Leqembi Mechanism of Action

Pharmacotherapeutic group: Psychoanaleptics, Other anti-dementia drugs. ATC code: N06DX04.
Pharmacology: Pharmacodynamics: Mechanism of action: Lecanemab is an IgG1 monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta and reduces amyloid beta plaques.
Pharmacodynamic effects: Effect of lecanemab on amyloid beta pathology: Lecanemab reduced amyloid beta plaque in a time-dependent manner compared with placebo. The effect of lecanemab on amyloid beta plaque levels in the brain was evaluated using PET imaging visual read, and was quantified using the Standard Uptake Value Ratio (SUVR) method and the Centiloid scale. In Study 301, the mean change from baseline relative to placebo was statistically significant for lecanemab 10 mg/kg every 2 weeks at Week 79 in the indicated population (-59.437).
Exposure-response relationships: Exposure response analysis showed that observed amyloid PET SUVR decreased with the increase in lecanemab exposure. PK/PD analysis showed that changes in CSF Aβ1-42, plasma Aβ42/40 ratio and plasma p-tau181 correlated with the increase in exposure to lecanemab.
Immunogenicity: The immunogenicity of lecanemab has not been sufficiently evaluated due to limitation of ADA assay. The impact of ADA on pharmacokinetics, efficacy and safety has not been sufficiently evaluated.
Clinical efficacy and safety: The efficacy of lecanemab was evaluated in a double-blind, placebo-controlled, parallel-group, randomized trial (Study 301) in patients with Early Alzheimer's disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment [62% of patients] or mild dementia stage of disease [38% of patients]).
Aβ pathology was determined by visual read using approved Aβ PET tracers according to the label and CSF by total tau (t-tau)/Aβ42 ratio with the validated cut-off >0.54 (assay (assay: Lumipulse G P-Amyloid 1-42).
Patients were enrolled with the following criteria: Clinical Dementia Rating (CDR) global score of 0.5, or 1.0 and a Memory Box score of 0.5 or greater.
The National Institute on Aging and the Alzheimer's Association (NIA-AA) core clinical criteria for mild cognitive impairment or probable Alzheimer's disease dementia.
Mini-Mental State Examination (MMSE) score of ≥22 and ≤30.
Objective impairment in episodic memory as indicated by at least 1 standard deviation below the age-adjusted mean in the Wechsler-Memory Scale-IV Logical Memory II (subscale) (WMS-IV LMII).
Patients were excluded for evidence of history of transient ischemic attacks (TIA), stroke or seizures within 12 months of screening, cerebral contusion, infective lesions, multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel or white matter disease, bleeding disorders that are not under adequate control, immunologic disorders that were not adequately controlled (e.g., active vasculitis) or required therapy with immunoglobulins, systemic monoclonal antibodies, systemic immunosuppressants or plasmapheresis.
The safety and efficacy of treatment in patients with moderate Alzheimer's disease, atypical Alzheimer's disease syndromes (without memory-predominant Alzheimer's disease), autosomal dominant Alzheimer's disease, or adults with Down syndrome is not established.
In Study 301, 1,795 patients were randomized to receive lecanemab 10 mg/kg every 2 weeks or placebo for 18 months, of which 1,521 were in the indicated population. Of the total number of patients randomized, 31% were non-carriers, 53% were heterozygotes and 16% were homozygotes. At baseline, the median age of randomized patients was 72 years, with a range of 50 to 90 years. Fifty-two percent of patients were women; 77% were Caucasian, 17% were Asian, and 3% were Black. Comorbidities included hyperlipidaemia (60%), hypertension (55%), obesity (17%), ischemic heart disease (16%) and diabetes (15%).
The randomization was stratified according to clinical subgroup; the presence or absence of concomitant symptomatic medication for Alzheimer's disease at baseline; ApoE ε4 carrier status; and region.
Study 301 results: The primary efficacy outcome was change from baseline at 18 months in the CDR-SB. Key secondary endpoints included change from baseline after 18 months for the following measures: amyloid PET using Centiloids, ADAS-Cog14, Alzheimer's Disease Composite Score (ADCOMS), and Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).
For the overall population, the difference between lecanemab and placebo in the change from baseline in CDR-SB was -0.401 (95% CI: -0.622, -0.180). The effect was similar in the overall and the indicated restricted population. Important findings from the study for the indicated population are presented in Table 1 as follows. (See Table 1.)

Click on icon to see table/diagram/image

Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with lecanemab in all subsets of the paediatric population in early Alzheimer's disease (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: The PK of lecanemab was characterized using a population PK analysis with concentration data collected from 1,619 patients with Alzheimer's disease who received lecanemab in single or multiple doses. Steady state concentrations of lecanemab were reached after 6 weeks of 10 mg/kg every 2 weeks treatment and systemic accumulation was approximately 1.4-fold. The peak concentration (C_max), and area under the plasma concentration versus time curve (AUC) of lecanemab increased dose proportionally in the dose range of 0.3 to 15 mg/kg following single dose.
Absorption: Not applicable.
Distribution: The mean value (95% CI) for volume of distribution at steady state is 5.52 (5.14-5.93) L.
Biotransformation: Lecanemab is a mAb that targets soluble and insoluble aggregated forms of amyloid beta, and is not expected to be involved in cytokine modulated pathways.
Elimination: Lecanemab is degraded by proteolytic enzymes in the same manner as endogenous IgGs. Lecanemab clearance (95% CI) is 0.370 (0.353-0.384) L/day. The terminal half-life is 5 to 7 days.
Linearity/non-linearity: Lecanemab exhibits linear pharmacokinetics.
Hepatic or renal impairment: Lecanemab elimination occurs through normal degradative pathways for immunoglobulins, and the systemic clearance should not be affected by renal or hepatic impairment. Liver function biomarkers (ALT, AST, ALP, total bilirubin) and creatinine clearance did not affect the PK parameters of lecanemab.
Toxicology: Preclinical safety data: Carcinogenesis: Carcinogenicity studies have not been conducted.
Mutagenesis: Genotoxicity studies have not been conducted.
Developmental and reproductive toxicity: No studies in animals have been conducted to assess the effects of lecanemab on male or female fertility or developmental and reproductive function. No adverse effects on male or female reproductive organs were observed in a 39-week intravenous toxicity study in monkeys administered lecanemab weekly at doses up to 100 mg/kg (corresponding to plasma exposures 27-fold higher than in humans at the recommended dose). The relevance of these data to humans is limited since aggregate Aβ species are not present in healthy monkeys.