Lecanemab

Lecanemab is the first anti-amyloid antibody that causally targets the causes of Alzheimer's disease and is intended to remove beta-amyloid protein deposits from the brain, thereby improving cognitive symptoms and slowing the progression and deterioration of quality of life.

As the exact cause and pathomechanisms of Alzheimer's disease are not yet fully understood, drug therapy options to date have essentially been limited to symptomatic treatment with the aim of at least temporarily improving cognitive impairment.

Lecanemab is one of the first approaches to the development of a causal therapy for Alzheimer's dementia and is based on the hypothesis that increasing deposition of amyloid fibrils is the cause of the occurrence and progression of cognitive symptoms. Antibodies are used to dissolve the amyloid deposits and thereby improve symptoms and/or prevent/delay progression of the disease.

In 2024, the EMA initially rejected the approval of lecanemab. Reason: the comparatively very small and clinically hardly relevant benefit does not outweigh the risk of serious side effects (negative benefit-risk balance). In addition, the considerable diagnostic effort associated with the treatment further restricts the quality of life of patients and leads to a not inconsiderable additional burden on the healthcare system, although there are already insufficient resources available for the complex care and support of these patients.

In the meantime, approval has been granted by the EMA with restriction to a subgroup of lower-risk patients in the very early stages of Alzheimer's disease and with the exclusion of homozygous carriers of the ApoE4 risk gene, which is associated with the increased occurrence of serious side effects of the treatment, was granted subject to conditions, as it is assumed that in this small subgroup of patients a slight improvement in cognitive symptoms with a slight delay in the manifestation of the disease by approx. 6 months with an acceptable risk of the occurrence of serious side effects justifies the approval.

Note: The high costs of lecanemab and the additional high costs and resources for the necessary diagnostics and therapy monitoring, with limited benefit for a rather small patient population at a very early stage of the disease, and already major challenges and lack of resources in the care for the majority of patients affected by Alzheimer's dementia, are to be assessed rather critically. The expectations of patients and the pressure for early treatment can currently only be met to a very limited, clearly indicated extent due to the lack of diagnostic resources and the treatment does not offer a general solution for the treatment of Alzheimer's dementia.

This treatment option is not suitable for patients who are homozygous ApoE4 carriers, who develop the disease earlier and often more severely, and who make up a large proportion (approx. 15%) of AD patients.

Mechanism of action:

The action of lecanemab is based on the amyloid hypothesis, i.e. on the assumption that the accumulation of amyloid plaques is a major pathomechanism and triggering factor of Alzheimer's disease.

Lecanemab is an IgG1 monoclonal antibody that targets aggregated soluble and insoluble forms of amyloid beta and is designed to dissolve and reduce amyloid beta plaques.

Lecanemab has been shown to reduce amyloid plaques in the brain and leads to moderately less deterioration of cognitive symptoms.

In patients with only very mild cognitive symptoms, it is assumed that the moderately reduced deterioration could correspond to a delay and possible improvement in quality of life of approximately 6 months. However, the results refer to the total number of patients evaluated in the subpopulation with only very mild symptoms and are not related to the course of individual patients.

In patients with more pronounced symptoms, it is not to be expected that the only moderate reduction in deterioration will be reflected in everyday abilities or lead to a significant change in quality of life.

The treatment does not lead to a cure for Alzheimer's dementia and cannot generally halt progression, but can only lead to a delay in progression.

Whether the reduction of amyloid plaques alone can lead to an improvement in symptoms is unclear, as other pathomechanisms for the disease are also being discussed and lecanemab can only address the pathomechanism of Alzheimer's plaques. Only further research and additional treatment options can shed light on this in the future.

Clinical phase III study CLARITY-AD: RCT multicenter study, 18 months, 1795 patients (898 lecanemab), age 50-90 yrs; mean CDR-SB score (Clinical Dementia Rating-Sum of Boxes, scale 0-18 with higher values for more severe impairment) at baseline approx. 3.2 in bd. groups; primary endpoint: impairment based on CDR-SB score after 18 months of treatment; secondary endpoint: change in amyloid burden based on PET; score on cogn. Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range: 0 to 90; higher values indicate more severe impairment), Alzheimer's Disease Composite Score (ADCOMS; range: 0 to 1.97; higher values indicate more severe impairment and score of the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range: 0 to 53; low values indicate more severe impairment).

Results: primary endpoint: adjust. least-squares mean change baseline after 18 mo. CDR-SB score: 1.21 lecanemab versus 1.66 placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). Secondary endpoints: moderate improvements in the other scales results in favor of lecanemab (for details see van Dyck et al 2023). Subgroup analysis of amyloid burden in PET in 698 patients shows mean amyloid level at baseline of 77.92 centiloids in the lecanemab group and 75.03 centiloids in the placebo group adj. mean change from baseline after 18 mo: -55.48 centiloids in lecanemab and 3.64 centiloids in placebo (difference, -59.12 centiloids; 95% CI, -62.64 to -55.60; P<0.001). Serious adverse events: 14.0% of patients in the lecanemab group and 11.3% in the placebo group (for details see van Dyck et al 2023).

Summary assessment: the clearly detectable reduction in amyloid plaques only leads to a slight delay in the progression of cognitive impairment. The difference in CDR-SB is not considered clinically significant by some experts. In contrast, treatment with lecanemab leads to an increase in serious side effects. The costs of treatment and additional diagnostics required are considered to be significantly too high (see also Jönsson L et al 2023).

Lecanemab is a recombinant, humanized, monoclonal immunoglobulin gamma 1 (IgG1) antibody (monoclonal antibody, mAb) produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells.

Steady-state concentrations of lecanemab are reached after 6 weeks of treatment with 10 mg/kg every 2 weeks.

Approximately 1.4-fold systemic accumulation is expected.

The peak concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of lecanemab increase dose-proportionally within the dose range of 0.3 mg/kg to 15 mg/kg after a single dose.

Lecanemab is degraded via proteolytic enzymes in a similar way to endogenous IgG.

The clearance of lecanemab (95% CI) is 0.370 l/day (0.353 - 0.384). The terminal elimination half-life is 5 to 7 days.

for the treatment of adult patients with

clinically diagnosed early Alzheimer's disease with signs of mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (clinical examination, cognitive testing, exclusion of other causes, MRI, CT if necessary).

and

confirmed amyloid pathology detected by amyloid PET scan (allows in-vivo quantification of cerebral amyloid plaques) and biomarkers from cerebrospinal fluid (in the near future, additional biomarkers from blood may also become available).

and

proven non-carriers of the apolipoprotein E ε4 (ApoE ε4) gene or only heterozygous carriers of the ApoE ε4 gene. A standardized, certified genetic test is mandatory before therapy, as homozygous carriers of the ApoE ε4 gene variant have an increased risk of severe adverse effects ARIA-E and ARIA-H and treatment with lecanemab is contraindicated in these patients! (see also: Apolipoprotein E).

Therapy initiation and treatment should only be carried out by a doctor with experience in the diagnosis and treatment of Alzheimer's dementia and the ability to carry out MRI examinations promptly.

Patients must be informed in detail about the treatment and informed about the risks and possible adverse effects. Patients receive a patient card, which they should carry with them at all times.

The infusion should only be carried out by appropriately trained personnel.

Recommended dose: 10 mg/kg body weight, as an intravenous (IV) infusion over a period of 1 hour once every 2 weeks; after the first application, monitor for 2.5 hours for signs of infusion-related reactions/adverse effects. Use as a diluted solution; for instructions on the preparation of the solution, see technical information.

Duration of therapy: as soon as progression to moderate Alzheimer's disease has occurred, treatment should be discontinued.

Course of therapy and monitoring: APO E genotyping must be performed prior to initiation of therapy using standardized, validated certified in-vitro tests. The APO E status must be available for the risk assessment of the occurrence of ARIA (Amyloid Related Imaging Abnormalities) as an expression of serious side effects of therapy with lecanemab (separate patient information and consent to the test must be observed!).

Cognitive progression: approximately every 6 months review of cognitive function and assessment of clinical symptoms to assess the course of the disease or the presence of progression to assess the effectiveness of the therapy and decide whether to continue or discontinue therapy.

Monitoring for amyloid-related imaging abnormalities (ARIA), which can also lead to discontinuation of therapy:

As a basis for radiological assessment, a baseline brain MRI must be available before the start of treatment (not older than 6 months) and a brain MRI must be performed before the 3rd^* 5th / 7th and 14th infusion. As a rule, the MRI should be carried out and the results obtained 1 week before the next planned ^infusion*.

* Red Hand Letter dated 26.09.2025^, as cases of ARIA have already occurred early on in treatment in non-European countries.

ARIA with edema (ARIA-E): recognizable on MRI as cerebral edema or fluid accumulation in the sulci.
ARIA with hemosiderin deposition (ARIA-H): recognizable as microbleeds and superficial siderosis.

In addition to ARIA, intracerebral hemorrhages with a diameter of more than 1 cm may occur during treatment with lecanemab. These always lead to the definitive, permanent discontinuation of therapy!

The extent and severity of ARIA is assessed on the basis of clinical and radiological findings and, in addition to the cognitive findings, is the most important basis for deciding whether to continue, interrupt or discontinue treatment. For recommendations on the classification of ARIA with regard to the decision to interrupt or discontinue treatment, see also the introductory information.

Delayed or missed dose: in case of a missed infusion, the next dose should be administered as soon as possible.

Special patient groups: no dose adjustment necessary in elderly patients (≥65 yrs); mild to moderate renal impairment; mild to moderate hepatic impairment. The drug has no relevance in children and adolescents.

For better monitoring of safety and efficacy, treatment is recorded in a central registry system.

For traceability, the name of the medicinal product and the batch number of the medicinal product used must be clearly documented.

1. Cohen S, van Dyck CH, Gee M et al.(2023) Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer's Disease. J Prev Alzheimers Dis. 10(4):771-777. doi: 10.14283/jpad.2023.123
2. Honig, L.S., Sabbagh, M.N., van Dyck, C.H. et al. (2024). Updated safety results from phase 3 lecanemab study in early Alzheimer's disease. Alz Res Therapy 16, 105. doi.org/10.1186/s13195-024-01441-8
3. Jönsson L, Wimo A, Handels R et. al. (2023). The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer's disease: an EADC-EC viewpoint. Lancet Reg Health Eur 29:100657. DOI: 10.1016/j.lanepe.2023.100657
4. Nelson SE and Lopez OL (2024).Lecanemab for Alzheimer Disease. Is It Worth It? neurology 102.7 doi/10.1212/WNL.0000000000209265
5. van Dyck CH, Swanson CJ, Aisen , et al (2023) Lecanemab in Early Alzheimer's Disease. N Engl J Med. 388(1):9-21. doi/full/10.1056/NEJMoa2212948
6. Villain N, Planche V, Lilamand M et al (2025). Lecanemab for early Alzheimer's disease: Appropriate use recommendations from the French federation of memory clinics. The Journal of Prevention of Alzheimer's Disease, Volume 12, Issue 4, 2025. doi.org/10.1016/j.tjpad.2025.100094

Technical information Lecanemab Lequembi ^®

Red Hand Letter Lecanemab from 26.09.2025