Lecanemab

Lecanemab (brand name Leqembi) is a humanized monoclonal antibody designed to bind soluble protofibrils and insoluble fibrils of amyloid beta for the treatment of early Alzheimer's disease in adults.^[1] Developed jointly by Eisai and Biogen, it received accelerated approval from the U.S. Food and Drug Administration (FDA) in January 2023 based on reductions in amyloid plaques observed via PET imaging, followed by conversion to traditional approval in July 2023 after confirmatory evidence of clinical benefit from the phase 3 CLARITY AD trial.^[2]^[3] The drug is administered via intravenous infusion biweekly initially, with maintenance dosing every four weeks approved in January 2025, and a subcutaneous formulation authorized in August 2025 to facilitate self-administration.^[4]^[5] In the CLARITY AD trial involving 1,795 participants with early Alzheimer's, lecanemab slowed cognitive and functional decline by 27% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale at 18 months compared to placebo, with reductions in amyloid markers and modest benefits on secondary outcomes like the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13).^[6] Long-term extension data up to four years indicate sustained slowing of decline and further amyloid clearance with continuous treatment, though absolute benefits remain small on a population level.^[7] These results represent the first phase 3 demonstration of clinical efficacy for an anti-amyloid therapy, supporting the amyloid cascade hypothesis through causal reduction of protofibrils posited to drive neurodegeneration.^[6] Treatment is associated with infusion-related reactions in approximately 26% of patients and amyloid-related imaging abnormalities (ARIA), including brain edema (ARIA-E) in 13% and microhemorrhages or superficial siderosis (ARIA-H) in 17%, with risks elevated up to threefold in APOE ε4 homozygotes.^[8] Three deaths linked to ARIA occurred in the trial, prompting FDA requirements for MRI monitoring and genotyping.^[9] Controversies persist regarding the clinical meaningfulness of the modest effect size—equivalent to delaying progression by about five to six months—versus risks, costs exceeding $26,000 annually, and ongoing skepticism about amyloid's causal primacy given prior trial failures and lack of robust correlation between plaque reduction and outcomes in some analyses.^[10]^[11] Independent assessments highlight increased adverse events, including ARIA, without proportional gains in quality-of-life metrics, underscoring debates on net benefit in real-world settings.^[12]^[13]

Medical Uses

Indications and Dosing

Lecanemab (Leqembi) is indicated for the treatment of Alzheimer's disease in adult patients with mild cognitive impairment or mild dementia stage of disease, following confirmation of amyloid beta pathology via amyloid PET imaging or cerebrospinal fluid testing.^[14]^[15] Treatment initiation is recommended in this early-stage population, as efficacy was demonstrated in clinical trials involving patients meeting these criteria.^[14] The U.S. Food and Drug Administration granted traditional approval on July 6, 2023, based on evidence of reduced clinical decline in early Alzheimer's disease.^[2] The recommended initiation dosage is 10 mg/kg body weight administered as an intravenous infusion over approximately 1 hour every 2 weeks, with no required titration.^[15]^[16] For patients completing at least 6 months (14 infusions) of biweekly intravenous dosing, maintenance options include intravenous 10 mg/kg every 4 weeks or subcutaneous 360 mg weekly via autoinjector (Leqembi Iqlik), approved by the FDA on September 3, 2025.^[17]^[18] Dosing adjustments are required for amyloid-related imaging abnormalities (ARIA), with temporary suspension or discontinuation based on severity, particularly in patients homozygous for the APOE ε4 allele who face higher ARIA risk.^[16]^[15] Premedication is not routinely recommended, but monitoring for hypersensitivity is advised during and post-infusion.^[16]

Clinical Efficacy Data

In the phase 2b Study 201, a randomized, double-blind, placebo-controlled trial involving 856 patients with early Alzheimer's disease (mild cognitive impairment due to AD or mild AD), lecanemab at doses up to 10 mg/kg biweekly over 18 months demonstrated dose-dependent reductions in brain amyloid burden via PET imaging, with the highest dose achieving a mean change of -84.9 centiloids from baseline compared to -2.9 for placebo (p<0.0001).^[19] On the primary endpoint of ADCOMS (Alzheimer's Disease Composite Score), the 10 mg/kg group showed a 0.02-point greater decline than placebo, which was not statistically significant overall but trended toward benefit in Bayesian analysis favoring efficacy at higher exposures.^[20] Secondary endpoints including ADAS-Cog13 (Alzheimer's Disease Assessment Scale-cognitive subscale) and CDR-SB (Clinical Dementia Rating-Sum of Boxes) indicated slower cognitive and functional decline at the highest dose, with 26% less decline on ADAS-Cog13 (least squares mean difference -1.6 points, posterior probability of benefit 96%).^[21] Sensitivity analyses confirmed consistency of these effects across various statistical methods and subgroups.^[22] The pivotal phase 3 Clarity AD trial (NCT03887455), enrolling 1,796 patients with early AD, evaluated lecanemab 10 mg/kg biweekly versus placebo over 18 months.^[6] The primary endpoint, change in CDR-SB from baseline to 18 months, showed a least squares mean difference of 0.45 points favoring lecanemab (-1.21 vs. -1.66 for placebo), equating to a 27% slower rate of decline (95% CI 0.24-0.67, p<0.001).^[6] Secondary endpoints corroborated this, with 1.2-point less decline on ADAS-Cog13 (p=0.03) and 1.6-point improvement on ADCS-MCI-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living for MCI-AD, p=0.01).^[6] In an amyloid PET substudy (n=698), lecanemab reduced plaque burden by a mean of -55.5 centiloids versus -3.0 for placebo at 18 months (p<0.001), with clearance sustained across timepoints.^[23] Bayesian analyses and post-hoc evaluations reinforced the probability of clinical benefit, particularly in APOE4 non-carriers and at higher amyloid levels at baseline.^[24] Open-label extension data from Clarity AD (up to 36 months total exposure) indicated continued slowing of decline, with a -0.95 CDR-SB difference versus projected placebo decline over three years, alongside further amyloid clearance to near-normal levels in many participants.^[25] Amyloid reduction correlated with clinical outcomes, supporting its role as a surrogate marker, though long-term functional impacts remain under evaluation.^[26] Overall, these results demonstrate modest but statistically robust efficacy in slowing early AD progression, primarily in amyloid-positive patients, without evidence of disease modification beyond amyloid targeting.^[6]

Adverse Effects and Risks

Amyloid-related imaging abnormalities (ARIA) encompass two primary subtypes observed with lecanemab treatment: ARIA with edema or effusions (ARIA-E), characterized by brain parenchymal or sulcal edema on MRI, and ARIA with hemorrhage (ARIA-H), involving microhemorrhages or superficial siderosis.^[6] These abnormalities are thought to arise from rapid clearance of amyloid plaques, potentially disrupting vascular integrity or perivascular spaces, though the exact causal mechanisms remain under investigation and are not fully elucidated by preclinical models alone.^[27] In the phase 3 Clarity AD trial involving 1,795 participants with early Alzheimer's disease, ARIA-E occurred in 12.6% of lecanemab-treated patients versus 1.7% on placebo, while ARIA-H was reported in 17.3% versus 9.0%.^[6] ^[8] Incidence varies significantly by apolipoprotein E ε4 (ApoE ε4) genotype, a key genetic risk factor for Alzheimer's. In Clarity AD, ARIA-E rates were 5.4% among ApoE ε4 non-carriers, 10.9% in heterozygotes, and 32.6% in homozygotes receiving lecanemab.^[28] Similarly, ARIA-H was more frequent in ApoE ε4 carriers, with isolated ARIA-H (without concurrent ARIA-E) occurring at higher rates in homozygotes compared to placebo in some analyses.^[29] ^[30] Most ARIA events (approximately 80-90%) are asymptomatic and detected via scheduled MRI surveillance, but symptomatic cases—manifesting as headache, confusion, dizziness, nausea, or seizures—affect about 20-30% of those with ARIA-E, with rare progression to serious outcomes like cerebral edema or macrohemorrhage.^[31] ^[32] ARIA typically emerges early in treatment, with ARIA-E peaking within 3-6 months, and is dose-dependent, correlating with higher amyloid removal rates.^[8] Management protocols emphasize MRI monitoring, particularly for ApoE ε4 homozygotes, who face elevated risks warranting pretreatment genetic testing and more frequent imaging (e.g., every 3 infusions initially).^[33] ^[28] In symptomatic or severe cases (e.g., marked edema or new hemorrhages), treatment interruption is recommended until resolution or stabilization, with resumption possible in milder instances after clinical and radiographic review; however, permanent discontinuation may be necessary for recurrent or high-grade events.^[32] Concomitant use of anticoagulants or antiplatelets increases hemorrhage risk, though data from Clarity AD showed no significant excess ICH incidence (0.9% versus 0.6% without such medications).^[34] FDA labeling mandates a Risk Evaluation and Mitigation Strategy (REMS) highlighting ARIA as a boxed warning, underscoring the need for vigilant neuroimaging over at least the first year of therapy.^[35] Real-world data post-approval, including case reports of ischemic stroke or atypical presentations, suggest ongoing vigilance, though trial-derived rates provide the primary evidence base without evidence of underreporting in controlled settings.^[36] ^[37]

Other Adverse Events

In the phase 3 Clarity AD trial, infusion-related reactions occurred in 26% of lecanemab-treated patients compared to 7% of those receiving placebo, with most events (96%) classified as mild to moderate and 75% occurring after the first infusion.^[6]^[16] Symptoms typically included fever, flu-like symptoms (such as chills, body aches, and joint pain), nausea, vomiting, dizziness, hypotension, hypertension, and oxygen desaturation; these reactions led to treatment discontinuation in approximately 1% of patients.^[16] Premedication with antihistamines or anti-inflammatory agents was not routinely required but could mitigate severity in some cases.^[6] Other common adverse reactions, reported in at least 5% of lecanemab-treated patients and at least 2% higher than placebo rates across pivotal trials, included headache (11-14% vs. 8-10%), cough (9% vs. 5%), diarrhea (8% vs. 5%), rash (6% vs. 4%), and nausea or vomiting (6% vs. 4%).^[16] Overall treatment-emergent adverse events were observed in 89% of the lecanemab group versus 82% in the placebo group, with trial-agent-related events in 45% versus 22%.^[6] Serious adverse events occurred in 14% of lecanemab-treated patients compared to 11% on placebo, though excluding ARIA, the difference was smaller and included isolated cases of serious infusion reactions (1.2% vs. 0%), atrial fibrillation (0.7% vs. 0.3%), syncope (0.7% vs. 0.1%), and angina pectoris (0.7% vs. 0%).^[6] Hypersensitivity reactions, potentially manifesting as angioedema, bronchospasm, or anaphylaxis, are contraindicated in patients with prior serious reactions to lecanemab or its excipients.^[16] Immunogenicity was notable, with anti-lecanemab antibodies detected in up to 41% of patients in earlier studies, including neutralizing antibodies in 25% of those seropositive, though impacts on pharmacokinetics, efficacy, or safety remain uncertain due to assay limitations.^[16] Deaths occurred at similar rates (0.7% lecanemab vs. 0.8% placebo), with none deemed related to the drug in trial analyses.^[6] Post-approval monitoring has identified no new major safety signals beyond trial findings, though real-world data continue to emphasize vigilance for infusion reactions and cardiovascular events in vulnerable populations.^[8]

Pharmacology

Mechanism of Action

Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to soluble amyloid-beta (Aβ) protofibrils, which are intermediate aggregates in the Aβ aggregation pathway and potent synaptotoxins implicated in neuronal injury.^[6] Its affinity for Aβ protofibrils is in the nanomolar range, approximately 200- to 1,000-fold higher than for Aβ monomers, enabling preferential targeting of toxic aggregated species over non-pathogenic soluble monomers.^[38] This selectivity extends to soluble Aβ oligomers and fibrils, though binding to Aβ40-enriched vascular fibrils is reduced compared to parenchymal protofibrils.^[39] By binding to protofibrils, lecanemab neutralizes their capacity to seed Aβ plaque formation and promotes the phagocytosis and clearance of amyloid plaques by microglia, thereby reducing overall Aβ burden in the brain.^[40] In preclinical models, this dual action—prevention of deposition and removal of existing aggregates—has been shown to mitigate synaptic loss and neuronal damage associated with protofibril toxicity.^[41] Unlike some anti-Aβ antibodies, lecanemab exhibits lower affinity for large, insoluble plaques relative to soluble protofibrils, potentially minimizing off-target effects while focusing on early pathogenic species.^[42]

Pharmacokinetics and Pharmacodynamics

Lecanemab is administered intravenously at a dose of 10 mg/kg every two weeks over approximately one hour, achieving steady-state serum concentrations after about six weeks with 1.4-fold systemic accumulation.^[16] The terminal half-life is 5 to 7 days, with mean clearance of 0.370 L/day (95% CI: 0.353-0.384 L/day) and central volume of distribution at steady-state of 3.24 L (95% CI: 3.18-3.30 L).^[16] Like endogenous immunoglobulin G, lecanemab undergoes degradation via proteolytic catabolic pathways without involvement of cytochrome P450 enzymes.^[43] Population pharmacokinetic modeling, based on data from phase 2 and 3 trials including over 2,000 participants, describes lecanemab kinetics using a two-compartment model with first-order elimination.^[44] Covariates such as body weight (exponent 0.403 on clearance), sex, albumin levels (exponent -0.243 on clearance), and anti-drug antibody status influence clearance, but these effects are not deemed clinically significant enough to warrant dose adjustments.^[44] ^[43] No dedicated studies evaluated pharmacokinetics in renal or hepatic impairment, though creatinine clearance and liver enzymes showed no meaningful impact in covariate analyses.^[16] Approximately 41% of patients developed anti-lecanemab antibodies, with 25% exhibiting neutralizing activity, potentially affecting exposure though data are limited by assay interference.^[16] Pharmacodynamically, lecanemab exposure correlates with dose- and time-dependent reductions in brain amyloid burden, as measured by amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR), with biweekly 10 mg/kg dosing yielding a least-squares mean reduction of 0.306 at 18 months versus placebo (p < 0.001).^[43] ^[44] Indirect response modeling with an Emax function (Emax = 1.54, EC50 = 75.0 µg/mL) links steady-state average concentrations to amyloid clearance, where higher exposures achieve greater SUVR reductions (e.g., 64.6% of patients reaching SUVR < 1.17 with biweekly versus 36.7% with monthly dosing) and slower recovery of amyloid post-treatment (half-life ~4 years).^[44] Treatment also alters plasma and cerebrospinal fluid biomarkers consistent with amyloid pathway modulation, including increased plasma Aβ42/40 ratio, reduced plasma and CSF phosphorylated tau-181 (p-tau181), and decreased CSF total tau, with changes proportional to exposure.^[16] ^[43] Exposure-response analyses from phase 2 data further associate higher lecanemab concentrations with attenuated clinical decline on scales such as Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), and Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14).^[43]

Development History

Preclinical Research and Early Trials

Lecanemab, originally designated BAN2401, originated from the murine monoclonal antibody mAb158, developed by BioArctic Neuroscience through screening hybridoma libraries for binders to amyloid-beta (Aβ) protofibrils generated from Arctic-mutated Aβ.^[45] In vitro studies demonstrated mAb158's high selectivity for soluble Aβ aggregates, including protofibrils and oligomers, with at least 1,000-fold preference over Aβ monomers or insoluble fibrils, enabling efficient clearance of protofibrils via phagocytosis without significant disruption of plaques.^[46] Humanization to BAN2401 preserved these binding characteristics, as confirmed by surface plasmon resonance assays showing equivalent affinity to mAb158.^[46] In preclinical animal models, particularly transgenic tg-ArcSwe mice expressing human Aβ with Swedish and Arctic mutations, passive immunization with mAb158 rapidly reduced soluble Aβ protofibril levels in brain tissue and cerebrospinal fluid by over 50% within 4 weeks of weekly dosing at 10 mg/kg, preceding reductions in insoluble amyloid deposits.^[47] Preventive treatment initiated before plaque onset prevented amyloid plaque formation and associated neuritic dystrophy, while therapeutic administration in aged mice cleared soluble protofibrils but yielded modest (approximately 20-30%) reductions in plaque burden only after prolonged dosing, highlighting dependence on early intervention.^[48] Ex vivo assays further showed mAb158 promoted microglial-mediated uptake of Aβ aggregates, reducing astrocytic accumulation and rescuing neuronal viability from Aβ-induced toxicity in co-culture systems.^[49] No evidence of exacerbated cerebral amyloid angiopathy or microhemorrhages was observed in these models at doses up to 30 mg/kg.^[38] Early clinical development began with Phase 1 trials evaluating BAN2401's safety, tolerability, pharmacokinetics, and pharmacodynamics. A single ascending dose study in healthy volunteers (up to 10 mg/kg intravenously) and patients with mild-to-moderate Alzheimer's disease (up to 15 mg/kg) reported no serious treatment-emergent adverse events attributable to amyloid modulation, with linear pharmacokinetics and dose-proportional increases in plasma Aβ protofibril clearance observed via proprietary ELISA assays.^[46] Multiple ascending dose cohorts in Alzheimer's patients confirmed tolerability at biweekly infusions up to 10 mg/kg, with preliminary pharmacodynamic data indicating peripheral reduction in free plasma Aβ42 levels, though central effects required further evaluation.^[46] These findings supported advancement to the adaptive Phase 2b Study 201 (NCT01767311), initiated in December 2012, which enrolled 856 patients with early Alzheimer's disease across doses of 2.5, 5, and 10 mg/kg biweekly, demonstrating dose-dependent amyloid removal on PET imaging and initial signals of cognitive stabilization at higher doses by 12 months, albeit with infusion reactions and ARIA events emerging as dose-limiting factors.^[50]^[20]

Pivotal Phase 3 Trials

The CLARITY AD trial (NCT03887455) served as the pivotal phase 3 confirmatory study for lecanemab, designed as an 18-month, multicenter, double-blind, randomized, placebo-controlled evaluation of its efficacy and safety in early Alzheimer's disease.^[6]^[51] Participants, numbering 1,795 in total, were adults aged 50 to 90 years with mild cognitive impairment or mild dementia attributed to Alzheimer's disease, evidenced by amyloid positivity confirmed via positron emission tomography (PET) or cerebrospinal fluid (CSF) analysis, alongside memory impairment at least 1 standard deviation below age-adjusted norms.^[6]^[51] Eligible individuals were randomized 1:1 to receive intravenous lecanemab at a dose of 10 mg/kg every two weeks or matching placebo, with stable use of symptomatic Alzheimer's treatments permitted but anti-amyloid therapies excluded.^[6] The primary efficacy endpoint was the change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score at 18 months, a global measure of cognition and function.^[6] Lecanemab demonstrated a statistically significant slowing of decline, with a least-squares mean change of 1.21 points versus 1.66 points for placebo (difference, −0.45 points; 95% confidence interval [CI], −0.67 to −0.23; P<0.001), equivalent to a 27% reduction relative to placebo.^[6] All key secondary endpoints were met with high statistical significance, including amyloid plaque reduction in a PET substudy (−55.48 centiloids for lecanemab versus +3.64 for placebo; difference, −59.12 centiloids; 95% CI, −62.64 to −55.60; P<0.001).^[6] Cognitive and functional outcomes further supported efficacy, as summarized below:

Endpoint	Lecanemab Least-Squares Mean Change	Placebo Least-Squares Mean Change	Difference (95% CI)	P-value
ADAS-cog14 (cognition)	4.14	5.58	−1.44 (−2.27 to −0.61)	<0.001
ADCOMS (composite cognition/function)	0.164	0.214	−0.050 (−0.074 to −0.027)	<0.001
ADCS-MCI-ADL (daily activities)	−3.5	−5.5	2.0 (1.2 to 2.8)	<0.001

Topline results were announced on September 27, 2022, with full publication following on November 29, 2022, confirming lecanemab's ability to modestly attenuate clinical progression while substantially lowering amyloid burden in early-stage disease.^[6] No other distinct pivotal phase 3 trials were conducted for lecanemab's core approval pathway, though supportive data from phase 2 studies informed its design.^[6]

Regulatory Approvals Timeline

Lecanemab received its first regulatory approval on January 6, 2023, when the U.S. Food and Drug Administration (FDA) granted accelerated approval for the treatment of Alzheimer's disease in patients with mild cognitive impairment or mild dementia, based on reductions in amyloid beta plaques as a surrogate endpoint.^[52] This was followed by traditional full approval on July 6, 2023, supported by clinical data from the Phase 3 Clarity AD trial demonstrating a 27% slower rate of disease progression on the Clinical Dementia Rating-Sum of Boxes scale.^[2] The next major approval occurred in Japan on September 25, 2023, by the Ministry of Health, Labour and Welfare (MHLW), marking the second country to authorize lecanemab for manufacturing and marketing in early Alzheimer's disease.^[53] China's National Medical Products Administration (NMPA) approved it on January 9, 2024, for mild cognitive impairment or mild dementia due to Alzheimer's, via priority review procedures.^[54] In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorization on August 22, 2024, for early Alzheimer's disease, relying primarily on Phase 3 trial data despite prior European Medicines Agency (EMA) advisory concerns.^[55] The European Commission approved lecanemab on April 16, 2025, following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in November 2024, after an initial negative recommendation in July 2024 was overturned.^[56] Subsequent developments included FDA approval for intravenous maintenance dosing (every four weeks after initial biweekly phase) on January 26, 2025, and for subcutaneous maintenance dosing in August 2025.^[17] ^[57] China's NMPA approved IV maintenance dosing on September 28, 2025.^[58] By late 2025, approvals extended to additional jurisdictions including South Korea, Hong Kong, Israel, United Arab Emirates, Mexico, and Macau.^[59]

Date	Jurisdiction	Key Details
January 6, 2023	United States (FDA)	Accelerated approval for amyloid reduction in early AD.
July 6, 2023	United States (FDA)	Traditional full approval based on clinical outcomes.
September 25, 2023	Japan (MHLW)	Approval for early AD; second country overall.
January 9, 2024	China (NMPA)	Priority approval for mild cognitive impairment or mild dementia.
August 22, 2024	United Kingdom (MHRA)	Marketing authorization for early AD.
April 16, 2025	European Union (EC)	Full approval post-CHMP positive opinion.
January 26, 2025	United States (FDA)	IV maintenance dosing approval.
August 2025	United States (FDA)	Subcutaneous maintenance dosing approval.
September 28, 2025	China (NMPA)	IV maintenance dosing approval.

Regulatory Status

United States

The U.S. Food and Drug Administration (FDA) granted accelerated approval to lecanemab-irmb (marketed as Leqembi) on January 6, 2023, for the treatment of Alzheimer's disease, based on its demonstrated reduction of amyloid beta plaques as a surrogate endpoint under the accelerated approval pathway for serious conditions addressing unmet medical needs.^[52] This approval applied to adult patients with mild cognitive impairment or mild dementia due to Alzheimer's disease, with administration via intravenous infusion approximately every two weeks. Due to risks of amyloid-related imaging abnormalities (ARIA), including brain edema and effusions, the FDA required a Risk Evaluation and Mitigation Strategy (REMS) program, mandating prescriber certification, patient monitoring with MRI scans before and during treatment, and enrollment in a registry to track ARIA incidence. On July 6, 2023, the FDA converted the accelerated approval to traditional full approval, confirming clinical benefit in slowing cognitive and functional decline as evidenced by the phase 3 Clarity AD trial, where lecanemab reduced decline by 27% on the Clinical Dementia Rating-Sum of Boxes scale over 18 months compared to placebo.^[2]^[6] This followed a unanimous recommendation from the Peripheral and Central Nervous System Drugs Advisory Committee in support of the benefit-risk profile, distinguishing lecanemab as the first amyloid-targeting monoclonal antibody to receive full FDA approval.^[60] The updated label retained warnings for ARIA, reported in 12.6% of patients (versus 1.6% placebo), with higher rates in APOE4 homozygotes, alongside requirements for genetic testing consideration and ongoing post-marketing surveillance.^[6] Subsequent supplemental approvals expanded dosing options. On January 26, 2025, the FDA approved intravenous maintenance dosing every four weeks following an initial 18-month biweekly regimen, supported by pharmacokinetic modeling predicting sustained amyloid clearance.^[4] On August 29, 2025, subcutaneous maintenance dosing was approved for patients completing the intravenous initiation phase, enabling self-administration via prefilled syringes or on-body injectors after training, with comparable bioavailability to intravenous routes.^[61] These updates aimed to improve long-term adherence while maintaining the core indication and safety mitigations.^[62]

European Union

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) initially issued a negative opinion on lecanemab's marketing authorisation application in July 2024, citing that the benefits did not outweigh the risks, particularly due to amyloid-related imaging abnormalities (ARIA).^[63] Following a re-examination requested by the applicant, the CHMP adopted a positive opinion on November 14, 2024, recommending approval for a restricted patient population where ARIA risks were lower.^[63] The European Commission granted marketing authorisation valid throughout the EU on April 15, 2025, determining that benefits exceeded risks with appropriate risk minimisation measures in place.^[64] Lecanemab is indicated for adults with mild cognitive impairment or mild dementia due to early Alzheimer's disease, confirmed by amyloid beta plaques via positron emission tomography or cerebrospinal fluid testing, and limited to those with one or no copies of the ApoE4 gene to reduce ARIA incidence.^[64] Efficacy is supported by the phase 3 Clarity AD trial, involving 1,795 patients, where lecanemab slowed cognitive decline by 27% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale after 18 months (mean increase of 1.22 points versus 1.75 for placebo in the relevant subgroup of 1,521 patients with one or no ApoE4 copies).^[63] Common adverse events include infusion-related reactions (affecting over 25% of patients) and ARIA, with ARIA-edema/effusion in 8.9% (versus 1.3% placebo) and ARIA-haemosiderin deposition in 12.9% (versus 6.8% placebo); the drug is contraindicated in patients with uncontrolled bleeding disorders or certain neuroimaging findings.^[63] Approval conditions mandate administration by specialists experienced in Alzheimer's care, with MRI scans required before initiation and after the 5th, 7th, and 14th infusions (or if symptoms arise), alongside genotyping for ApoE4 status.^[64] A controlled-access programme ensures monitoring compliance, and post-authorisation obligations include an EU-wide patient registry and a safety study to further evaluate long-term risks, particularly ARIA in real-world use.^[64] Initial launches occurred in Austria and Germany on August 25, 2025, marking the first EU markets for the drug.^[65] The restricted labelling reflects EMA's assessment that broader use, including in ApoE4 homozygotes (who face up to threefold higher ARIA risk), lacked sufficient benefit-risk justification.^[63]

Other Jurisdictions

In Japan, the Ministry of Health, Labour and Welfare approved lecanemab on September 25, 2023, for the treatment of mild cognitive impairment or mild dementia due to Alzheimer's disease, marking the second national approval worldwide following the United States.^[53]^[66] The approval was based on data from the phase 3 Clarity AD trial, with the drug launched commercially in December 2023.^[67] In China, the National Medical Products Administration granted marketing approval on January 9, 2024, through priority review procedures for early Alzheimer's disease, with commercial launch occurring in June 2024 under the trade name 乐意保 (Leqembi).^[54]^[68] A supplemental approval for intravenous maintenance dosing followed on September 29, 2025.^[69] The United Kingdom's Medicines and Healthcare products Regulatory Agency authorized lecanemab on August 22, 2024, for adults with early Alzheimer's disease who carry one or no copies of the apolipoprotein E4 gene, reflecting concerns over amyloid-related imaging abnormalities in homozygous carriers.^[70]^[71] This conditional approval relies on ongoing data collection for full assessment.^[72] In Australia, the Therapeutic Goods Administration initially declined approval in February 2025 citing insufficient evidence of net benefit, but reversed the decision on September 24, 2025, following a sponsor appeal and additional review.^[73]^[74] Additional approvals include South Korea, Hong Kong, Israel, the United Arab Emirates, Mexico, and Macau, primarily based on Clarity AD trial results without genotype restrictions in most cases.^[75]^[76] As of October 2025, Health Canada continues review without approval.^[77]

Scientific Debates and Controversies

Validation of Amyloid Hypothesis

The amyloid hypothesis posits that the accumulation of amyloid-beta (Aβ) peptides in the brain initiates a cascade leading to tau pathology, neurodegeneration, and clinical symptoms of Alzheimer's disease (AD).^[78] Lecanemab, a monoclonal antibody targeting soluble Aβ protofibrils and plaques, demonstrated in the phase 3 Clarity AD trial (conducted from 2019 to 2021, results published in 2023) a 27% slower rate of cognitive and functional decline over 18 months compared to placebo, measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale with a treatment difference of -0.45 points (95% CI -0.67 to -0.23; p<0.001).^[79] This trial involved 1,795 participants with early AD (mild cognitive impairment or mild dementia) confirmed by amyloid PET positivity, and lecanemab reduced brain amyloid burden by approximately 59 centiloids via PET imaging.^[19] Proponents argue that these findings provide direct evidence supporting the hypothesis, as amyloid clearance correlated with clinical benefits in a dose-dependent manner, distinguishing lecanemab from prior failed anti-amyloid therapies that lacked sufficient plaque removal.^[80] For instance, secondary endpoints showed improvements in cognition (ADAS-Cog13: -1.21 points) and daily functioning (ADCS-MCI-ADL: 2.0 points), suggesting interruption of the pathological cascade.^[79] Eisai's preclinical and mechanistic studies further indicate lecanemab neutralizes toxic protofibrils, reducing synaptic damage and microglial activation without excessive inflammation.^[81] However, critics contend that the modest effect size—equivalent to delaying progression by about six months—does not substantiate causation, as amyloid reduction may represent a biomarker effect rather than addressing root drivers like tau hyperphosphorylation or neuroinflammation.^[82] The trial reported amyloid-related imaging abnormalities (ARIA) in 12.6% of treated patients (ARIA-E in 12.5%, with symptomatic cases in 2.8%), including three deaths potentially linked to the therapy, raising questions about net benefit.^[79] Longitudinal data from extension studies remain limited, and the hypothesis faces scrutiny from decades of unsuccessful trials, with some researchers viewing amyloid as an epiphenomenon downstream of primary metabolic or vascular insults.^[11] Academic and industry entrenchment in amyloid-centric research, despite repeated setbacks, has been cited as potentially biasing interpretation toward validation claims.^[83] Empirical validation requires demonstrating that amyloid removal halts or reverses core neurodegeneration, which lecanemab has not achieved; tau PET imaging in subsets showed no significant change, and benefits wane post-treatment.^[84] Alternative views prioritize multifactorial etiology, with lecanemab's results interpreted as supportive but insufficient to overturn evidence from genetic, imaging, and autopsy studies challenging amyloid's primacy.^[85] Thus, while offering correlative evidence, lecanemab does not conclusively validate the hypothesis, prompting calls for broader therapeutic targets.^[86]

Efficacy Skepticism and Alternative Views

Critics have questioned the clinical meaningfulness of lecanemab's efficacy as demonstrated in the phase 3 Clarity AD trial, where it slowed cognitive decline by 27% relative to placebo on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale over 18 months, corresponding to an absolute difference of -0.45 points (1.21 vs. 1.66).^[6] ^[87] This effect size, while statistically significant, falls below thresholds often considered perceptible to patients or caregivers, with independent assessments rating the changes on CDR-SB and other scales as not clinically meaningful.^[88] ^[10] Moreover, the trial's relative risk reductions (e.g., 27% on CDR-SB, 26% on ADAS-Cog13) obscure the small absolute benefits, equivalent to delaying progression by roughly 4-7 months in early Alzheimer's, without evidence of reversal or stabilization.^[88] ^[72] Neurologists and researchers have expressed doubt about whether these outcomes justify widespread use, noting that lecanemab's benefits appear inferior to those of symptomatic treatments like donepezil in head-to-head comparisons of effect sizes.^[88] Matthew Schrag of Vanderbilt University has argued that "any reasonable assessment of the risks versus the benefit of this drug should lead people to be very sceptical of it," emphasizing the marginal gains amid infusion requirements and monitoring needs.^[72] Similarly, Lon Schneider of USC has highlighted the "tiny effect after 18 months," questioning projections of long-term utility, while Thomas Südhof of Stanford contends that continued dementia progression despite amyloid clearance undermines claims of robust efficacy.^[83] Alternative perspectives challenge the primacy of amyloid-beta clearance, positing that lecanemab's plaque reduction does not address multifactorial drivers of Alzheimer's pathology, such as tau tangles, synaptic loss, vascular issues, or inflammation.^[83] Observations that amyloid-positive individuals can maintain normal cognition, coupled with post-treatment disease advancement even after plaque clearance, suggest amyloid as neither necessary nor sufficient for cognitive decline.^[83] ^[13] Critics like Zaven Khachaturian, formerly of the National Institute on Aging, argue that entrenched amyloid focus has suppressed exploration of non-amyloid targets, potentially delaying more effective interventions.^[83] These views advocate prioritizing therapies targeting synaptic function or metabolic pathways over amyloid-centric approaches, given lecanemab's failure to halt underlying neurodegeneration.^[83]

Risk-Benefit Analysis Criticisms

Critics contend that lecanemab's clinical benefits, while statistically significant in the Clarity AD phase 3 trial, are too modest to offset the drug's safety risks, particularly amyloid-related imaging abnormalities (ARIA). The trial reported a 0.45-point mean difference on the 18-point Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale over 18 months, equating to a 27% relative reduction in decline versus placebo, but this absolute change has been deemed insufficiently meaningful for patients' daily functioning or quality of life by some analysts.^[6] ^[72] The Institute for Clinical and Economic Review (ICER) rated the evidence as promising but inconclusive for net health benefit, with a 12-3 panel majority concluding it inadequate compared to standard supportive care due to limited long-term data and uncertain real-world translation.^[89] ARIA events, including brain edema (ARIA-E) and hemorrhages (ARIA-H), occurred in 21.3% of lecanemab-treated patients versus 9.3% on placebo, with ARIA-E at 12.6% versus 1.7% and ARIA-H at 17.3% versus 10.7%.^[6] ^[90] Risks escalated markedly in APOE ε4 homozygotes, where ARIA-E incidence reached 66.7%, prompting recommendations against use in this genotype due to unfavorable risk-benefit ratios.^[91] Symptomatic ARIA affected about 2.8% of recipients, often necessitating MRI monitoring, treatment pauses, or hospitalization, while post-trial analyses linked at least three deaths to ARIA complications, exacerbated by concurrent anticoagulants.^[92] ^[93] Updated open-label extension data reported 24 total deaths across core and extension phases, with three attributed to ARIA and four deemed possibly treatment-related.^[94] Post-marketing pharmacovigilance has amplified concerns, revealing disproportionality signals for ARIA-H (microhemorrhages) and ARIA-E, alongside other adverse events, suggesting real-world risks may exceed trial estimates and underscoring the need for individualized risk assessment.^[95] Groups like Doctors for America have faulted the FDA's accelerated approval process for insufficient emphasis on these safety signals, arguing it prioritized surrogate amyloid reduction over robust clinical outcomes.^[96] Broader debates highlight that anti-amyloid therapies like lecanemab may not address Alzheimer's multifactorial pathology, rendering the amyloid hypothesis' validation—and thus the drug's mechanistic rationale—questionable amid persistent efficacy skepticism.^[13]

Societal and Economic Aspects

Access and Pricing

In the United States, lecanemab (branded as Leqembi) has been commercially available since 2023 following FDA full approval, with eligibility limited to patients with mild cognitive impairment or mild Alzheimer's disease due to amyloid plaques, confirmed via amyloid PET imaging or cerebrospinal fluid testing.^[97] The drug requires biweekly intravenous infusions initially, transitioning to maintenance dosing, though a subcutaneous formulation (Leqembi IQLIK) was approved in August 2025 for at-home self-administration after an initial clinic dose, potentially improving access by reducing clinic dependency.^[98] Access remains uneven due to limited infusion sites and diagnostic facilities; for instance, a 2025 analysis in Georgia identified disparities across counties, with rural areas facing greater barriers to amyloid PET scans and treatment centers.^[99] The annual U.S. list price for lecanemab is $26,500, covering approximately one year of treatment at full dose, excluding administration and monitoring costs.^[100] Medicare Part B covers 80% of the approved amount after the 2025 deductible of $257, leaving beneficiaries with roughly $5,300 in annual out-of-pocket coinsurance for the drug alone, though supplemental plans or assistance programs from Eisai can reduce this further.^[101] Medicare spending projections estimate $3.5 billion annually if uptake reaches certain levels, factoring in provider markups and monitoring for risks like amyloid-related imaging abnormalities (ARIA).^[100] Private insurers vary in coverage, with some requiring prior authorization based on clinical criteria. Internationally, access expanded following European Commission conditional approval in April 2025, with initial launches in Austria and Germany in August 2025, though national pricing and reimbursement negotiations continue amid cost-effectiveness concerns; one estimate projected €133 billion in EU-wide implementation costs, equivalent to half of total pharmaceutical spending.^[102]^[65] In Japan, where approval preceded in 2023, reimbursement prices were reduced by 15% effective November 2025 following a health technology assessment deeming it the highest cut among evaluated therapies, aiding broader adoption under high-cost care systems.^[103] Approvals in regions like the UK, South Korea, and China have enabled limited availability by mid-2025, but subcutaneous options and real-world data collection are ongoing to address infusion logistics and equity.^[104] Overall, high costs and infrastructure needs constrain access, with subcutaneous lecanemab projected to save $72,891–$80,925 per patient over four years versus intravenous due to reduced administration expenses.^[105]

Public and Expert Reception

Expert reception of lecanemab has been divided, with proponents highlighting its demonstration of modest slowing of cognitive decline in early Alzheimer's disease as a landmark achievement validating the amyloid hypothesis, while critics emphasize the limited clinical meaningfulness of benefits relative to safety risks. In June 2023, an FDA advisory committee unanimously endorsed lecanemab's efficacy and clinical benefit based on phase 3 trial data showing a 27% reduction in decline on the Clinical Dementia Rating-Sum of Boxes scale over 18 months. Neurologists such as Zaldy Tan at Cedars-Sinai described it as "a positive step forward" despite imperfections, noting its role in clearing amyloid plaques. Conversely, experts including Michael Greicius have argued that while amyloid removal occurs, the overall benefit remains unproven in altering disease trajectory, potentially diverting resources from alternative pathologies. In Europe, the EMA's initial negative opinion in July 2024 cited insufficient evidence of efficacy outweighing risks like amyloid-related imaging abnormalities (ARIA), prompting criticism from researchers like Bart De Strooper for excessive risk aversion; the agency later recommended conditional approval in November 2024 for a narrower population.^[106]^[6]^[107]^[108]^[13]^[63] Patient advocacy groups have generally welcomed lecanemab as a potential tool against progression, influencing regulatory decisions amid desperation for options, though real-world experiences reveal frequent tolerability issues tempering enthusiasm. The Alzheimer's Association supported FDA traditional approval in July 2023, viewing it as advancing disease-modifying therapies. Patient reports from forums and reviews describe manageable infusion reactions like headaches in up to 37% after initial doses, but also highlight severe ARIA events, including macrohemorrhages and one reported death in early post-approval monitoring of 71 patients. In a retrospective clinic series, 88% of side effects emerged within 24 hours, with neuropsychiatric symptoms and tremors noted beyond trial data. UK patient groups via Alzheimer's Society expressed hope for slowed decline but noted NICE's rejection in 2025 due to unfavorable cost-benefit, limiting access. Overall, while families report sustained treatment for potential long-term gains, concerns over monitoring requirements and ApoE4 genotype risks have led to discontinuation rates around 20-30% in observational settings.^[109]^[2]^[93]^[110]^[111]^[112]^[113]

Nomenclature and Availability

Lecanemab is the international nonproprietary name (INN) assigned by the World Health Organization for this humanized monoclonal antibody targeting amyloid-beta protofibrils. The drug was originally developed under the code name BAN2401 by Eisai and Biogen before receiving its INN designation.^[114] In regulatory contexts, it is specified as lecanemab-irmb in the United States to denote its unique biologic characteristics under FDA nomenclature for proprietary names.^[115] The primary brand name for lecanemab is Leqembi, marketed by Eisai in collaboration with Biogen.^[2] Formulations include intravenous infusions for initial and maintenance dosing, with a subcutaneous injection variant (Leqembi IQLIK) approved for maintenance in the US in August 2025 and made available starting October 2025.^[98]^[61] As of October 2025, lecanemab (Leqembi) has received regulatory approval in 50 countries worldwide, including the United States (full FDA approval July 2023), the European Union (EMA authorization April 15, 2025), Japan, China, and Great Britain, with ongoing reviews in 10 additional jurisdictions.^[98]^[64] In the US, broader Medicare coverage followed traditional FDA approval, facilitating access for eligible early Alzheimer's patients.^[97] Availability remains limited by requirements for specialized infusion centers, amyloid confirmation via PET or CSF testing, and monitoring for risks like amyloid-related imaging abnormalities (ARIA).^[116]

Ongoing Research

Long-Term Extension Studies

The CLARITY AD open-label extension (OLE) study, designated NCT03887455, evaluates the long-term safety, tolerability, and efficacy of lecanemab in participants with early Alzheimer's disease who completed the 18-month core phase of the phase 3 CLARITY AD trial.^[51] Enrolling 1,385 participants, the OLE provides lecanemab at 10 mg/kg biweekly following the core period, with assessments extending up to 48 months or longer to assess sustained effects on cognition, function, and amyloid pathology.^[117] Data through 24 months indicate that participants receiving continuous lecanemab, including those switching from placebo, maintained reductions in amyloid plaque burden and showed slower decline across clinical endpoints such as the CDR-SB and ADAS-Cog13 compared to projected natural history.^[117] Four-year treatment data, presented at the Alzheimer's Association International Conference (AAIC) in July 2025, demonstrate that continuous lecanemab administration from the core study onward resulted in participants remaining in the early stage of Alzheimer's disease longer than expected based on untreated progression models.^[118] Over three to four years, lecanemab-treated groups exhibited approximately 27% less decline on the CDR-SB scale relative to external controls, with benefits accruing in low-tau subgroups and on functional measures like the ADCS-MCI-ADL, where 51% showed improvement or stability.^[119] These outcomes suggest a potential disease-modifying effect, as amyloid clearance persisted and correlated with moderated clinical progression, though absolute changes remain modest and long-term data derive primarily from sponsor analyses.^[7] Safety profiles in the OLE remained consistent with core study findings, with no new signals emerging over extended exposure. Amyloid-related imaging abnormalities (ARIA-E and ARIA-H) occurred primarily early in treatment, with incidence rates of ARIA-E at 12.6% and ARIA-H at 17.3% through 36 months, decreasing over time and mostly asymptomatic or mild.^[94] Infusion-related reactions affected about 26% of participants, resolving without discontinuation in most cases, and mortality rates aligned with early Alzheimer's populations, with no lecanemab-attributable deaths reported.^[120] Independent reviews note that while ARIA risk is higher in APOE4 homozygotes, long-term monitoring supports tolerability, though real-world applicability requires further validation beyond controlled settings.^[121]

Real-World Evidence and Comparisons

Real-world evidence for lecanemab, administered as Leqembi, has emerged from post-approval observational studies and registries, primarily in the United States following its full FDA approval on January 6, 2023. A retrospective multicenter study across 15 U.S. medical centers, involving 178 patients with early Alzheimer's disease treated for up to two years as of July 2025, reported that 83.6% of participants maintained or improved their clinical stage, with 76.9% stable and 6.7% transitioning from mild dementia to mild cognitive impairment.^[122]^[123] Baseline characteristics included 57.6% with mild cognitive impairment due to Alzheimer's and 42.4% with mild Alzheimer's dementia, with a mean age of 71 years. Cognitive trajectories in early real-world use, tracked over nine months in another cohort, aligned with the phase 3 Clarity AD trial, showing gradual decline rates.^[124] Safety profiles in real-world settings have mirrored trial data, with amyloid-related imaging abnormalities (ARIA) occurring at rates consistent with controlled studies, including approximately 12-17% incidence of symptomatic ARIA with edema or effusion.^[125] Post-marketing pharmacovigilance from the FDA Adverse Event Reporting System (FAERS) through early 2025 identified disproportionate signals for ARIA, cerebral hemorrhage, and hypersensitivity, though causality remains unestablished without controlled comparisons.^[126] In a tertiary hospital cohort of 86 patients initiated on treatment between July 2023 and January 2025, administration proved feasible with no unexpected severe adverse events beyond trial-known risks.^[127] Regulatory bodies, such as the UK's Medicines and Healthcare products Regulatory Agency, have restricted use in APOE ε4 homozygotes due to elevated ARIA risks outweighing benefits in that subgroup.^[128] Direct real-world comparisons to other anti-amyloid therapies like donanemab (Kisunla, approved July 2, 2024) remain limited due to the latter's shorter post-approval period and differing protocols, such as donanemab's plaque-dependent dosing cessation versus lecanemab's biweekly maintenance. Pre-approval network meta-analyses suggested donanemab's edge in cognitive slowing (e.g., greater CDR-SB improvements) but higher ARIA rates (up to 37% with brain swelling or bleeding), while lecanemab excelled in amyloid PET reduction.^[129]^[130] Versus non-anti-amyloid standards like donepezil, lecanemab demonstrates superior slowing of decline in early disease stages, though absolute benefits are modest (e.g., 27% reduction in progression risk over 18 months in trials extrapolated to real-world stability data). Ongoing registries may clarify head-to-head outcomes, but current evidence underscores lecanemab's consistency with trial efficacy amid practical challenges like infusion logistics and monitoring demands.^[131]