combined lecanemab/donanemab use yielded small but significant improvements on ADCOMS and CDR‑SB compared with placebo [6] [7]. Authors and reviewers quantify effect sizes as modest—examples include estimated cognitive slowing around 8–14% depending on metric and trial, and the group‑level changes are often smaller than conventional minimal clinically important differences on scales like ADAS‑Cog [8] [9].
3. Safety: ARIA and other harms constrain use
Both drugs carry a clinically important risk of amyloid‑related imaging abnormalities (ARIA), including edema and microhemorrhages, and safety analyses show nontrivial rates of ARIA and other adverse events that affect risk‑benefit calculations [1] [8]. Reviews estimating harm metrics report an overall number‑needed‑to‑harm on the order of a few patients when counting all toxic effects for each antibody, underscoring that adverse events are common enough to materially influence treatment decisions [8]. Donanemab dosing strategies and ongoing trials explicitly explore regimen adjustments to reduce ARIA frequency, reflecting a different safety‑management emphasis in its development program [5] [3].
4. Comparative effect size and subgroup signals
Direct head‑to‑head data remain limited; indirect comparisons and network meta‑analyses rank donanemab and lecanemab among the most effective immunotherapies for slowing certain cognitive measures, but confidence intervals and metric choices matter and ranking does not erase modest clinical magnitude [10]. Donanemab analyses highlight stronger plaque clearance and possible greater effect in low‑to‑medium tau subgroups, while lecanemab’s CLARITY‑AD demonstrated consistent modest slowing across global and composite measures [3] [1]. Re‑analyses caution that measures like ADCOMS or CDR‑SB can give differing impressions and individual‑level clinical meaningfulness cannot be established without patient‑level data [9] [2].
5. Limitations, controversies and biological interpretation
Critical perspectives note that despite dramatic amyloid removal, the clinical benefits are limited and could reflect trial timing, target specificity, or intrinsic limits of amyloid‑centric approaches; mechanistic critiques argue effects may be constrained if downstream tau or intraneuronal processes are already active [11] [2]. Sponsorship, endpoint selection and adaptive designs differ between sponsors and trials and have prompted debates about generalizability, long‑term durability and which patients truly benefit [1] [7]. Meta‑analyses conclude statistically significant benefits but repeatedly stress modest size and heterogeneity in measures and follow‑up [6] [7].
6. Practical takeaway: targeted promise with guarded expectations
The two antibodies represent the clearest clinical translation yet of anti‑amyloid therapy—both reliably clear amyloid and modestly slow decline in early AD—but differences in molecular target, trial endpoints, subgroup signals and ARIA risk mean choice of agent, monitoring intensity and interpretation of benefit will require individualized assessment and more head‑to‑head and long‑term data before firm conclusions about superiority or broad clinical impact can be made [1] [3] [8].