Which FDA‑approved therapies exist for early Alzheimer’s disease and what evidence supports their use?
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Executive summary
Two biologic therapies have been FDA‑approved to treat early Alzheimer’s disease: lecanemab (Leqembi®) and donanemab (Kisunla™), both monoclonal antibodies that target and clear beta‑amyloid plaques and were studied in people with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease with confirmed amyloid pathology [1] [2] [3]. Clinical trials show both drugs reduce amyloid and produce modest but statistically significant slowing of cognitive and functional decline in early‑stage patients, while safety, patient selection, cost and access remain important caveats echoed across regulatory and clinical sources [1] [4] [5] [6].
1. The new disease‑modifying category: what the approvals are and whom they target
Lecanemab (marketed as Leqembi) received traditional FDA approval after a confirmatory Phase 3 trial (CLARITY‑AD/Study 301) demonstrated clinical benefit, and its labeling specifies use in patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease with confirmed elevated brain amyloid [1] [3]. Donanemab (marketed as Kisunla) won FDA approval for adults with early symptomatic Alzheimer’s disease—defined as MCI or mild dementia—with trials enrolling participants who had biomarker confirmation of Alzheimer’s pathology [2] [4]. Both drugs are intravenous monoclonal antibodies directed at amyloid beta and were tested specifically in early‑stage disease, and regulators note there are no safety or effectiveness data for starting them outside the studied stages [1] [7].
2. The evidence for lecanemab: trials, effect size, and regulatory reasoning
The FDA converted lecanemab to full approval after the CLARITY‑AD confirmatory Phase 3 trial showed statistically significant slowing of decline on cognitive and functional measures over 18 months, with pooled and secondary endpoint improvements cited by the agency and the sponsors [1] [5]. Published summaries and regulatory statements quantify that lecanemab slowed disease progression (variously reported as ~24–26% slowing on prespecified endpoints) and reduced amyloid, leading FDA reviewers to call the result a verification that an amyloid‑targeting drug can show clinical benefit [1] [5]. The FDA and professional sources emphasize that the benefit was demonstrated in the early symptomatic population and requires biomarker confirmation of amyloid [1] [3].
3. The evidence for donanemab: trials, outcomes, and practical notes
Donanemab’s approval rested on the TRAILBLAZER‑ALZ program including a large Phase 3 study in which patients treated with Kisunla showed statistically significant reductions in clinical decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) and component measures at Week 76 versus placebo (iADRS difference 2.92, p<0.0001; ADAS‑Cog13 −1.33, p=0.0006; ADCS‑iADL 1.70, p=0.0001), and subgroups with lower tau burden appeared to derive larger relative benefit [2] [4]. Eli Lilly highlights that donanemab can be dosed monthly and in trials produced amyloid clearance that, for some patients, permitted stopping therapy when plaques were removed—an approach the company frames as reducing treatment burden [4].
4. How these drugs compare to older symptomatic medications
Traditional symptomatic drugs—cholinesterase inhibitors (like donepezil, rivastigmine) and memantine—remain FDA‑approved for cognitive or behavioral symptoms in Alzheimer’s but do not target amyloid and were developed to mitigate symptoms rather than slow underlying disease progression; clinical reviews list these older agents alongside the newer anti‑amyloid antibodies as the two broad categories of FDA‑approved treatments [8] [9]. Regulatory and advocacy summaries stress that lecanemab and donanemab are the first widely accepted examples of therapies that address underlying biology in early disease rather than solely providing symptomatic relief [7] [9].
5. Safety, controversy, and system‑level constraints
Safety issues, heterogeneous efficacy across patient subgroups, and prior controversy around aducanumab’s approval have shaped the rollout and reimbursement landscape: aducanumab’s fast‑track approval in 2021 was contentious because cognitive benefit was unclear and adverse events were common, prompting restrictive Medicare coverage and close scrutiny of subsequent anti‑amyloid approvals [6]. Sources also note operational hurdles—need for biomarker confirmation (amyloid PET or CSF), infusion logistics, monitoring for amyloid‑related imaging abnormalities, and healthcare system readiness—that will constrain who can access these therapies in practice [6] [7] [10].
6. The bottom line: modest but meaningful gains, with real world limits
Regulatory and trial data collectively support that lecanemab and donanemab reduce brain amyloid and produce modest, statistically significant slowing of cognitive and functional decline in carefully selected patients with early Alzheimer’s disease, yet the magnitude of benefit, safety monitoring needs, patient selection criteria and cost/access barriers mean these are important but partial advances rather than cures—an interpretation reflected by FDA statements, sponsor reports and independent reviews [1] [2] [11] [6].