Lecanemab: A Humanized Monoclonal Antibody for the Treatment of Early Alzheimer Disease

Mechanism of Action

Lecanemab, also called lecanemab-irmb, BAN2401, or Leqembi, is a humanized monoclonal antibody that targets soluble Aβ aggregates including oligomers and protofibrils.^13,21,22 Aβ exists in various conformational states such as soluble monomers, soluble aggregates of different sizes (eg, oligomers, protofibrils), and insoluble fibrils in plaques.^13,14 Lecanemab has a high selectivity (at least 1000-fold) for soluble Aβ aggregates over soluble monomers and insoluble fibrils.^13,21,23

Soluble Aβ aggregates are considered more neurotoxic than soluble monomers and insoluble fibrils. Therefore, removing these soluble Aβ aggregates could be a promising approach for treating early AD.^13,14 Trials have been demonstrated that suppressing the neurotoxicity of Aβ results in a decrease in tau pathology.^13,14 This could indicate that amyloid toxicity is a contributing factor to the rise of tau formation and deposition. ²²

Lecanemab, a humanized version of murine mAb158 antibody, was developed by Swedish-based BioArctic and Japanese-based Eisai, starting from the murine mAb158 antibody generated at Uppsala University. ¹⁴ The murine antibody mAb158 was generated by immunizing mice with E22G (APP E693G) mutant Aβ protofibrils, also known as the “Arctic” mutation, which are characterized by elevated amounts of Aβ protofibrils. ¹⁵ In animal models, mAb158 antibody demonstrated reductions in Aβ deposition prior to plaque formation, as well as levels of Aβ protofibrils and Aβ plaques.^13-15 However, in older mice that already had plaques, the treatment with mAb158 did not affect levels of insoluble Aβ in their brains. ²³

Lecanemab binds to Aβ which flags the immune system to clear them from the brain, thus preventing the formation of Aβ aggregates and plaques. ²⁴ By targeting these aggregates, lecanemab reduces Aβ plaques, which are one of the defining pathophysiologic characteristics of AD during the early asymptomatic or preclinical stage.^13-16

Pharmacodynamics

Lecanemab, administered in a phase II clinical trial (NCT01767311), exhibited a dose-dependent reduction in brain Aβ plaques. ¹³ The quantification of amyloid plaque accumulation was accomplished through positron emission tomography with standardized uptake value ratio (PET SUVR). ¹³ The outcomes of the NCT01767311 study showcased a statistically significant decline in Aβ plaque levels among the lecanemab treatment groups, relative to the placebo group (P < 0.001), at the 12- and 18-month intervals.^11,13 The visual assessment revealed that 65% of subjects at 12 months and 81% of subjects at 18 months exhibited a conversion from amyloid positive to amyloid negative status. ¹³ The reduction in Aβ plaques potentially indicates a positive response to the treatment aligning with the hypothesis that these plaques contribute to cognitive decline.

PK/PD simulations demonstrated that biweekly dosing of lecanemab resulted in a greater and more rapid decrease in SUVR and phosphorylated tau 181 (p-tau 181), as well as an increase in the Aβ 42/40 ratio, in contrast to monthly dosing. ²⁵ This is noteworthy as the abnormal phosphorylation of tau protein at the 181st amino acid position is thought to be a key characteristic of AD and is linked to the formation of neurofibrillary tangles. ²⁶ p-tau 217 is a more novel biomarker associated with AD that is thought to be diagnostically superior to p-tau 181. ²⁶ However, the results of the correlation between p-tau 217 and lecanemab have not yet undergone investigation. This inquiry is being addressed in the AHEAD 3-45 Study, anticipated for completion in 2027.^27,28 During the off-treatment period where lecanemab was discontinued, there was an average yearly increase of 2.6 Centiloids in both SUVR and Centiloid values, indicating an increase in Aβ plaque levels. ¹¹ The Centiloid scale is a quantitative measurement used to assess amyloid burden in the brain in a standardized way where an increase in Centiloid values represents a greater amyloid burden, suggesting more extensive amyloid plaque deposition in the brain. ²⁹ Nevertheless, the difference between the plaque levels of the lecanemab and placebo groups was still maintained at the end of Study 201 suggesting the potential of lecanemab as a promising treatment for AD, even after discontinuation. ¹¹

In addition, Study 201 showed that the combined lecanemab 10 mg/kg dose interventions (10 mg/kg monthly and 10 mg/kg biweekly) showed increased cerebrospinal fluid Aβ-42 (CSF Aβ-42) levels and reduced p-tau levels compared to placebo. ¹¹ The reduction of CSF Aβ-42 may indicate Aβ aggregation in the brain.^11,30 However, inconsistent results were observed for total tau (t-tau) at months 12 and 18. ¹³ The least squares (LS) mean difference between the combined lecanemab 10 mg/kg treatment groups at 18 months was significant for CSF Aβ-42 (205.6, P < 0.001) and p-tau (–12.3, P = 0.013) compared to placebo, but not for t-tau (18.8, P = 0.67). ¹³

The study revealed that there was a positive correlation between higher exposures to lecanemab and greater increase in plasma Aβ 42/40 ratio and greater reduction in plasma p-tau, where a decreased Aβ 42/40 ratio and high p-tau levels are strong indicators of AD.^11,13,25

In terms of safety, ApoE4-positive homozygous subjects had the highest risk for symptomatic amyloid–related imaging abnormalities-edema (ARIA-E), on the highest dose of lecanemab (10 mg/kg biweekly) compared to heterozygotes and ApoE4-negative subjects.^11,13 ARIA-E is characterized by the accumulation of fluid in the brain swelling and inflammation in the brain. Although some patients with ARIA-E may present asymptomatic, others may experience a range of symptoms including headache, nausea, abnormal gait, dizziness, focal neurologic deficits, and visual disturbance. ²¹ Although there are no current differences in management of ARIA between ApoE4 carriers and noncarriers, it is recommended by the manufacturer to consider testing for ApoE4 status prior to initiating lecanemab to assess the risk of developing ARIA-E. ¹¹

Alzheimer Disease Composite Score (ADCOMS) was used in Study 201 to measure cognitive decline which is a composite score consisting of 4 items from the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog), 2 items from the Mini-Mental State Examination (MMSE), and all 6 items from the Clinical Dementia Rating-Sum of Boxes (CDR-SB). ³¹ It is thought that ADCOMS is more sensitive to clinical decline than the individual scales that it is based on and is undergoing evaluation for use as a standard outcome measure in clinical trials. ³¹ Lecanemab 10 mg/kg biweekly had a 64% probability of surpassing placebo with a 25% reduction in clinical decline on ADCOMS after 12 months and a 76% probability of achieving the same outcome after 18 months in the Bayesian analysis of Study 201.^11,13 A dose-dependent reduction in ADCOMS from baseline was observed with lecanemab at 18 months, resulting in a 30% and 15% decrease in clinical decline at 10 mg/kg biweekly and 10 mg/kg monthly doses, respectively, compared to placebo, according to the conventional analysis.^13,14,32 Lecanemab at 10 mg/kg biweekly and 10 mg/kg monthly doses demonstrated reductions of 26% and 17%, respectively, in clinical decline on the CDR-SB at 18 months; however, these differences did not reach nominal significance (P = 0.125 and 0.255, respectively). ¹³ On the other hand, at the over 10 mg/kg biweekly dose at 18 months, there was a significant reduction (47%, P = 0.017) in clinical decline in ADAS-Cog14, but in the 10 mg/kg monthly dose the clinical decline reduction was not significant (6%, P = 0.74). ¹³

Volumetric magnetic resonance imaging (MRI) results showed an increase in total hippocampal volume loss at the lecanemab 10 mg/kg biweekly dose compared to placebo, but did not reach nominal significance. ¹³ In addition, a decline in whole brain volume and ventricular volume was observed in the lecanemab treatment group compared to placebo. ¹³ It is important to note that the volumetric MRI results have not yet been fully analyzed by the Clarity AD investigators, as stated in the New England Journal of Medicine (NEJM) 2023 publication. ¹³ However, there is an ongoing open-label extension (OLE) study that may further explore the clinical significance and long-term effects of these volumetric changes. ¹³

During Study 201, 40.9% of subjects treated with lecanemab 10 mg/kg every 2 weeks developed anti-lecanemab antibodies, but the assays used to measure these antibodies were subject to interference by serum lecanemab concentrations, so the impact of these antibodies on the drug’s PK, PD, safety, or effectiveness remains unclear. ¹¹

Pharmacokinetics

The mean maximum plasma concentration and area under the concentration-time curve values of the first dose and final dose of BAN2401 were consistent across the Single Ascending Dose and Multiple Ascending Dose cohorts and increased proportionately with dose.^11,17 The median time to maximum concentration was reached within 1.8 to 2.2 hours after the initiation of lecanemab infusion. ¹⁷ The PK profile of lecanemab during the elimination phase showed first-order kinetics, with a mean half-life ranging from approximately 5 to 7 days.^9,11,23 No accumulation was observed at 28-day intervals, and biweekly infusions of 10 mg/kg achieved steady-state serum concentrations after the third dose, with a minimum observed concentration at steady state of approximately 40 μg/mL, with an accumulation factor of approximately 1.4. ²³ The volume of distribution at steady state was 3.22 L (95% CI, 3.15-3.28). ¹¹ Lecanemab is metabolized by proteolytic enzymes which in the same manner endogenous immunoglobulin G is degraded.^9,11 The clearance is 0.434 L/day (95% CI, 0.420-0.451). ¹¹

The sex, body weight, and albumin of the patient impact the exposure to lecanemab; however, they were not found to be clinically significant. ¹¹ There are no clinical studies evaluating the PK of lecanemab in patients with renal or hepatic impairment. ¹¹ However, since lecanemab is degraded by proteolytic enzymes it is not likely to undergo elimination or metabolism by hepatic enzymes. ¹¹

There have been no animal studies on the effects of lecanemab on male or female fertility. ¹¹ When lecanemab was administered intravenously every week at doses up to 100 mg/kg, there were no adverse effects observed on male or female reproductive organs in 39 weeks. ¹¹ Plasma exposures at the highest dose tested were approximately 24 times higher than those observed in humans receiving the recommended human dose of 10 mg/kg administered every 2 weeks. ¹¹

Phase II Trials

The safety, tolerability, and efficacy of lecanemab in adults with early AD were investigated in NCT01767311 (Study 201), a randomized, double-blind, phase IIb proof-of-concept clinical trial. ³² This study is divided into 3 sections: the 79-week double-blinded, placebo-controlled period (core), the OLE for up to 260 weeks, and the gap period which is time between the core study and OLE ranging between 9 and 59 months.^13,14,32,34 The key inclusion criteria for the patients in the core study were subjects who meet the National Institute of Aging-Alzheimer Association core clinical criteria and subjects with a CDR score of 0.5 to 1.0 and a Memory Box score of 5.0 or greater at baseline and screening. ³⁴ Some key exclusion criteria in the core study were subjects with any neurologic conditions that can contribute to cognitive impairment beyond that is caused by the subject’s AD, history of transient ischemic attacks (TIA), stroke or seizures within 12 months of screening, and any psychiatric diagnoses or symptoms which could interfere with study procedures. ³⁴ All subjects in this study with ARIA-E as assessed by MRI were discontinued immediately per protocol, regardless of radiologic severity or symptomatic status. ³⁴

In the core study, 857 subjects were assigned employing response adaptive randomization 1 of 5 doses of lecanemab (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly [n = 161]) or placebo [n = 247]).^34,35 The primary endpoint was to analyze the 12-month clinical change on ADCOMS for the ED90 dose using Bayesian analysis, which aimed to achieve an 80% probability of at least a 25% clinical reduction in decline compared to the placebo.^34,35 At 12 months of treatment, results of the study showed that the biweekly ED90 dose of 10 mg/kg had a 64% chance of outperforming the placebo by 25% on ADCOMS. However, this result did not meet the primary outcome which was the prespecified 80% probability threshold for success. ³⁴

The core study had several secondary endpoints at 18 months, including changes in Brain Amyloid Pathophysiology, ADCOMS, ADAS-Cog14, and CDR-SB from baseline. ³⁵ This included reduction of amyloid by PET SUVR accumulated in the brain (−0.30 adjusted mean change from baseline). ³⁵ Bayesian analyses revealed that compared to placebo, lecanemab 10 mg/kg biweekly resulted in a reduction of clinical decline at 18 months on ADCOMS (27%, mean difference from control −0.047, [95% CI, −0.093, −0.001], CDR-SB (33%, mean difference from control −0.413, [95% CI, −0.870, 0.038], and ADAS-Cog14 (56%, mean difference from control −2.021, [95% CI, –3.795, −0.273]), which were consistent with results from frequentist analyses. ³⁵ Conventional analyses revealed that over the 18-month period, lecanemab exhibited a dose-dependent reduction in clinical decline on ADCOMS, resulting in 30% (P = 0.034, LS mean difference −0.057) and 15% (P = 0.23, LS mean difference −0.028) reduction in clinical decline at 10 mg/kg biweekly and 10 mg/kg monthly, respectively, compared to placebo. ³⁵ This is also considered a clinically meaningful change as a change of 0.05 and 0.10 on ADCOMS is considered to be a clinically meaningful change in patients with mild cognitive impairment and dementia, respectively. ³⁶ The drug also showed a 47% (P = 0.017, LS mean difference −2.313) reduction in clinical decline on ADAS-Cog14 at 10 mg/kg biweekly compared to placebo where a 4-point change in ADAS-Cog indicates a clinically meaningful change.^35,37 However, on CDR-SB, the drug resulted in a 26% (P = 0.125, LS mean difference −0.396) less decline at 10 mg/kg biweekly and 17% (P = 0.255, LS mean difference −0.250) at 10 mg/kg monthly compared to placebo, but these differences were not clinically significant.^13,35,38

Demographic and baseline characteristics of each treatment group were balanced with the exception of ApoE4 status and that there were more male subjects in the lecanemab group compared to placebo (54% vs 42%, respectively). ³⁵ Following an emerging study that found that ApoE4-positive homozygous subjects on the highest dose of lecanemab 10 mg/kg biweekly had the highest risk of developing ARIA-E, the trial was amended to exclude ApoE4 carriers from being randomized to 10 mg/kg biweekly dose, leading to an imbalance in the distribution of ApoE4 status across treatment groups. ³⁵

The most common treatment-emergent adverse effects were mild to moderate infusion reactions and ARIA-E.^13,35 The incidence of ARIA-E/H on MRI was comparable to that of the placebo group.^23,24,35

Phase III Trials

Clarity AD (NCT03887455) is a randomized, placebo-controlled, double-blind, parallel-group phase III trial evaluating the efficacy of lecanemab in subjects with early AD by determining the superiority of lecanemab compared with placebo on change in cognition from baseline via CDR-SB.^20,39 The study included subjects 50 to 90 years of age with key inclusion criteria of either mild cognitive impairment due to AD or mild AD–related dementia on the basis of National Institute on Aging–Alzheimer Association criteria, positive biomarker for brain amyloid pathology by PET or CSF assessment of t-tau/Aβ, and MMSE score ≥22 but ≤30 at screening and baseline. ²⁰ Some key exclusion criteria include hypersensitivity to lecanemab, pregnant or breastfeeding females, individuals with neurologic conditions other than AD contributing to cognitive impairment, history of TIA, stroke or seizures within 12 months of screening, subjects scoring 9 or higher on the Geriatric Depression Scale, the presence of bleeding disorder that is inadequately controlled, and the presence of unstable or inadequately controlled medical conditions, such as cardiac, respiratory, gastrointestinal, or renal diseases. ²⁰

Overall participants had a mean age of 71 years, 52% were female, and majority of subjects were of white ethnicity (76%), followed by 2.5% black, 17% Asian, and 12.4% with Hispanic ethnicity. ²⁰ Most participants (80.8%) exhibited a global CDR score of 0.5, had an average CDR-SB score of 3.2, and a mean amyloid burden on PET scans of 76.6 Centiloids. ²⁰ Approximately 68.8% of participants tested positive for ApoE4, with 15.5% of them being homozygotes. ²⁰ The primary outcome of this study is the change from baseline in the CDR-SB at 18 months.^20,39 Participants (N = 1795) received lecanemab 10 mg/kg biweekly administered IV (n = 898) or placebo (n = 897).^8,39,40 At 18 months, the adjusted mean change from baseline in the CDR-SB score was 1.21 in the lecanemab group and 1.66 in the placebo group (95% CI, −0.67 to −0.23, P < 0.001). ⁸ The substudy of amyloid burden on PET (n = 698) showed reductions in brain amyloid plaques with treatment with lecanemab compared to placebo with a difference of −59.1 Centiloids (95% CI, −62.6 to −55.6). ⁸ The mean difference of ADAS-Cog14 score between lecanemab and placebo was −1.44 (95% CI, −2.27 to −0.61; P < 0.001) and for the ADCOMS was −0.050 (95% CI, −0.074 to −0.027; P < 0.001). ⁸ The mean difference of Alzheimer Disease Cooperative Study—Mild Cognitive Impairment—Activities of Daily Living score between the two groups was 2.0 (95% CI, 1.2-2.8; P < 0.001). ⁸ The most common adverse effects in the lecanemab group were infusion-related reactions (26.4%) and ARIA-E or effusions (12.6%). ⁸

The AHEAD 3-45 trial (also known as NCT04468659 and BAN2401-G000-303) is a phase III study that utilizes a placebo-controlled, double-blind, and parallel-treatment arm design. Its primary objective is to investigate the safety and effectiveness of lecanemab in patients with preclinical AD and elevated amyloid (A45 trial) and intermediate amyloid (A3 trial).^27,39,40 The study aims to determine whether initiating treatment during the preclinical, asymptomatic stages can potentially slow biomarker changes and/or cognitive decline in affected individuals. ²⁸ The dose of lecanemab used in the trial is 5 mg/kg administered intravenously every 2 weeks from weeks 0 to 6. ²⁸ This is followed by a dose of 10 mg/kg administered every 2 weeks from weeks 8 to 96. ²⁸ Subsequently, the dose is adjusted to 10 mg/kg administered every 4 weeks from weeks 96 to 216.^27,39 The A3 trial in the AHEAD 3-45 study will include cognitively unimpaired individuals ages 55 to 80 with intermediate amyloid levels (≈20-40 Centiloids) on screening PET scans and elevated amyloid (>40 Centiloids) for A45 trial. ²⁸ The A3 trial’s primary outcome is change from baseline in amyloid PET SUVR at week 216.^27,39 The A45 trial’s primary outcome is the change from baseline in preclinical Alzheimer Cognitive Composite 5 Score at week 216.^27,39 Both trials share a common screening process and assessment schedule, and the treatment period lasts for 4 years. ²⁸ The phase III trial is estimated to be completed in October 2027. ³⁹