LEQEMBI Concentrate for solution for infusion Ref.[115156] Active ingredients: Lecanemab

Pharmacotherapeutic group: Psychoanaleptics, Other anti-dementia drugs
ATC code: N06DX04

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, 1795 patients were randomized to receive lecanemab 10 mg/kg every 2 weeks or placebo for 18 months, of which 1521 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 3 below.

Table 3. Results for CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in Study 301:

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 section 4.2 for information on paediatric use).