Lecanemab

Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. Lecanemab reduces amyloid beta plaques, as evaluated in Study 1 and Study 2.

Effect of lecanemab on Amyloid Beta Pathology

The effect of lecanemab on amyloid beta plaque levels in the brain was evaluated using Positron Emission Tomography (PET) imaging. The PET signal was quantified using the both the Standard Uptake Value Ratio (SUVR) and Centiloid scale to estimate levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer’s disease pathology (frontal, parietal, lateral temporal, sensorimotor, and anterior and posterior cingulate cortices), compared to a brain region expected to be spared of such pathology (cerebellum).

Lecanemab reduced amyloid beta plaque in a dose- and time-dependent manner in the dose-ranging study (Study 1) and in a time-dependent manner in single-dosing regimen study (Study 2) compared with placebo [see Clinical Studies (14)].

In Study 1, treatment with lecanemab 10 mg/kg every two weeks reduced amyloid beta plaque levels in the brain, producing reductions in PET SUVR compared to placebo at both Weeks 53 and 79 (p<0.0001). The magnitude of the reduction was time- and dose-dependent.

During an off-treatment period in Study 1 (range from 9 to 59 months; mean of 24 months), SUVR and Centiloid values began to increase with a mean rate of increase of 2.6 Centiloids/year, however, treatment difference relative to placebo at the end of the double-blind, placebo-controlled period in Study 1 was maintained.

In Study 2, treatment with lecanemab 10 mg/kg every two weeks reduced amyloid beta plaque levels in the brain, producing reductions compared to placebo starting at Week 13 and continuing through Week 79 (p<0.0001).

An increase in plasma Aβ42/40 ratio (Table 6) and CSF Aβ[1-42] was observed with lecanemab 10 mg/kg every two weeks dosing compared to placebo.

Effect of lecanemab on Tau Pathophysiology

A reduction in plasma p-tau181 (Table 6), CSF p-tau181, and CSF t-tau was observed with lecanemab 10 mg/kg every two weeks compared to placebo.

Table 6. Effect of lecanemab on Plasma Aβ42/40 and Plasma p-tau181 in Study 1 and Study 2:

N is the number of patients with baseline value.
¹ P-values were not statistically controlled for multiple comparisons.
² Results should be interpreted with caution due to uncertainties in bioanalysis.
³ Month 18 represents Week 79 in Study 1 and Week 77 in Study 2

A substudy was conducted in Study 2 to evaluate the effect of lecanemab on neurofibrillary tangles composed of tau protein using PET imaging ( ¹⁸F-MK6240 tracer). The PET signal was quantified using the SUVR method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer’s disease pathology (whole cortical gray matter, meta-temporal, frontal, cingulate, parietal, occipital, medial temporal, and temporal) in the study population compared to a brain region expected to be spared of such pathology (cerebellum). The adjusted mean change from baseline in tau PET SUVR, relative to placebo, was in favor of lecanemab in the medial temporal (p<0.01), meta temporal (p<0.05), and temporal (p<0.05) regions. No statistically significant differences were observed for the whole cortical gray matter, frontal, cingulate, parietal, or occipital regions.

Exposure-Response Relationships

Model based exposure-response analyses demonstrated that higher exposures to lecanemab were associated with greater reduction in clinical decline on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) and Alzheimer Disease Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14). In addition, higher exposures to lecanemab were associated with greater reduction in amyloid beta plaque. An association between reduction in amyloid beta plaque and clinical decline on CDR-SB and ADAS-Cog14 was also observed.

Higher exposures to lecanemab were also associated with greater increase in plasma Aβ42/40 ratio and greater reduction in plasma p-tau181.

Steady-state concentrations of lecanemab were reached after 6 weeks of 10 mg/kg administered every 2 weeks and systemic accumulation was 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.

Distribution

The mean value (95% CI) for central volume of distribution at steady-state is 3.24 (3.18-3.30) L.

Elimination

Lecanemab is degraded by proteolytic enzymes in the same manner as endogenous IgGs. The clearance of lecanemab (95% CI) is 0.370 (0.353-0.384) L/day. The terminal half-life is 5 to 7 days.

Specific Populations

Sex, body weight, and albumin were found to impact exposure to lecanemab. However, none of these covariates were found to be clinically significant.

Patients with Renal or Hepatic Impairment

No clinical studies were conducted to evaluate the pharmacokinetics of lecanemab in patients with renal or hepatic impairment. Lecanemab is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes.