What are the approved indications for Lecanemab?

Introduction to Lecanemab

Overview of Lecanemab
Lecanemab is a humanized immunoglobulin G1 monoclonal antibody that has been developed specifically for the treatment of Alzheimer’s disease (AD). It is engineered to bind selectively to amyloid-beta (Aβ) soluble protofibrils, a toxic species believed to drive AD pathology by promoting the formation of amyloid plaques in the brain. The drug’s design relies on the concept that by targeting these protofibrils, lecanemab can reduce the amyloid burden and thereby exert disease-modifying effects. It represents a new category of anti-Aβ therapies which differentiates itself from earlier therapies by favoring the binding to soluble, aggregated forms of the Aβ peptide rather than the highly aggregated amyloid plaques. Developed under a collaboration between BioArctic AB, Eisai, and Biogen, lecanemab has attracted significant attention as it not only aims to alter pathological markers in patients’ brains but also to slow the progression of clinical decline in early AD. Its development took into account decades of research on the biochemical, pathological, and clinical aspects of Alzheimer’s disease, with the hopes of addressing some of the limitations seen with previous symptomatic treatments.

Mechanism of Action
Lecanemab has a targeted mechanism of action that directly addresses one of the hallmark features of AD: the accumulation of aggregated Aβ peptides. Its binding affinity is specifically geared toward Aβ protofibrils, a form that is not yet fully fibrillized into amyloid plaques but is thought to be neurotoxic. By binding to these protofibrils, lecanemab helps mitigate the formation of new plaques and promotes the clearance of pre-existing aggregated deposits. This mode of action is critical because the reduction of amyloid burden, as measured by amyloid positron emission tomography (PET) scan outcomes or changes in cerebrospinal fluid (CSF) biomarkers, correlates with a slowdown in cognitive decline, albeit modestly, in patients with early AD. The antibody’s selectivity enhances its safety profile, as it tends to spare monomeric Aβ, which may play a role in normal neuronal functioning, while effectively targeting the aggregated forms that contribute to neurotoxicity. Thus, the mechanism of lecanemab bridges basic science with clinical outcomes—a principle that underpins its regulatory approval and subsequent clinical use for a defined patient population.

Regulatory Status

Approval Process
Lecanemab underwent a comprehensive regulatory review process before it received its approval—primarily in the United States. Its journey through the clinical development stages was marked by pivotal phase 2 and phase 3 trials with evidentiary support for both its impact on biomarkers and modest improvements in clinical endpoints. The U.S. Food and Drug Administration (FDA) granted accelerated approval to lecanemab on January 6, 2023, based on its effects on surrogate endpoints such as the reduction of amyloid plaques in the brain. This accelerated approval pathway is used for drugs that address serious conditions with an unmet medical need and is contingent on demonstrating an effect on a surrogate marker that is reasonably likely to predict a clinical benefit.
During the approval process, the FDA evaluated data from multicenter, double-blind, randomized clinical trials such as the Clarity AD study. These trials not only measured reductions in brain amyloid burden via imaging and biomarker analysis but also assessed clinical outcomes using cognitive scales like the Clinical Dementia Rating-Sum of Boxes (CDR-SB). The evidence from these trials, despite the controversy over the magnitude of clinical benefit, was sufficient to justify the entry of lecanemab into the market for a specific patient population. Post-approval requirements include further verification through confirmatory trials, which is a common stipulation in accelerated approvals to ensure that the surrogate markers do accurately predict long-term clinical outcomes.

Approved Indications
Lecanemab is approved specifically for use in the treatment of Alzheimer’s disease in patients at an early stage of the condition. More precisely, its approved indication is for patients diagnosed with early Alzheimer’s disease—comprising individuals with mild cognitive impairment (MCI) due to AD or mild dementia due to AD—provided that there is confirmatory evidence of amyloid pathology in the brain. This evidence of amyloid pathology is typically determined through amyloid PET scans or cerebrospinal fluid (CSF) testing. The selection of this patient population is critical: clinical trials for lecanemab enrolled individuals in the early symptomatic stages, where the disease-modifying effects are expected to be most beneficial.
In this context, lecanemab is not designated for later-stage Alzheimer’s disease. The rationale behind limiting its indication to early AD is rooted in both the disease’s pathophysiology and the design of the clinical trials. Since sustained amyloid accumulation and related neurodegenerative processes have a long-standing impact, interventions aimed at modulating these processes may yield the greatest benefits when initiated early in the disease course. Thus, the FDA approval hinges on the notion that early intervention can slow the progression of cognitive and functional decline, even if the measured improvements in clinical trial outcomes are modest. This targeted indication also reflects the risk-benefit ratio observed in clinical studies, where adverse effects such as amyloid-related imaging abnormalities (ARIA) were closely monitored and found to be acceptable within the tested population.
The approved label for lecanemab therefore stipulates that treatment should only be initiated in patients with confirmed amyloid pathology and early-stage clinical symptoms of Alzheimer’s disease, ensuring that the therapeutic intervention is applied where it is most likely to yield a tangible benefit in the progression of the disease. This indication is a reflection of both the regulatory review process and the clinical trial data, which underscore its use in a specific, well-defined patient cohort.

Clinical Applications and Studies

Clinical Trials and Studies
The clinical development program for lecanemab was structured around large-scale, multicenter trials aimed at establishing both its safety and efficacy in individuals with early AD. The phase 3 Clarity AD trial, for instance, included 1795 participants with a mean baseline CDR-SB score of approximately 3.2. In these trials, patients received biweekly infusions of 10 mg/kg lecanemab. Results from the trial demonstrated that lecanemab was associated with a statistically significant reduction in the rate of clinical decline compared to placebo, with an adjusted least-squares mean difference of −0.45 on the CDR-SB at 18 months. In addition to cognitive outcomes, imaging biomarkers such as amyloid PET scans showed a significant decrease in amyloid burden in a substudy of 698 participants, with a difference of approximately 59 centiloids between the lecanemab and placebo groups.
Other clinical endpoints evaluated included changes on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog14), the Alzheimer’s Disease Composite Score (ADCOMS), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL). These multiple measures provided a composite view of the drug’s effects on cognition and daily functioning. Moreover, safety data highlighted the occurrence of infusion-related reactions and ARIA, with an incidence of ARIA with edema (ARIA-E) reported at around 12.6% in the lecanemab group compared to 1.7% in the placebo group.
Thus, the clinical trials reinforced the notion that lecanemab’s primary utility lies in its ability to slow disease progression in early AD rather than reversing established cognitive deficits. These studies form the backbone of the approved indication, ensuring that the drug is administered to patients who are in the early symptomatic stages and have elevated amyloid levels. Consequently, its therapeutic application is well anchored in evidence generated from randomized, controlled clinical studies that demonstrate both a reduction in amyloid pathology and a modest improvement in clinical endpoints.

Real-world Applications
In clinical practice, the real-world application of lecanemab is expected to mirror the rigorously defined parameters seen in clinical trials. Its approval under the accelerated pathway means that clinicians are advised to start treatment only in patients with early AD—specifically, those exhibiting mild cognitive impairment or mild dementia due to Alzheimer’s disease with confirmed amyloid pathology. In real-world scenarios, the assessment of amyloid pathology typically involves the use of amyloid PET imaging or CSF biomarker analyses to ensure that the treatment is appropriately targeted.
Given that the clinical trials used strict inclusion criteria, the translation of these protocols into everyday practice will involve considerable diagnostic effort, including the optimization of imaging infrastructure and the training of clinicians to properly interpret PET images. As such, the use of lecanemab in a community setting is not solely a matter of prescribing the drug but also of robustly verifying that the patient meets the stringent diagnostic criteria that underpin its approval.
Furthermore, the well-defined indication ensures that healthcare providers are implementing lecanemab therapy in a patient population that is most likely to benefit from its disease-modifying effects, minimizing exposure to potential adverse effects in patients who fall outside the early AD spectrum. This precise patient selection is critical in maximizing the therapeutic efficacy and maintaining patient safety, which in turn influences insurance coverage, reimbursement strategies, and overall clinical guidelines on the use of monoclonal antibodies in Alzheimer’s disease.
Real-life experiences, as they begin to accumulate over the forthcoming years, will provide additional insights into the long-term safety profile of lecanemab and its impact on patients' quality of life. Clinicians are expected to rigorously monitor for adverse events, including ARIA and infusion-related reactions, and adjust treatment protocols based on evolving real-world data, thereby complementing the controlled trial findings.

Future Directions and Considerations

Ongoing Research
Despite its current approved indication, ongoing clinical research is actively exploring the potential of lecanemab beyond the earliest stages of Alzheimer’s disease. There are multiple studies designed to evaluate whether earlier intervention before the onset of overt clinical symptoms might yield even more substantial benefits. For instance, the AHEAD 3-45 trial focuses on individuals in the preclinical phase of AD—patients who are cognitively normal but exhibit intermediate or elevated levels of cerebral amyloid as measured by PET. These studies may eventually expand the understanding of lecanemab’s utility in delaying the onset of clinical symptoms, thereby potentially broadening its labeled indication in the future.
Furthermore, long-term extension studies are underway which aim to provide more data on the sustained effects of lecanemab on disease progression, cognitive function, and overall patient outcomes. These studies are critical, as the current indications are based on 18-month trial data, leaving a need for longer observational periods to assess durability, safety over time, and optimal treatment durations. Additionally, research is also focusing on understanding differential treatment responses in various patient subpopulations, including potential sex differences and the influence of genetic markers such as the presence of APOE4 alleles.
The continued investigation into the precise relationship between amyloid clearance and clinical benefit will be pivotal in addressing ongoing controversies regarding the net clinical impact of lecanemab. This expanding body of research is essential to refine patient selection criteria further and optimize the therapeutic regimen while mitigating risks such as ARIA.

Potential Future Indications
While the approved indication for lecanemab currently stands as treatment for patients with MCI due to AD or mild AD dementia with amyloid positivity, the evolving landscape of Alzheimer’s therapeutic research may offer potential future indications. There is significant interest in determining whether lecanemab can be therapeutically effective in populations with later-stage Alzheimer’s disease or even as a preventive strategy in high-risk individuals. However, such applications would require rigorous evaluation in dedicated clinical trials because the progression of neurodegeneration and the related risk–benefit profiles are markedly different in moderate or advanced stages of the disease.
Future indications could also involve combination therapies, where lecanemab is administered alongside other agents that target different pathological processes such as tau accumulation, neuroinflammation, or synaptic dysfunction. These combination approaches might offer a more comprehensive strategy to tackle the multifactorial nature of AD and could further justify the early therapeutic intervention. Moreover, as biomarkers and diagnostic technologies continue to advance, there is a possibility that the criteria for amyloid positivity may be refined, leading to a more personalized approach to treatment. If such trends persist, lecanemab might be indicated for a broader spectrum of patients based on a more nuanced understanding of disease progression and individual risk factors.
The regulatory framework is also being revisited as health authorities worldwide contemplate the introduction of accelerated pathways and conditional approvals for drugs addressing serious unmet needs. This could potentially facilitate the future expansion of lecanemab’s indication in regions outside the United States, especially as additional confirmatory data become available and real-world evidence is accumulated. In essence, while the current approved use for lecanemab is narrowly defined, the groundwork is being laid for potential future indications that could encompass preventive strategies, combination regimens, and even treatment modalities for more advanced stages of Alzheimer’s disease.

Conclusion
To summarize, lecanemab has been approved for a very specific indication: the treatment of early Alzheimer’s disease in individuals who either have mild cognitive impairment due to AD or mild Alzheimer’s dementia. The approval is contingent upon the confirmation of amyloid pathology, as verified by imaging or biomarker analyses, to ensure that only those patients most likely to benefit from the amyloid reduction effect receive the therapy.
The approval was achieved through a rigorous regulatory process that emphasized the role of surrogate biomarkers, such as amyloid plaque reduction, and modest clinical benefit as measured by scales like the CDR-SB. The clinical trials, particularly the Clarity AD study, provided compelling evidence—albeit modest in absolute clinical terms—that early intervention can slow the progression of cognitive decline and function deterioration.
From a global perspective, lecanemab’s development and approval represent a significant milestone in Alzheimer’s disease therapeutics. Its mechanism of action, which targets soluble Aβ protofibrils, signals a shift from purely symptomatic treatments to those intended to modify the underlying disease pathology. However, despite its promising impact on biomarker outcomes, its true clinical benefit remains a subject of ongoing debate and investigation, particularly regarding the long-term outcomes and safety profile.
In clinical practice, lecanemab is expected to be used with careful patient selection and close monitoring for adverse effects such as ARIA, which underscores the importance of adhering strictly to its approved indication in early AD. Ongoing research endeavors, including trials in preclinical AD populations and long-term extension studies, may eventually broaden its indication and improve our understanding of its impact on disease progression.
In conclusion, the currently approved indication for lecanemab is a critically important first step―targeting early Alzheimer’s disease in a carefully defined patient group. This reflects both the promise of disease modification in AD and the inherent challenges of balancing modest clinical benefits with safety considerations. As further evidence accumulates, the therapeutic role of lecanemab may evolve, potentially extending its benefits to a broader patient population or in combination with other treatment modalities. For now, the focus remains on its established indication in early AD, serving as a cornerstone for ongoing efforts to transform the management of this devastating disease.