A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody

Abstract

Background: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia.

Methods: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging.

Results: A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly.

Conclusions: BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway.

Trial registration: Clinical Trials.gov NCT01767311 .

Keywords: ADCOMS; Alzheimer’s disease; Amyloid; Amyloid PET; BAN2401; Biomarker; Clinical trial; Lecanemab; Neurofilament light; Neurogranin; p-tau.

Fig. 1

Lecanemab Study 201 study design. Study 201 (NCT01767311) was an 18-month, multicenter, double-blind, placebo-controlled Bayesian design clinical trial employing response adaptive randomization across placebo and five lecanemab arms (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) to assess safety and efficacy in subjects with early Alzheimer's disease. At the first three interim analyses, if there is a .5% posterior probability that the most likely ED90 is superior to placebo by the (clinically significant difference; 25%), the trial will stop early for futility. Beginning at the 350-subject IA, and continuing to completion of the trial, the futility criterion is increased to 7.5%. Interim monitoring for early success occurs at each IA beginning when 350 subjects have been enrolled. At this point, if enrollment were to stop for early success, enough subjects would be available to complete the trial so that the full dose response could be modeled. If there is a .95% posterior probability that the most likely ED90 is better than placebo by the CSD, then early success is declared. Enrollment is stopped, but all randomized subjects continue for the full 18-month duration of the study. If the trial is not stopped early for futility or success, then trial success is evaluated at the completion of the trial when both accrual and follow-up for the primary endpoint are complete. At that time, if there is a .80% probability that the most likely ED90 is better than placebo by the CSD, the trial will be considered a success. R, randomization

Fig. 2

Randomization allocations by treatment group per protocol-defined interim analyses. The response adaptive randomization correctly allocated subjects into the dose groups likely to be ED90 doses (10 mg/kg monthly and biweekly) as early as the first interim analysis at 197 subjects, with both emerging by the 300th subject randomized, and these doses remained the most likely doses to demonstrate efficacy throughout the remainder of the study. However, before the interim analysis of 350 subjects, Health Authorities restricted randomization around ApoE4 carrier status, whereby ApoE4 carriers (hetero- or homozygous) were not to be randomized to the 10 mg/kg biweekly dose going forward. As a consequence, the response adaptive randomization algorithm was revised. After each subsequent interim analysis (starting with 350 subjects randomized), the randomization probability vector was split between ApoE4 carrier and non-carrier strata to ensure no ApoE4 carriers were enrolled on the 10 mg/kg biweekly dose (more details in Appendix C). At the same time, the revised response adaptive randomization preserved the overall randomization probabilities

Fig. 3

Change from baseline in brain amyloid pathophysiology. Results as measured by amyloid PET SUVr are shown in a. Outcomes from the qualitative (binary) visual read of the PET scans for conversion of brain amyloid pathology from positive to negative are depicted in b. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (all nominal). For PET analysis, N = 306 at 12 months and N = 288 at 18 months. The PET substudy was optional, so only a portion of the total enrolled subject population opted to participate

Fig. 4

Efficacy assessments. a Change from baseline for 10 mg/kg biweekly and monthly doses in the Alzheimer’s Disease Composite Score (ADCOMS). The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal). The primary analysis conducted at month 12 of treatment for all subjects indicated that the 10 mg/kg biweekly dose had a 64% probability to be better than placebo by 25% on ADCOMS at 12 months, missing the pre-specified 80% probability threshold for success. Bayesian analysis at 18 months determined that the lecanemab 10 mg/kg biweekly dose had a 76% probability of being better than placebo by 25% on ADCOMS. In addition, Bayesian analyses indicated a 98% probability of being superior to placebo by any magnitude at both 12 and 18 months, respectively, which is consistent with subsequent conventional analysis results. b Results for 10 mg/kg biweekly and monthly doses on CDR-SB. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal). c Results for 10 mg/kg biweekly and monthly doses on ADAS-Cog14. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal)

Fig. 5

Change from baseline in CSF biomarker measures. a Change from baseline in CSF Aβ_1–42 measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.001. b Change from baseline in p-tau measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.001, **P = 0.005. c Change from baseline in t-tau measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P = 0.029