A Comprehensive Clinical and Pharmacological Review of Lecanemab (Leqembi) for the Treatment of Early Alzheimer's Disease

Executive Summary

Lecanemab, marketed as Leqembi, represents a significant, albeit complex, advancement in the therapeutic landscape for Alzheimer's disease (AD). As a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, its development is predicated on the amyloid cascade hypothesis, but with a refined focus. Lecanemab's novel mechanism involves high-affinity, selective binding to soluble amyloid-beta (Aβ) protofibrils, the species increasingly considered to be the most neurotoxic. This targeted action is designed to neutralize these toxic oligomers, prevent their aggregation into insoluble plaques, and facilitate their clearance from the brain.

The pivotal Phase 3 Clarity AD trial provided the foundational evidence for Lecanemab's approval, demonstrating a statistically significant slowing of cognitive and functional decline in patients with early AD. Over 18 months, treatment resulted in a 27% reduction in the rate of decline on the primary endpoint, the Clinical Dementia Rating-Sum of Boxes (CDR-SB), compared to placebo. This clinical benefit was corroborated by robust biomarker evidence, including a profound reduction in brain amyloid plaque burden and favorable changes in downstream markers of tau pathology.

However, the clinical utility of Lecanemab is tempered by a significant and complex safety profile, dominated by the risk of Amyloid-Related Imaging Abnormalities (ARIA). The prescribing information carries a Boxed Warning for ARIA, which manifests as vasogenic edema (ARIA-E) or hemosiderin deposition, including microhemorrhages (ARIA-H). The incidence of ARIA is strongly correlated with a patient's apolipoprotein E ε4 (APOE ε4) genotype, with homozygotes facing a substantially elevated risk. This has necessitated the integration of pharmacogenomic testing into the standard of care for this therapy, alongside a rigorous regimen of magnetic resonance imaging (MRI) for monitoring.

Lecanemab's regulatory journey has been divergent globally, achieving traditional approval from the U.S. Food and Drug Administration (FDA) while facing initial rejection and subsequent restricted approval from the European Medicines Agency (EMA), reflecting international debate over the balance of its modest clinical benefit against its safety risks and high cost. Priced at approximately $26,500 annually in the U.S., with substantial additional costs for administration and monitoring, Lecanemab poses considerable economic and logistical challenges to patients and healthcare systems. This report provides an exhaustive review of Lecanemab, synthesizing the pharmacological data, clinical trial evidence, safety profile, regulatory history, and clinical use guidelines to offer a comprehensive perspective on its role in the management of early Alzheimer's disease.

1. Drug Profile and Development

1.1. Identification and Properties

Lecanemab is a biologic therapeutic agent developed for Alzheimer's disease. It is a humanized IgG1 monoclonal antibody, signifying that it originates from a murine (mouse) antibody (mAb158) that has been genetically engineered to contain human protein sequences, thereby reducing the potential for immunogenicity in patients.[1] This classification defines its fundamental characteristics as a large-molecule protein drug that requires parenteral administration. Its key identifiers and physicochemical properties are summarized in Table 1.

Parameter	Value / Description	Source(s)
Generic Name	Lecanemab	3
Brand Name	Leqembi	3
Developmental Codes	BAN2401, lecanemab-irmb	3
Drug Class	Alzheimer Disease Agents, Monoclonal Antibodies	4
Drug Type	Biotech, Whole Antibody	3
Source (Origin)	Humanized	3
CAS Number	1260393-98-3	3
DrugBank ID	DB14580	3
UNII	12PYH0FTU9	3
Molecular Formula	C6544​H10088​N1744​O2032​S46​	3
Molar Mass	147181.62 g·mol⁻¹ (approx. 147 kDa)	3
Developers	Eisai, Biogen, BioArctic	3

The designation as an IgG1 antibody is functionally significant. The IgG1 isotype is known to effectively engage the fragment crystallizable (Fc) region receptors on immune cells, such as microglia in the central nervous system. This engagement is a critical step in antibody-dependent cell-mediated phagocytosis, the process by which microglia are activated to clear the antibody-target complex from the brain parenchyma. Thus, the very classification of Lecanemab as an IgG1 antibody provides a direct mechanistic basis for its therapeutic action of clearing amyloid aggregates.[8] Concurrently, the proteinaceous and partially non-human origin of the antibody underpins the potential for immune-mediated infusion-related reactions, a common adverse event associated with its use.[3]

1.2. Development and Commercialization

Lecanemab is the product of a long-term, multi-company strategic collaboration that began in 2005 between the Swedish research company BioArctic and the Japanese pharmaceutical company Eisai.[9] In 2007, Eisai obtained global rights to develop, manufacture, and market Lecanemab for the treatment of AD.[9] The partnership was later expanded to include the U.S.-based biotechnology company Biogen.[1]

Under the terms of the collaboration, Eisai serves as the lead entity for the global development of Lecanemab and for regulatory submissions worldwide. Following approval, Eisai and Biogen co-commercialize and co-promote the product in major markets. A key aspect of the agreement is that Eisai retains final decision-making authority over the product's lifecycle.[10] This tripartite alliance combines BioArctic's foundational research, Eisai's clinical development and regulatory leadership, and Biogen's expertise in neurology and commercialization.

2. Pharmacology and Mechanism of Action

2.1. The Amyloid Cascade Hypothesis: Therapeutic Context

The scientific rationale for Lecanemab is firmly grounded in the amyloid cascade hypothesis of Alzheimer's disease.[4] This hypothesis, which has guided AD research for decades, posits that the initiating pathological event is an imbalance between the production and clearance of amyloid-beta (Aβ) peptides in the brain.[4] These peptides are proteolytic fragments of the larger amyloid precursor protein (APP). Over time, Aβ monomers misfold and aggregate into a spectrum of species with increasing size and insolubility: from small, soluble oligomers to larger soluble protofibrils, and ultimately to the insoluble amyloid fibrils that constitute the core of senile plaques—a defining neuropathological hallmark of AD.[3] This accumulation of Aβ is believed to trigger a cascade of downstream events, including the hyperphosphorylation and aggregation of tau protein into neurofibrillary tangles, synaptic dysfunction, neuroinflammation, and widespread neuronal death, which collectively manifest as progressive cognitive and functional decline.[8]

2.2. Molecular Target and Binding Affinity

Lecanemab is an amyloid beta-directed antibody that distinguishes itself from previous therapies through its highly selective molecular target.[3] Its primary innovation is its strong binding affinity for

soluble Aβ protofibrils, a large, intermediate aggregated species (75-5000 kDa) that is considered to be one of the most neurotoxic forms of Aβ.[1] These protofibrils are implicated in direct neuronal injury, synaptic disruption, and the potentiation of neuroinflammation, potentially causing damage even before the formation of mature, insoluble plaques.[16]

Lecanemab's binding profile is characterized by remarkable selectivity. It binds with 10 to 15 times higher affinity to protofibrils compared to the insoluble Aβ fibrils found in established plaques, and with over 1000-fold greater selectivity for protofibrils than for Aβ monomers.[1] This preferential targeting of a highly toxic, soluble Aβ species represents a refinement of the amyloid hypothesis. Instead of focusing solely on the removal of the relatively inert "tombstone" plaques, Lecanemab is designed to neutralize the more dynamic and actively damaging "aggressor" species in the amyloid cascade. This specific choice of target is a plausible explanation for the positive clinical outcomes observed in the Clarity AD trial, offering renewed, albeit more nuanced, support for the central role of Aβ in AD pathogenesis.

2.3. Proposed Mechanisms of Clearance

By targeting Aβ protofibrils, Lecanemab is thought to exert its therapeutic effect through a dual mechanism that both prevents new plaque formation and clears existing pathology.[8]

1. Neutralization and Inhibition of Aggregation: By binding with high affinity to soluble protofibrils, Lecanemab effectively sequesters these toxic species, preventing them from further aggregating into larger, insoluble amyloid plaques. This action intercepts the pathological cascade at a critical, early stage of plaque formation.[8]
2. Immune-Mediated Clearance: Once bound to Aβ aggregates, the Lecanemab-Aβ complex acts as a signal for the brain's innate immune system. The Fc region of the antibody is recognized by receptors on microglia, the brain's primary phagocytic cells, triggering them to engulf and clear the toxic aggregates from the brain parenchyma.[8]

While its highest affinity is for protofibrils, Lecanemab also binds to and facilitates the removal of existing insoluble plaques. This effect is robustly demonstrated by the significant reduction in brain amyloid burden as measured by positron emission tomography (PET) imaging in clinical trials.[3] This combined action—neutralizing soluble toxins and clearing insoluble plaques—is believed to reduce the overall amyloid-driven neuropathology, thereby slowing the progression of downstream neurodegeneration and clinical decline.[2]

The very biological process that makes Lecanemab effective, however, is also inextricably linked to its primary safety concern. The clearance of Aβ from both the brain parenchyma and the walls of cerebral blood vessels (a condition known as cerebral amyloid angiopathy, or CAA) can transiently disrupt vascular integrity. This can lead to increased permeability of the blood-brain barrier, resulting in localized inflammation, fluid shifts (edema), and microhemorrhages. This phenomenon, known as ARIA, is a direct consequence of the drug's potent amyloid-clearing mechanism, creating an inherent and delicate balance between therapeutic efficacy and potential toxicity.[16]

2.4. Pharmacokinetics

Lecanemab is administered via intravenous infusion at a weight-based dose of 10 mg/kg every two weeks.[4] Pharmacokinetic analyses from clinical trials have established key parameters for its use:

• Kinetics and Steady State: The drug follows first-order elimination kinetics. At the recommended biweekly dosing schedule, it reaches steady-state plasma concentrations after the third dose (i.e., at 6 weeks).[17]
• Half-Life: The mean terminal half-life of Lecanemab is approximately 5.3 days.[17]
• Metabolism and Elimination: As a monoclonal antibody, Lecanemab is catabolized into smaller peptides and amino acids via proteolytic pathways throughout the body. Its clearance is not dependent on hepatic or renal function, an important consideration for the elderly patient population who may have comorbidities affecting these organs.[17]
• Immunogenicity: During the 18-month Clarity AD study, anti-drug antibodies (ADAs) were detected in approximately 25% of patients treated with Lecanemab. The clinical significance of these ADAs on the drug's efficacy or safety profile is not yet fully understood.[17]

3. Pivotal Clinical Evidence: The Clarity AD Trial (NCT03887455)

The regulatory approval and clinical adoption of Lecanemab are primarily based on the results of the landmark Clarity AD study, a large-scale, global Phase 3 trial designed to confirm its efficacy and safety in early Alzheimer's disease.

3.1. Study Design and Patient Population

• Trial Design: Clarity AD was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted over an 18-month core treatment period. Participants who completed the core study were eligible to enroll in an ongoing open-label extension (OLE) phase to evaluate long-term outcomes.[20]
• Participants: The trial enrolled 1,795 individuals between the ages of 50 and 90. The study population was specifically defined as having "early Alzheimer's disease," which included patients with either Mild Cognitive Impairment (MCI) due to AD or mild-stage AD dementia.[3]
• Inclusion Criteria: A critical inclusion criterion was the confirmed presence of brain amyloid pathology, established by either amyloid PET imaging or cerebrospinal fluid (CSF) analysis. Participants were also required to meet specific scoring thresholds on cognitive assessments, such as a Mini-Mental State Examination (MMSE) score of 22 or higher.[22] The trial enrolled a population representative of clinical practice, with 63.7% of patients having at least two comorbid conditions. In the U.S., the study made efforts to recruit a diverse population, with 22.5% of participants identifying as Hispanic and 4.5% as Black.[22]
• Intervention: Participants were randomized on a 1:1 basis to receive either Lecanemab at a dose of 10 mg/kg via intravenous infusion every two weeks (n=898) or a matching placebo (n=897).[20]

3.2. Primary and Key Secondary Efficacy Endpoints

The Clarity AD trial successfully met its primary endpoint and all key secondary endpoints, demonstrating a consistent, statistically significant benefit of Lecanemab over placebo.

• Primary Endpoint: The primary outcome measure was the change from baseline to 18 months on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a comprehensive scale that assesses both cognitive and functional abilities across six domains.
• Result: The mean increase (worsening) in CDR-SB score was 1.21 in the Lecanemab group, compared to 1.66 in the placebo group. This resulted in an adjusted mean difference of -0.45 (95% Confidence Interval [CI], -0.67 to -0.23; P<0.001).[25]
• Interpretation: This statistically robust result translates to a 27% slowing in the rate of clinical decline for patients treated with Lecanemab compared to those on placebo.[24] The therapeutic benefit was evident as early as 6 months into treatment and the separation between the groups continued to widen throughout the 18-month study period.[22]
• Key Secondary Endpoints: The positive finding on the primary endpoint was supported by statistically significant results across all key secondary endpoints (P<0.001 for all), indicating a broad effect on cognition, function, and disease biomarkers.[3] The key clinical secondary endpoints demonstrated:
• A 26% slowing of cognitive decline as measured by the Alzheimer's Disease Assessment Scale–Cognitive Subscale 14 (ADAS-Cog14).[22]
• A 37% slowing of functional decline in activities of daily living, as measured by the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL).[22]

The central debate surrounding Lecanemab stems from these results. While the trial was an unambiguous statistical success, marking a historic achievement in a field characterized by failures, the absolute magnitude of the clinical benefit—a 0.45-point difference on an 18-point scale over 18 months—is considered modest. This has led to extensive discussion regarding its clinical meaningfulness and whether such a change would be perceptible to an individual patient or their family. This disconnect between statistical significance at a population level and perceived impact at an individual level is a primary driver of the divergent opinions on the drug's value among clinicians, patients, and regulatory and reimbursement bodies worldwide.[25]

3.3. Biomarker and Imaging Outcomes

The clinical findings were strongly supported by dramatic changes in AD-related biomarkers, confirming robust target engagement and biological activity.

• Amyloid Plaque Reduction: In a PET substudy involving 698 participants, Lecanemab treatment led to a profound and rapid reduction in brain amyloid plaque burden. The adjusted mean difference versus placebo at 18 months was -59.1 centiloids (95% CI, -62.6 to -55.6).[26] This marked reduction in the surrogate endpoint of amyloid plaques was the basis for the FDA's initial accelerated approval and its successful linkage to clinical benefit in the full trial dataset validated this regulatory pathway.[7]
• Downstream Pathological Changes: Lecanemab also demonstrated effects on biomarkers of pathology downstream of amyloid. Treatment was associated with a reduction in markers of tau pathology, including plasma phosphorylated tau 181 (p-tau181), and a slowing of tau accumulation in the brain on tau PET scans.[22] This provides compelling evidence that removing upstream Aβ pathology can mitigate downstream tau-related neurodegeneration, thereby reinforcing the mechanistic link between target engagement and clinical outcome.

3.4. Quality of Life and Caregiver Burden Outcomes

Exploratory analyses from Clarity AD suggested that the clinical benefits of Lecanemab extended to patient-reported outcomes and caregiver burden.

• Health-Related Quality of Life (HRQoL): At 18 months, patients treated with Lecanemab reported less decline in HRQoL. Compared to placebo, there was a 49% smaller decline on the European Quality of Life-5 Dimensions (EQ-5D-5L) scale and a 56% smaller decline on the Quality of Life in AD (QOL-AD) scale.[20]
• Caregiver Burden: Study partners of participants receiving Lecanemab reported a 38% smaller increase in caregiver burden, as measured by the Zarit Burden Interview (ZBI).[20] These findings suggest that the modest slowing of disease progression can translate into tangible benefits for both patients and their families.

3.5. Open-Label Extension (OLE) Findings

Data from the ongoing OLE of Clarity AD provide insights into the long-term effects of Lecanemab.

• Sustained Benefit: The clinical benefit observed in the core study was maintained for up to 36 months of continuous treatment.[32]
• Disease-Modifying Effect: A "delayed-start" analysis compared participants who received Lecanemab from the beginning ("early start") with those who were on placebo during the core study and then switched to Lecanemab in the OLE ("delayed start"). The analysis showed that the clinical separation between the two groups achieved at 18 months was maintained over time. The delayed-start group did not "catch up" to the early-start group, following a similar trajectory of decline but from a lower baseline. This finding is consistent with a disease-modifying effect, suggesting that earlier initiation of treatment provides a lasting benefit that cannot be fully recovered with later treatment.[32]

The key efficacy outcomes from the Clarity AD trial are summarized in Table 2.

Endpoint	Lecanemab Group (Mean Change from Baseline)	Placebo Group (Mean Change from Baseline)	Difference vs. Placebo (95% CI)	% Slowing of Decline	P-value
CDR-SB (Primary)	1.21	1.66	-0.45 (-0.67 to -0.23)	27%	<0.001
ADAS-Cog14	Data not specified	Data not specified	Data not specified	26%	<0.001
ADCS-MCI-ADL	Data not specified	Data not specified	Data not specified	37%	<0.001
Amyloid Burden on PET (centiloids)	-55.48	3.64	-59.12 (CI not directly comparable)	N/A	<0.001

Note: Specific mean change values for secondary endpoints were not consistently available across sources, but the percentage slowing and statistical significance were reported.[22]

4. Comprehensive Safety and Tolerability Profile

The safety profile of Lecanemab is a critical component of its clinical evaluation and is dominated by the class-specific risk of Amyloid-Related Imaging Abnormalities (ARIA). This risk necessitates a rigorous approach to patient selection, monitoring, and management.

4.1. Amyloid-Related Imaging Abnormalities (ARIA): A Boxed Warning

The U.S. prescribing information for Lecanemab includes a Boxed Warning, the FDA's most stringent warning, for ARIA.[13] ARIA is a radiological finding detected on brain MRI scans and is a known adverse event associated with the class of amyloid-targeting monoclonal antibodies.[3] While often asymptomatic, ARIA can be serious and, in rare cases, life-threatening.[3] It is categorized into two types:

• ARIA-E (Edema/Effusions): This refers to vasogenic edema, or swelling in the brain, caused by fluid shifts across a temporarily compromised blood-brain barrier.
• Incidence: In the Clarity AD core study, ARIA-E occurred in 12.6% of patients treated with Lecanemab, compared to just 1.7% of those on placebo.[24]
• Characteristics: The majority of ARIA-E events (88.5%) were radiographically classified as mild-to-moderate.[16] They typically occurred early in the treatment course, with most cases detected within the first 7 doses (approximately 3-6 months).[16] The condition is generally transient, with MRI evidence of resolution occurring in 81% of cases by 17 weeks and in 100% of cases over time.[22]
• Symptomatic ARIA-E: While most ARIA-E is asymptomatic, clinical symptoms occurred in 2.8% to 3% of Lecanemab-treated patients.[11] Common symptoms include headache, confusion, dizziness, visual disturbances, nausea, and gait difficulty.[3]
• ARIA-H (Hemorrhage/Hemosiderin Deposition): This category includes new cerebral microhemorrhages (small spots of bleeding), superficial siderosis (iron deposits on the surface of the brain), and, rarely, larger intracerebral macrohemorrhages.
• Incidence: ARIA-H was observed in 17.3% of the Lecanemab group versus 9.0% of the placebo group in Clarity AD.[24]
• Characteristics: An important nuance is that the incidence of isolated ARIA-H (i.e., ARIA-H occurring without concurrent ARIA-E) was similar in both the Lecanemab (8.9%) and placebo (7.8%) groups. This suggests that Lecanemab primarily increases the risk of ARIA-H that occurs in conjunction with the inflammatory process of ARIA-E, while the background rate of spontaneous microhemorrhages in an AD population remains relatively unaffected.[33]

4.2. Risk Stratification: The Role of the APOE ε4 Genotype

The risk of developing ARIA is not uniform; it is powerfully stratified by a patient's genetic makeup, specifically the presence of the apolipoprotein E ε4 (APOE ε4) allele, a well-known risk factor for developing AD itself.[18]

• Incidence by Genotype: The presence of one (heterozygote) or two (homozygote) copies of the APOE ε4 allele dramatically increases the risk, severity, and symptomatic nature of ARIA. Data from the combined Clarity AD core and OLE studies show a clear gene-dose effect on the incidence of ARIA-E [16]:
• Non-carriers (no APOE ε4 alleles): 6.5%
• Heterozygotes (one APOE ε4 allele): 11.6%
• Homozygotes (two APOE ε4 alleles): 34.5%

This profound risk differential has fundamentally altered the clinical approach to this class of drugs. It has effectively established pharmacogenomic testing as a standard of care prior to treatment initiation. The FDA prescribing information recommends APOE genotyping to inform the risk-benefit discussion, and some international regulatory bodies, such as those in the United Kingdom and the European Union, have gone further by restricting the use of Lecanemab in APOE ε4 homozygotes due to the unfavorable risk-benefit balance in this subpopulation.[3] This marks a significant step for mainstream neurology, where routine genetic testing to guide therapy and manage safety has not previously been common practice.

4.3. Infusion-Related Reactions (IRRs)

IRRs are the most common adverse event associated with Lecanemab treatment.

• Incidence: In Clarity AD, IRRs occurred in 26.4% of participants receiving Lecanemab, compared to 7.4% in the placebo group.[16]
• Characteristics: The reactions are typically mild-to-moderate in severity (96% of cases) and characteristically occur with the first infusion (75% of cases).[15]
• Symptoms: Common symptoms are flu-like and include fever, chills, body aches, joint pain, nausea, vomiting, and transient changes in blood pressure.[13]
• Management: IRRs are generally manageable by slowing or temporarily stopping the infusion. For subsequent treatments, premedication with antihistamines, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroids can effectively prevent or mitigate reactions.[15]

4.4. Other Adverse Events and Long-Term Safety

• Headache: Headache was reported more frequently in the Lecanemab group (11.1%) than in the placebo group (8.1%).[16]
• Intracerebral Hemorrhage (>1 cm): While rare, macrohemorrhages are a serious risk. The rate of intracerebral hemorrhage (ICH) in the combined Core + OLE dataset was 0.5% with Lecanemab.[36] The prescribing information recommends exercising additional caution when considering Lecanemab in patients taking anticoagulant medications, as their concurrent use was associated with an increased number of ICH events in clinical studies.[31]
• Mortality: During the 18-month double-blind portion of the Clarity AD trial, the mortality rate was similar between the two groups (0.7% in the Lecanemab group vs. 0.8% in the placebo group), and no deaths were considered by the investigators to be related to Lecanemab or ARIA.[16]

Table 3 summarizes the incidence of key adverse events from the Clarity AD core study, while Table 4 highlights the critical impact of APOE ε4 genotype on ARIA-E risk.

Adverse Event	Lecanemab (n=898) %	Placebo (n=897) %
Infusion-Related Reactions	26.4	7.4
ARIA-E (Any)	12.6	1.7
ARIA-E (Symptomatic)	2.8	0.0
ARIA-H (Any)	17.3	9.0
Headache	11.1	8.1

Source(s): [16]

APOE ε4 Genotype	ARIA-E Incidence (%)
Non-carriers	6.5
Heterozygotes (one copy)	11.6
Homozygotes (two copies)	34.5

Source(s): [16]

5. Global Regulatory Trajectory

The path of Lecanemab through global regulatory agencies has been a landmark case study, highlighting differing philosophies on risk tolerance, the definition of clinical benefit, and the role of pharmacogenomics in drug approval.

5.1. United States (FDA)

The U.S. Food and Drug Administration (FDA) utilized a two-step process for Lecanemab's approval, leveraging its pathways for drugs addressing serious, unmet medical needs.

• Accelerated Approval (January 6, 2023): The FDA initially granted Lecanemab accelerated approval based on data from a Phase 2 study.[11] This pathway allows for earlier approval of drugs based on their effect on a surrogate endpoint that is considered "reasonably likely to predict a clinical benefit." For Lecanemab, this surrogate endpoint was the observed reduction in amyloid beta plaques in the brain.[11]
• Traditional Approval (July 6, 2023): As a condition of accelerated approval, the manufacturer was required to conduct a confirmatory trial. The successful results of the Phase 3 Clarity AD study, which demonstrated a statistically significant clinical benefit on the CDR-SB, fulfilled this requirement.[31] Following a unanimous positive vote from its Peripheral and Central Nervous System Drugs Advisory Committee, the FDA converted Lecanemab to traditional approval.[31] This made it the first amyloid-directed antibody for AD to achieve this status, a crucial step that also triggered broader reimbursement coverage by the Centers for Medicare & Medicaid Services (CMS).[37] The final approval included the Boxed Warning for ARIA and a recommendation for pre-treatment APOE ε4 genotyping.[31]

5.2. European Union (EMA)

The regulatory journey in the European Union was more contentious and protracted, reflecting a higher degree of skepticism regarding the drug's risk-benefit profile.

• Initial Negative Recommendation (July 2024): The EMA's Committee for Medicinal Products for Human Use (CHMP) initially recommended refusal of the marketing authorization for Lecanemab. The committee concluded that the modest clinical benefit demonstrated in the Clarity AD trial did not outweigh the significant safety risks, particularly ARIA.[3]
• Re-examination and Positive Opinion (November 2024): Following a request for re-examination by the manufacturer, the CHMP reversed its initial opinion and recommended granting a marketing authorization, but with significant restrictions.[3] The positive opinion was limited to patients with early AD who have only one or no copies of the APOE ε4 allele, effectively excluding APOE ε4 homozygotes from treatment due to their high risk of ARIA.[3]
• Formal Authorization (April 15, 2025): The European Commission formally granted marketing authorization for Lecanemab, adopting the CHMP's restricted indication.[3] This decision made Lecanemab the first disease-modifying therapy for AD to be authorized in the EU, but for a more limited patient population than in the U.S..[38]

5.3. Other Key Markets

Lecanemab has also received approval in several other major markets, generally following the broader indication seen in the U.S. rather than the restricted EU label. These include:

• Japan: Approved in September 2023.[14]
• China: Approved in January 2024.[9]
• United Kingdom: The Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorization in August 2024, but like the EMA, restricted its use in APOE ε4 homozygotes. However, the National Institute for Health and Care Excellence (NICE) issued draft guidance not recommending its use within the National Health Service (NHS), citing that its small benefit does not justify its cost.[3]
• Other Approvals: The drug has also been approved in South Korea, Hong Kong, Israel, the United Arab Emirates, and Mexico, among others.[3]

This divergent regulatory landscape underscores the global debate on how to value an incremental but statistically proven benefit in the face of tangible safety risks and high costs, a challenge that will likely define the introduction of future AD therapies.

6. Clinical Application and Expert Guidelines

The introduction of Lecanemab into clinical practice requires a significant shift in the diagnostic and management workflow for early Alzheimer's disease. To guide this process, expert bodies like the Alzheimer's Association have developed Appropriate Use Recommendations (AURs) that translate clinical trial protocols into real-world guidance.[40]

6.1. Patient Selection and Eligibility

The AURs emphasize that the safety and efficacy of Lecanemab have only been established in a population mirroring that of the clinical trials. Therefore, patient selection should adhere closely to these criteria.[41]

• Key Inclusion Criteria:
• Clinical Stage: Patients must have a diagnosis of Mild Cognitive Impairment (MCI) due to AD or mild-stage AD dementia.[23] The drug is not indicated for preclinical (asymptomatic) individuals or those with moderate to severe dementia, as these populations were not studied.[3]
• Amyloid Confirmation: The presence of brain amyloid pathology must be confirmed via amyloid PET or CSF analysis prior to initiating treatment.[18] A clinical diagnosis alone is insufficient.
• Age: While the trial included patients aged 50-90, clinical judgment is advised for those outside this range.[23]
• Care Partner: The presence of a reliable care partner or family member is crucial to ensure adherence to the demanding treatment and monitoring schedule.[43]
• Key Exclusion Criteria (Contraindications):
• MRI Contraindications: Any condition that precludes undergoing repeated MRI scans is an absolute contraindication.[23]
• Hemorrhagic Risk: Patients with a baseline MRI showing more than 4 microhemorrhages, any prior macrohemorrhage (>1 cm), or evidence of superficial siderosis should be excluded due to an elevated risk of bleeding complications.[43]
• Anticoagulation: The AURs strongly recommend that patients requiring treatment with anticoagulants (e.g., warfarin, direct oral anticoagulants) should not receive Lecanemab until more safety data are available, due to the increased risk of ICH.[41]
• Unstable Medical Conditions: Any significant, unstable medical, neurological, or psychiatric condition that could interfere with treatment or confound assessment is a contraindication.[43]

6.2. Pre-Treatment Evaluation and Counseling

A comprehensive evaluation is mandatory before the first infusion.

1. Confirm Diagnosis and Stage: Establish a clinical diagnosis of MCI due to AD or mild AD dementia.
2. Confirm Amyloid Pathology: Obtain a positive amyloid PET scan or CSF Aβ42/40 ratio.
3. Baseline MRI: A brain MRI within one year of initiation is required to screen for pre-existing abnormalities (e.g., microhemorrhages) that would exclude the patient from treatment.[18]
4. APOE Genotyping: APOE ε4 genetic testing should be performed to quantify the patient's individual risk of ARIA. This is essential for an informed consent discussion.[31] Genetic counseling should be available to discuss the implications of the test results for the patient and their family members.
5. Informed Consent: A detailed discussion with the patient and their care partner is critical. This must cover the potential for modest benefits, the significant risks of ARIA and IRRs, the demanding schedule of biweekly infusions and frequent MRI monitoring, and the associated costs.[40]

6.3. Dosing, Administration, and Monitoring

• Dosing and Administration: The recommended dose is 10 mg/kg administered as an intravenous infusion over approximately one hour, once every two weeks.[4] A recent FDA approval allows for a transition to a monthly (every four weeks) maintenance dosing schedule after an 18-month initiation phase of biweekly treatment.[10]
• ARIA Monitoring: A strict MRI monitoring schedule is required to detect ARIA, which is often asymptomatic. The FDA-approved label mandates MRI scans prior to the 5th, 7th, and 14th infusions.[18] Expert guidelines may recommend additional scans, particularly for APOE ε4 carriers or those who develop ARIA.[43]
• Management of ARIA: Detailed protocols guide the management of ARIA based on its radiographic severity and the presence of clinical symptoms.
• Asymptomatic, Mild ARIA: Treatment may often continue with increased monitoring (e.g., monthly MRI).[43]
• Symptomatic or Radiographically Moderate/Severe ARIA: Treatment should be suspended. Dosing may be resumed if symptoms resolve and the MRI findings stabilize or resolve.[43]
• Permanent Discontinuation: Is recommended for severe ARIA, any macrohemorrhage, or recurrent ARIA events.[43]

7. Economic and Health System Considerations

The introduction of Lecanemab presents substantial financial and logistical challenges for healthcare systems, payers, and patients, stemming from its high price and the intensive resources required for its safe administration.

7.1. Drug Pricing and Treatment Costs

• List Price: The manufacturers, Eisai and Biogen, set the wholesale acquisition cost (list price) for Lecanemab in the U.S. at $26,500 per patient, per year.[46]
• Ancillary Costs: The cost of the drug itself is only one component of the total cost of care. Treatment with Lecanemab necessitates significant additional expenditures, including:
• Costs for amyloid confirmation (PET or CSF).[49]
• APOE genotyping.
• Frequent physician visits and consultations.
• Regular MRI scans for ARIA monitoring (at least 3 in the first year).[49]
• The cost of intravenous infusion administration, which varies significantly depending on the site of care (hospital outpatient vs. infusion center).[50]
• Total Annual Cost: Independent analyses estimate that these ancillary services add approximately $7,300 to $9,000 per year, bringing the total estimated cost of treatment to $33,800 to $35,500 or more per patient per year.[49] Some estimates place the total cost to the healthcare system as high as $82,500 per patient per year when all safety monitoring and care are included.[52]

7.2. Cost-Effectiveness and Value-Based Pricing

The Institute for Clinical and Economic Review (ICER), an independent U.S. watchdog organization, conducted a detailed analysis of Lecanemab's cost-effectiveness.

• ICER's Conclusion: ICER's appraisal committee voted that the evidence was not adequate to demonstrate a net health benefit for Lecanemab when compared to standard supportive care, citing the modest clinical gains and significant safety risks.[53]
• Value-Based Price: ICER calculated that for Lecanemab to meet common cost-effectiveness thresholds (i.e., to be considered a good value for the health benefit it provides), its annual price would need to be in the range of $8,900 to $21,500.[52] At its current list price of $26,500, ICER concluded that Lecanemab represents a "low" long-term value for money.[53] Other academic models have suggested an even lower cost-effective price, below $5,100 per year.[54]

7.3. Payer Coverage and Budget Impact

• Medicare Coverage: In the U.S., the Centers for Medicare & Medicaid Services (CMS) provides broad coverage for Lecanemab for eligible patients following its traditional FDA approval. Patients are typically responsible for a 20% coinsurance, which can amount to over $5,000 per year for the drug alone.[47] While supplemental insurance (Medigap) or Medicare Advantage plans may cover this, out-of-pocket costs could still be a substantial barrier for many seniors on fixed incomes.[51]
• Budget Impact: The widespread use of Lecanemab is projected to have a significant impact on healthcare budgets. Estimates suggest that treating the eligible population could cost Medicare between $2 billion and $5 billion annually, making it one of the most expensive drugs funded by the program.[52] This level of spending could potentially lead to increases in Medicare Part B premiums for all beneficiaries, not just those receiving the treatment.[50]

8. Comparative Landscape: Lecanemab, Aducanumab, and Donanemab

Lecanemab is one of three prominent amyloid-beta-directed monoclonal antibodies that have reached late-stage development or approval for Alzheimer's disease. Understanding its profile requires comparison with its peers, aducanumab (Aduhelm) and donanemab.

8.1. Mechanism of Action and Target Specificity

While all three antibodies target Aβ, they bind to different forms or epitopes of the peptide, which may account for differences in their efficacy and safety profiles.

• Lecanemab: As detailed, it selectively targets soluble Aβ protofibrils with high affinity, while also binding to fibrils. Its binding epitope is the N-terminus of Aβ (residues 1-16).[55]
• Aducanumab: Binds preferentially to aggregated forms of Aβ, including both soluble oligomers and insoluble fibrils found in plaques. Its epitope is also on the N-terminus (residues 3-7).[55]
• Donanemab: Uniquely targets a modified form of Aβ called pyroglutamated Aβ (N3pG), which is present only in established amyloid plaques. It is designed specifically to clear existing plaques rather than targeting soluble precursor species.[56]

8.2. Clinical Efficacy

Direct head-to-head trials are lacking, so comparisons are based on results from their respective pivotal Phase 3 trials.

• Lecanemab (Clarity AD): Demonstrated a 27% slowing of decline on the CDR-SB primary endpoint, with consistent, statistically significant benefits across all key secondary endpoints.[26]
• Aducanumab (EMERGE and ENGAGE): Produced highly controversial and conflicting results. The identical EMERGE and ENGAGE trials yielded divergent outcomes. EMERGE met its primary endpoint, showing a 22% slowing of decline on CDR-SB in the high-dose group, while ENGAGE failed to show any benefit.[57] Post-hoc analyses suggested that higher cumulative drug exposure was associated with the positive outcome, but the discordant results created significant uncertainty about its true efficacy.[60]
• Donanemab (TRAILBLAZER-ALZ 2): Showed a 35% slowing of decline on its primary endpoint, the integrated Alzheimer's Disease Rating Scale (iADRS).[56] Network meta-analyses suggest donanemab may have a greater effect on cognitive outcomes, while Lecanemab may be more effective at reducing total amyloid burden on PET scans.[55]

8.3. Safety Profile (ARIA Incidence)

The incidence of ARIA varies across the three drugs, which may be related to their different binding targets and clearance efficiencies.

• Lecanemab: ARIA-E: 12.6%; ARIA-H: 17.3%.[56]
• Aducanumab: ARIA-E: 35%; ARIA-H: ~19% (rates varied slightly between trials).[60]
• Donanemab: ARIA-E: 24.0%; ARIA-H: 31.4%.[56]

Based on these cross-trial comparisons, Lecanemab appears to have a more favorable ARIA profile with a lower incidence of ARIA-E compared to both aducanumab and donanemab.

8.4. Regulatory and Dosing Status

• Lecanemab: Holds traditional FDA approval and restricted EU approval. Dosed biweekly, with a monthly maintenance option.[13]
• Aducanumab: Received a controversial accelerated approval from the FDA but was later withdrawn from the market by Biogen due to challenges with reimbursement and adoption. It never received approval in Europe.[25]
• Donanemab: Is currently under regulatory review. It is dosed once every four weeks.[56]

9. Emerging Evidence and Future Directions

The field of anti-amyloid therapy is rapidly evolving, with ongoing research focused on improving safety, expanding indications, and understanding real-world performance.

9.1. Real-World Evidence (RWE)

As Lecanemab is adopted into clinical practice, real-world studies are beginning to emerge, providing data on its use outside the controlled environment of a clinical trial.

• Early Findings: Initial retrospective case series from medical centers in the U.S. and Israel are confirming the feasibility of implementing the complex treatment and monitoring protocols.[64] These studies generally report ARIA rates (e.g., 12.9% - 18.6%) and IRR rates (e.g., 22.1%) that are consistent with the pivotal Clarity AD trial.[64]
• Patient Characteristics and Access: RWE studies are also shedding light on patient access. Early data suggest that uptake has been limited and may be concentrated among patients with higher socioeconomic status, highlighting potential disparities in access to this costly and resource-intensive therapy.[66]
• Long-Term Outcomes: The primary goal of RWE, including national registries mandated by payers like Medicare, is to collect long-term data on the safety and effectiveness of Lecanemab in a broader, more diverse patient population than was included in the clinical trials.[49]

9.2. Subcutaneous Formulation and Dosing Flexibility

To reduce the burden of biweekly intravenous infusions, a subcutaneous formulation of Lecanemab is in late-stage development.

• Development Status: The FDA has accepted a Biologics License Application (BLA) for a subcutaneous autoinjector intended for weekly maintenance dosing, with a decision expected in late 2025.[3]
• Potential Impact: A subcutaneous option could significantly improve convenience for patients and caregivers, potentially increasing treatment adherence and reducing the strain on infusion center capacity.[10]

9.3. Expansion into Preclinical Alzheimer's Disease

The ultimate goal of disease-modifying therapy is to intervene as early as possible, before significant irreversible neurodegeneration has occurred.

• The AHEAD 3-45 Study: This major ongoing Phase 3 clinical trial is evaluating the efficacy and safety of Lecanemab in individuals with preclinical AD. These are cognitively unimpaired individuals who have evidence of intermediate or elevated brain amyloid pathology.[27]
• Implications: If successful, the AHEAD study could support expanding the indication for Lecanemab to an even earlier stage of the disease continuum, shifting the treatment paradigm from slowing progression to primary or secondary prevention of clinical symptoms.

10. Synthesis and Conclusion

Lecanemab (Leqembi) unequivocally marks a pivotal moment in the history of Alzheimer's disease therapeutics. It is the first treatment to convincingly demonstrate, in a large and well-conducted Phase 3 trial, that targeting the underlying amyloid pathology can translate into a statistically significant slowing of clinical decline. The success of the Clarity AD study provides the strongest validation to date for a refined version of the amyloid hypothesis, confirming that the removal of Aβ aggregates, particularly the neurotoxic protofibril species, can favorably alter the course of the disease. The robust correlation between profound biomarker changes and modest but consistent clinical benefits across cognitive and functional domains establishes a new benchmark for future drug development.

However, the arrival of Lecanemab also ushers in an era of profound clinical, ethical, and systemic challenges. The central paradox of the drug is the disconnect between its statistical success and the modest magnitude of its clinical effect. The 27% slowing of decline, while a landmark scientific achievement, may not always be readily apparent in the day-to-day life of an individual patient, forcing a difficult conversation about what constitutes a "meaningful" benefit.

This debate is sharpened by the drug's significant safety profile, which is dominated by the risk of ARIA. The management of ARIA necessitates a paradigm shift in dementia care, requiring an infrastructure capable of supporting routine pharmacogenomic testing, intensive MRI monitoring, and rapid management of potential neurological complications. The strong association between ARIA risk and APOE ε4 status has thrust genetic testing into the forefront of therapeutic decision-making, raising complex issues of patient counseling and risk communication.

Furthermore, the high cost of Lecanemab, compounded by the substantial expenses of its administration and monitoring, poses a formidable barrier to access and threatens to place an immense strain on healthcare budgets. The divergent decisions of global regulatory and reimbursement bodies reflect a fundamental uncertainty about whether the drug's incremental benefits justify its risks and societal costs.

In conclusion, Lecanemab is not a cure for Alzheimer's disease, but a first-generation, disease-modifying therapy that offers a modest but real opportunity to slow its relentless progression. Its approval has transformed the landscape from one of nihilism to one of tangible, albeit complex, therapeutic options. The successful implementation of Lecanemab in clinical practice will depend on the ability of healthcare systems to build the necessary infrastructure, the skill of clinicians in navigating nuanced risk-benefit discussions, and the capacity of society to grapple with the profound economic and ethical questions raised by a landmark drug that is both a symbol of hope and a testament to the immense challenges that remain in the fight against Alzheimer's disease.

Works cited

1. lecanemab | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 10, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=12202
2. (PDF) Novel anti-amyloid-beta (Aβ) monoclonal antibody ..., accessed September 10, 2025, https://www.researchgate.net/publication/375092940_Novel_anti-amyloid-beta_Ab_monoclonal_antibody_lecanemab_for_Alzheimer's_disease_A_systematic_review
3. Lecanemab - Wikipedia, accessed September 10, 2025, https://en.wikipedia.org/wiki/Lecanemab
4. Lecanemab - LiverTox - NCBI Bookshelf, accessed September 10, 2025, https://www.ncbi.nlm.nih.gov/books/NBK589468/
5. Lecanemab | Beta Amyloid - TargetMol, accessed September 10, 2025, https://www.targetmol.com/compound/lecanemab
6. Lecanemab - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 10, 2025, https://synapse.patsnap.com/drug/5059376f2c9543d1b381ce3a5b8a94c6
7. Drug Information | TheMarker, accessed September 10, 2025, https://themarker.idrblab.cn/data/drug?id=DM4J9E
8. What is the mechanism of Lecanemab? - Patsnap Synapse, accessed September 10, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-lecanemab
9. The Committee for Medicinal Products for Human Use (CHMP) Reaffirms Positive Opinion for Lecanemab in Early Alzheimer's Disease | News Release：2025 - Eisai, accessed September 10, 2025, https://www.eisai.com/news/2025/news202513.html
10. FDA Approves LEQEMBI® (lecanemab-irmb) IV Maintenance Dosing for the Treatment of Early Alzheimer's Disease | News Release：2025 | Eisai Co., Ltd., accessed September 10, 2025, https://www.eisai.com/news/2025/news202506.html
11. FDA Approves LEQEMBI™ (lecanemab-irmb) Under the Accelerated Approval Pathway for the Treatment of Alzheimer's Disease - Biogen | Investor Relations, accessed September 10, 2025, https://investors.biogen.com/news-releases/news-release-details/fda-approves-leqembitm-lecanemab-irmb-under-accelerated-approval
12. Lecanemab: A Novel Therapeutic Approach for Alzheimer's Disease, accessed September 10, 2025, https://www.ijsrtjournal.com/article/Lecanemab+A+Novel+Therapeutic+Approach+for+Alzheimers+Disease
13. Lecanemab: Uses, Dosage, Side Effects & Warnings - Drugs.com, accessed September 10, 2025, https://www.drugs.com/lecanemab.html
14. [Mechanism of action and clinical trial results of Lecanemab ..., accessed September 10, 2025, https://pubmed.ncbi.nlm.nih.gov/38692883/
15. Mechanism of Action - LEQEMBI ® [(lecanemab-irmb), accessed September 10, 2025, https://www.leqembihcp.com/about-leqembi/mechanism-of-action
16. Updated safety results from phase 3 lecanemab study in early Alzheimer's disease - PMC, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11084061/
17. Lecanemab: A Second in Class Therapy for the Management of Early Alzheimer's Disease - PMC - PubMed Central, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11107961/
18. What's the mechanism of action for Leqembi (lecanemab-irmb)? - Drugs.com, accessed September 10, 2025, https://www.drugs.com/medical-answers/mechanism-action-leqembi-lecanemab-irmb-3573237/
19. Neuropharmacology of Lecanemab-irmb: A new drug granted in the treatment of Alzheimer's disease | NeuroPharmac Journal, accessed September 10, 2025, https://www.neuropharmac.com/neuropharmacology-of-lecanemab-irmb-a-new-drug-granted-in-the-treatment-of-alzheimers-disease/
20. Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer's Disease - PubMed, accessed September 10, 2025, https://pubmed.ncbi.nlm.nih.gov/37874099/
21. Study Details | NCT03887455 | A Study to Confirm Safety and ..., accessed September 10, 2025, https://www.clinicaltrials.gov/study/NCT03887455
22. Clarity AD Phase 3 Trial Data | LEQEMBI® (lecanemab-irmb), accessed September 10, 2025, https://www.leqembihcp.com/about-leqembi/study-2-clarity-ad
23. Lecanemab: Appropriate Use Recommendations by Korean Dementia Association - PMC, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11538855/
24. Lecanemab reduces clinical decline in early Alzheimer's disease, accessed September 10, 2025, https://www.ccjm.org/page/aan-2023/lecanemab-alzheimers
25. What clinical evidence supports the use of lecanemab for Alzheimer disease?, accessed September 10, 2025, https://dig.pharmacy.uic.edu/faqs/april-2023-faqs/what-clinical-evidence-supports-the-use-of-lecanemab-for-alzheimer-disease/
26. Lecanemab in Early Alzheimer's Disease - PubMed, accessed September 10, 2025, https://pubmed.ncbi.nlm.nih.gov/36449413/
27. NIA statement on report of lecanemab reducing cognitive decline in Alzheimer's clinical trial, accessed September 10, 2025, https://www.nia.nih.gov/news/nia-statement-report-lecanemab-reducing-cognitive-decline-alzheimers-clinical-trial
28. NEJM publishes lecanemab Alzheimer's study results - European Pharmaceutical Review, accessed September 10, 2025, https://www.europeanpharmaceuticalreview.com/news/176966/nejm-publishes-lecanemab-alzheimers-study-results/
29. Draft guidance consultation | Lecanemab for treating mild cognitive impairment or mild dementia caused by - NICE, accessed September 10, 2025, https://www.nice.org.uk/guidance/gid-ta11220/documents/draft-guidance
30. What's the State of Anti-Amyloid Therapy in the Wake of Initial Clarity AD Findings?, accessed September 10, 2025, https://consultqd.clevelandclinic.org/whats-the-state-of-anti-amyloid-therapy-in-the-wake-of-initial-clarity-ad-findings
31. FDA Converts Novel Alzheimer's Disease Treatment to Traditional ..., accessed September 10, 2025, https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
32. The Lecanemab Clarity AD Open-Label Extension in Early Alzheimer's Disease (P1-3.003), accessed September 10, 2025, https://www.neurology.org/doi/10.1212/WNL.0000000000211489
33. Eisai Presented New Analyses of ARIA and QOL on Lecanemab in Clarity AD at the AD/PD™ 2023 Annual Meeting - Biogen | Investor Relations, accessed September 10, 2025, https://investors.biogen.com/news-releases/news-release-details/eisai-presented-new-analyses-aria-and-qol-lecanemab-clarity-ad
34. Meta-Analysis Reveals Safety Differences Between Lecanemab and Donanemab in Early Alzheimer's Disease Treatment - MedPath, accessed September 10, 2025, https://trial.medpath.com/news/16cbf9231526abfa/meta-analysis-reveals-safety-differences-between-lecanemab-and-donanemab-in-early-alzheimer-s-disease-treatment
35. Lecanemab: Experts criticise European Commission approval of Alzheimer's drug | The BMJ, accessed September 10, 2025, https://www.bmj.com/content/389/bmj.r796
36. Updated safety results from phase 3 lecanemab study in early ..., accessed September 10, 2025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11084061/
37. FDA converts lecanemab to traditional approval | Alzheimer's Disease International (ADI), accessed September 10, 2025, https://www.alzint.org/news-events/news/fda-converts-lecanemab-to-traditional-approval/
38. Leqembi®∇ (lecanemab) is the First Medicine that Slows Progression of Early Alzheimer's Disease to be Authorized in the European Union - Biogen | Investor Relations, accessed September 10, 2025, https://investors.biogen.com/news-releases/news-release-details/leqembir-lecanemab-first-medicine-slows-progression-early
39. European Commission approves first disease-modifying treatment for Alzheimer's disease in the EU, accessed September 10, 2025, https://www.alzint.org/news-events/news/european-commission-approves-first-disease-modifying-treatment-for-alzheimers-disease-in-the-eu/
40. Lecanemab Resources for Health Care Professionals - ALZPro - Alzheimer's Association, accessed September 10, 2025, https://pro.alz.org/hub/care-pathway/treatment/lecanemab-toolkit
41. Lecanemab: Appropriate Use Recommendations - Mayo Clinic, accessed September 10, 2025, https://mayoclinic.elsevierpure.com/en/publications/lecanemab-appropriate-use-recommendations
42. Lecanemab: Appropriate Use Recommendations - PubMed, accessed September 10, 2025, https://pubmed.ncbi.nlm.nih.gov/37357276/
43. Lecanemab Toolkit - Alzheimer's Association, accessed September 10, 2025, https://alz.org/getmedia/31b11f61-4e72-4353-91bb-3e12825553bd/lecanemab-toolkit.pdf
44. In Brief: Once-Monthly Lecanemab (Leqembi) for Alzheimer's ..., accessed September 10, 2025, https://secure.medicalletter.org/TML-article-1726f
45. Lecanemab for early Alzheimer•s disease, accessed September 10, 2025, https://www.jpreventionalzheimer.com/download.html?type=pdf&id=1185
46. Lecanemab Approved for Treatment of Early Alzheimer's | alz.org, accessed September 10, 2025, https://www.alz.org/alzheimers-dementia/treatments/lecanemab-leqembi
47. Lecanemab, the New Alzheimer's Treatment: 3 Things To Know - Yale Medicine, accessed September 10, 2025, https://www.yalemedicine.org/news/lecanemab-leqembi-new-alzheimers-drug
48. Lecanemab: US Veterans Health Administration will cover cost of new Alzheimer's drug - The BMJ, accessed September 10, 2025, https://www.bmj.com/content/bmj/380/bmj.p628.full.pdf
49. Lecanemab | Alosa Health, accessed September 10, 2025, https://alosahealth.org/wp-content/uploads/2024/05/Dementia_Handout_Lecanemab_Info_clinician_5.24.pdf
50. Estimated Annual Spending on Lecanemab and Its Ancillary Costs in the US Medicare Program, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10176174/
51. How Much Does Leqembi (Lecanemab) Cost? - Local Infusion, accessed September 10, 2025, https://mylocalinfusion.com/leqembi-lecanemab-cost/
52. The Real Costs of the New Alzheimer's Drug, Most of Which Will Fall to Taxpayers, accessed September 10, 2025, https://kffhealthnews.org/news/article/the-real-costs-of-the-new-alzheimers-drug-most-of-which-will-fall-to-taxpayers/
53. ICER Publishes Final Evidence Report on Lecanemab for Alzheimer's Disease, accessed September 10, 2025, https://icer.org/news-insights/press-releases/icer-publishes-final-evidence-report-on-lecanemab-for-alzheimers-disease/
54. Cost-Effectiveness of Lecanemab for Individuals With Early-Stage Alzheimer Disease, accessed September 10, 2025, https://www.neurology.org/doi/10.1212/WNL.0000000000209218
55. Donanemab outperformed Aducanumab and Lecanemab on cognitive, but not on biomarker and safety outcomes: systematic review, frequentist and Bayesian network meta-analyses | medRxiv, accessed September 10, 2025, https://www.medrxiv.org/content/10.1101/2024.03.31.24305134v1.full-text
56. Leqembi (Lecanemab) vs Donanemab For Alzheimer's: What's The ..., accessed September 10, 2025, https://mylocalinfusion.com/donanemab-vs-lecanemab/
57. ENGAGE and EMERGE: Truth and consequences? - PMC - PubMed Central, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8248059/
58. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease - PubMed, accessed September 10, 2025, https://pubmed.ncbi.nlm.nih.gov/35542991/
59. Detailed Results of Phase 3 Trials of Aducanumab for Alzheimer's Disease Presented, accessed September 10, 2025, https://practicalneurology.com/news/detailed-results-of-phase-3-trials-of-aducanumab-for-alzheimers-disease-presented/2469092/
60. Biogen announces topline results from the EMERGE and ENGAGE Phase III clinical trials of Aducanumab | Alzheimer Europe, accessed September 10, 2025, https://www.alzheimer-europe.org/news/biogen-announces-topline-results-emerge-and-engage-phase-iii-clinical-trials-aducanumab?language_content_entity=en
61. Donanemab outperformed Aducanumab and Lecanemab on cognitive, but not on biomarker and safety outcomes: systematic review, frequentist and Bayesian network meta-analyses | medRxiv, accessed September 10, 2025, https://www.medrxiv.org/content/10.1101/2024.03.31.24305134v1
62. EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to ..., accessed September 10, 2025, https://investors.biogen.com/static-files/928e1511-6d2c-46ec-98ca-74e3de792fb6
63. Aducanumab and Lecanemab: How are they different? - CC Young Senior Living, accessed September 10, 2025, https://www.ccyoung.org/news/aducanumab-and-lecanemab-how-are-they-different/
64. Two-Year Real-World Study of LEQEMBI® in the United States Presented at Alzheimer's Association International Conference (AAIC) 2025 - Biogen | Investor Relations, accessed September 10, 2025, https://investors.biogen.com/news-releases/news-release-details/two-year-real-world-study-leqembir-united-states-presented
65. Lecanemab in clinical practice: real-world outcomes in early Alzheimer's disease - PMC, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12117801/
66. Characterizing the Journey of Early Alzheimer's Disease in Patients Initiating Lecanemab Treatment in the United States: A Real-World Evidence Study, accessed September 10, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12089008/
67. Real-World Prescribing of Lecanemab in the United States - ISPOR, accessed September 10, 2025, https://www.ispor.org/heor-resources/presentations-database/presentation/intl2024-3895/139682
68. Eisai To Present Four-Year Efficacy And Safety Data On Continuous Treatment With Lecanemab At The Alzheimer's Association International Conference 2025 | News Release, accessed September 10, 2025, https://www.eisai.com/news/2025/news202548.html
69. Lecanemab Active Not Recruiting Phase 3 Trials for Preclinical Alzheimer's Disease / Early ... - DrugBank, accessed September 10, 2025, https://go.drugbank.com/drugs/DB14580/clinical_trials?conditions=DBCOND0137189%2CDBCOND0067640&phase=3&purpose=treatment&status=active_not_recruiting