What are the long‑term extension and real‑world safety/efficacy data available so far for lecanemab and donanemab?
Executive summary
Two monoclonal antibodies—lecanemab and donanemab—have randomized-trial evidence of modest slowing of cognitive decline at 18 months and emerging longer-term data for lecanemab suggesting continued, small benefits out to roughly 30–36 months in open‑label follow-up, while both drugs carry a materially elevated risk of amyloid-related imaging abnormalities (ARIA) including edema and hemorrhage [1] [2] [3]. Real‑world safety and effectiveness data are only beginning to accrue through registries and early rollouts, and important questions about clinical meaningfulness, subgroup risks (especially ApoE4 carriers), fatalities linked to hemorrhage, and cost-effectiveness remain unresolved [4] [5] [6] [7].
1. What long-term extension data exist and what do they show?
Lecanemab has the clearest open‑label extension (OLE) evidence: participants from the 18‑month CLARITY‑AD core trial entered an OLE and published analyses report continued separation between those randomized to early lecanemab versus delayed start through 30–36 months across clinical and health‑related quality of life endpoints, with biomarker evidence of sustained amyloid lowering [2] [3] [1]. Donanemab’s pivotal TRAILBLAZER‑ALZ 2 trial demonstrated robust amyloid clearance and clinical slowing at 18 months, but published long‑term OLE outcomes comparable to lecanemab’s 30–36‑month follow‑up are more limited in the public record cited here [8] [9].
2. How durable and clinically meaningful are the efficacy signals?
Both drugs produced statistically significant but modest clinical effects at 18 months: lecanemab’s prespecified primary difference on CDR‑SB was 0.373 points and effect‑size metrics in trials are small (Cohen’s d ≈ 0.21 for lecanemab, 0.23 for donanemab), similar in magnitude to some symptomatic therapies and leaving debate about individual clinical meaningfulness unresolved [1] [10] [9]. Extension data for lecanemab suggest maintained benefit out to 36 months for group‑level outcomes, but authors and commentators caution that group differences do not equate to predictable, perceptible benefit for any given patient and that long‑term, objective divergence versus symptomatic treatments remains to be robustly demonstrated [2] [9] [10].
3. What long‑term and real‑world safety signals have emerged?
ARIA—both edema/effusion (ARIA‑E) and microhemorrhages/hemosiderin (ARIA‑H)—is the principal safety issue: pooled analyses show roughly a fourfold increased risk of ARIA with these antibodies versus control, lecanemab’s ARIA‑E rates in trials were lower than some other anti‑Aβ antibodies but still nontrivial (~9–12% depending on source), while donanemab reported higher ARIA‑E (~24% in its dosing regimen), and several severe hemorrhagic events including fatalities were observed in trials [5] [11] [2] [6]. Risk is higher in ApoE4 carriers and often occurs within the first year of treatment, a pattern that has driven careful monitoring requirements in clinical rollout [11] [5].
4. What does early real‑world experience and health‑system analysis say?
Real‑world effectiveness and safety are being tracked via registries linked to reimbursement programs (for example, CMS coverage conditions in the U.S.), and commentators emphasize that these datasets will be crucial to detect rarer harms, measure durability in routine practice, and assess subgroup differences not fully represented in trials [7] [4]. Economic modeling suggests measurable value to individuals and families from lecanemab over multi‑year horizons but also highlights high price and system capacity challenges, and analyses commissioned by health consortia stress the need for continued evidence collection before broad conclusions can be drawn [7] [12].
5. Bottom line, uncertainties and competing perspectives
The best current evidence supports that lecanemab offers modest, sustained group‑level slowing of decline through roughly 2.5–3 years in trial extensions while donanemab shows strong 18‑month effects with higher ARIA rates but less publicly available long‑term OLE data; both drugs increase ARIA risk substantially, with serious but uncommon hemorrhagic events reported [2] [8] [5] [6]. Proponents point to biomarker‑linked disease modification and maintained separation in OLE data for lecanemab [2] [1]; critics emphasize small effect sizes, risks, potential unblinding and caregiver‑report bias, limited long‑term randomized comparisons, and open questions about who benefits most [10] [9]. Registries and real‑world surveillance required by payers and investigators will determine whether trial‑period modest benefits translate into meaningful, safe gains at population scale [4] [7].