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In a phase 3 trial, participants with early Alzheimer’s disease who received the monoclonal antibody lecanemab had less decline on measures of cognition and function at 18 months than those who received placebo.

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 .

Background Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. Methods The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). Results At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181. Conclusions Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. Trial registration ClinicalTrials.gov NCT01767311 .

INTRODUCTION Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at amyloid plaques. Amyloid‐related imaging abnormalities (ARIA) profiles appear to differ for various anti‐amyloid antibodies. Here, we present ARIA data from a large phase 2 lecanemab trial (Study 201) in early Alzheimer's disease. METHODS Study 201 trial was double‐blind, placebo‐controlled (core) with an open‐label extension (OLE). Observed ARIA events were summarized and modeled via Kaplan‐Meier graphs. An exposure response model was developed. RESULTS In the phase 2 core and OLE, there was a low incidence of ARIA‐E (<10%), with <3% symptomatic cases. ARIA‐E was generally asymptomatic, mild‐to‐moderate in severity, and occurred early (<3 months). ARIA‐E was correlated with maximum lecanemab serum concentration and incidence was higher in apolipoprotein E4 (ApoE4) homozygous carriers. ARIA‐H and ARIA‐E occurred with similar frequency in core and OLE. DISCUSSION Lecanemab can be administered without titration with modest incidence of ARIA.

Background Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer’s disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer’s Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. Methods The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. Results The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. Conclusions The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

Soluble amyloid-β protofibrils (Aβ-PF) are synaptotoxic species and are in equilibrium with amyloid plaques. Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ protofibrils. We developed a sensitive immunoassay using lecanemab as the capture antibody that selectively quantifies Aβ-PF in cerebrospinal fluid (CSF), and found CSF Aβ-PF levels significantly increased in Alzheimer's disease (AD) and correlated with neurodegeneration biomarkers (Shinohara-Noguchi, Ann Neurol. 2025). In this report, we further characterized CSF Aβ-PF in the Phase 3 study of lecanemab (Clarity AD): (1) at baseline, (2) longitudinally in placebo arm (natural history), and (3) demonstrated the target engagement (in vivo protofibril binding) of lecanemab. CSF samples collected from the Clarity AD were analyzed using the developed immunoassay. The assay is tolerant to therapeutic lecanemab in the CSF, and measures total Aβ-PF (bound and unbound). 410 subjects (Placebo=207, Lecanemab=203) had a CSF sample at baseline and 253 subjects (Placebo=127, Lecanemab=126) had a CSF sample at baseline and at least one post-baseline sample. Other biomarker assessments including amyloid-PET, and CSF biomarkers including neurogranin were described previously and used for correlation analyses. Baseline CSF Aβ-PF showed significant correlation with neurogranin, a biomarker of synaptic dysfunction (r=0.153, p =0.0127). In the placebo arm, there was an increase from baseline in CSF Aβ-PF levels which significantly correlated with the increase from baseline observed in CSF neurogranin levels. In the lecanemab-treatment arm, the CSF total Aβ-PF levels (free and bound) increased relative to placebo at each of the post-baseline assessments (p =0.0126 at 12 months and numerically higher at 18 month). In the subjects achieving amyloid-negativity defined as Centiloid<30 at 18 months, lecanemab-treatment group demonstrated a larger percent change from baseline compared with subjects who remained amyloid-positive (Centiloid≥30) at 18 months. The novel immunoassay for the CSF Aβ-PF indicates that soluble Aβ-PF is quantifiable in human CSF in vivo. Increase in total (free and bound) CSF Aβ-PF with lecanemab-treatment is consistent with binding of Aβ-PF to lecanemab (target engagement), and mobilization of Aβ-PF from amyloid plaques (pharmacodynamic effect), confirming the unique dual mechanism of lecanemab targeting toxic Aβ-PF and plaques.

A subcutaneous formulation of the anti-amyloid antibody lecanemab is being developed to improve patient convenience and safety. Herein, we will give an update on the early development history of subcutaneous lecanemab, including establishing the bioavailability and bioequivalence of a lecanemab subcutaneous formulation relative to the intravenous formulation. Two single-dose phase 1 clinical trials in healthy adult participants were performed. The first study was a randomized, parallel-group study in 60 participants evaluating the absolute bioavailability and pharmacokinetic profile of lecanemab when administered subcutaneously in a 700 mg fixed dose compared to 10 mg/kg of intravenous lecanemab. The second study was a randomized, parallel-group study in 160 participants to establish the bioequivalence of 720 mg subcutaneous lecanemab when administered by vial compared to autoinjector. Concentrations of lecanemab in serum were measured for 50 days, and noncompartmental PK parameters were calculated. Exposure-response modeling was conducted to predict efficacy for subcutaneous formulations. In the bioavailability study (subcutaneous:29; intravenous:30 subjects), mild/moderate injection site reactions were experienced by 6 (20.7%) subjects who received subcutaneous lecanemab, whereas grade 1 and 2 infusion-related reactions were experienced by 10 (33.3%) subjects who receive intravenous lecanemab. The absolute bioavailability of subcutaneous vial was 49.7% (90% CI: 43.5, 56.8). In the bioequivalence study (vial/syringe:80; autoinjector: 80 subjects), the mean Cmax for vial/syringe (53.7 μg/mL) was lower than the mean Cmax for the autoinjector (67.4 μg/mL). The mean AUC(0-t) and AUC(0-inf) were lower for vial/syringe (17,100 and 17,500 ug·h/mL, respectively) compared to the autoinjector (20,600 and 20,900 ug·h/mL, respectively). The half-life of lecanemab was approximately 7 days in both treatment groups. Autoinjector administration resulted in approximately 25% higher Cmax and 20% higher AUC compared to administration with vial/syringe. The upper 90% CI of the difference in geometric means were outside the standard reference of 125%, therefore bioequivalence of the autoinjector and vial/syringe administrations was not demonstrated. However, based on these results, exposure-response models predicted similar amyloid plaque lowering and efficacy for intravenous, subcutaneous vial and autoinjector. Subcutaneous injection of lecanemab using a vial or autoinjector yielded comparable average steady-state concentrations to intravenous administration of lecanemab in healthy patients.

Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid-beta (Aβ) protofibrils. In the 18-month, phase 3 Clarity AD study, lecanemab demonstrated amyloid reduction and cognition and function decline slowing in participants with early symptomatic Alzheimer's disease (AD). An ongoing open-label extension (OLE) of Clarity AD is evaluating long-term safety and efficacy of lecanemab. Herein, we report the initial findings up to 48 months from the ongoing Clarity AD OLE study. Clarity AD is an 18-month, randomized study (Core) followed by an OLE phase in individuals with early AD. Clinical (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) outcomes and safety were evaluated from OLE data out to 48 months. Continued lecanemab treatment in the OLE beyond the 18 months from the Core study was compared to a matched control from Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Subgroup analyses were conducted for participants with no/low baseline tau. Efficacy assessments were also summarized as the percentage of participants who had 'no decline' or had 'improvement' from Core baseline at each timepoint. Overall, 1734 participants were treated with lecanemab across the Core and OLE. Across clinical endpoints, lecanemab-treated participants continued to benefit through 48 months. In the OLE, lecanemab treatment continued to delay progression through 48 months compared to ADNI matched control, with differences in CDR-SB increasing over 18 months (0.52), 36 months (1.01), and 48 months (1.75). Consistent rates of clinical stability or improvements were observed across assessments regardless of baseline tau levels, with the highest rates of improvements observed for the no/low tau group at 48 months (CDR-SB: no decline:69%, improvement:56%; ADAS-Cog14: no decline:51%, improvement:51%; ADCS MCI-ADL: no decline:64%, improvement:58%). No new safety signals were observed. ARIA rates were low and similar to ARIA rates on placebo after 6 months. In Clarity AD, the observed increasing treatment difference with ongoing lecanemab treatment in participants treated through 48 months versus ADNI matched placebo data is consistent with a durable disease-modifying effect. The long-term safety profile of lecanemab was confirmed, with no new safety signals.

Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously was shown in the Clarity AD trial to slow the progression of Alzheimer's disease (AD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady-state concentrations (Cav, ss) are associated with amyloid plaque lowering and efficacy, while maximum steady-state concentrations (Cmax, ss) are correlated with ARIA-E. A subcutaneous lecanemab formulation was hypothesized to have similar or better safety profile, with lower rates of systemic administration reactions. Herein, we provide an update on the clinical results from the subcutaneous lecanemab development program. Clarity AD is a phase 3, double-blind, placebo-controlled study of 18-month treatment duration with an ongoing open-label extension (OLE) in patients with early AD. Eligible patients were randomized to placebo or 10 mg/kg lecanemab biweekly. Subcutaneous dosing is under development based on pharmacokinetic (PK) and pharmacodynamic (PD) modeling, bioavailability data, as well as clinically in a substudy of the OLE. A subset of participants in the subcutaneous substudy were lecanemab naïve. Validated anti-drug antibodies (ADA) and neutralizing antibody (Nab) assays were performed using a tiered approach. In the Clarity AD phase 3 study, lecanemab subcutaneous weekly dosing with a single 360 mg autoinjector has low rate of ADA (2%) with low titers and maintains plasma biomarkers at levels consistent with inhibition of AD pathology and neuroinflammation; PK was not affected by immunogenicity. From modeling data, initiating subcutaneous maintenance dosing of 360 mg weekly at 18- or 24-months results in similar effect on amyloid PET and CDR-SB compared to biweekly dosing for 4 years. There was no ARIA-E, ARIA-H, or deaths reported in participants receiving 360 mg subcutaneous lecanemab. Injection site reactions were infrequent and mostly of mild or moderate severity. Systemic reactions to subcutaneous treatment were uncommon. Among dosing options tested, lecanemab subcutaneous 360 mg autoinjector was selected as the optimal formulation for maintenance therapy. Subcutaneous lecanemab has low-risk for immunogenicity. Lecanemab, administered subcutaneously, has a safety, tolerability, and pharmacodynamic profile that favorably compares to the approved 10mg/kg biweekly intravenous dose, and autoinjector administration provides greater patient convenience.

BACKGROUND This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer's disease (AD). METHODS Plasma pTau217R was measured using immunoprecipitation‐mass spectrometry. Models for predicting tau PET SUVR, developed with 144 early AD individuals using [18F]MK6240, were validated in two validation sets, VS1 (98 early AD) and VS2 (47 preclinical/early AD with a different tracer, flortaucipir (Tauvid)), all amyloid‐beta positive (Aβ+). RESULTS The pTau217R‐based model predicted tau levels up to an SUVR of 2 in multiple brain regions, effectively assessing tau status at different tau levels with receiver operating characteristic (ROC) curve areas of 0.84–0.95 in VS1 and 0.71–0.88 in VS2 (using a different tracer). It reduced PET scan needs by 65% while maintaining 95% sensitivity. DISCUSSION PTau217R reliably predicts regional tau accumulation in early AD, reducing reliance on tau PET scans and broadening its clinical application. CLINICAL TRIAL REGISTRATION NUMBER: NCT03887455 (ClarityAD) Highlights Developed a model using plasma pTau217R to predict tau levels across brain regions. pTau217R model outperformed models based on clinical, MRI, and other blood biomarkers. The model reliably predicted tau levels exceeding tau positivity and higher thresholds. Screening with pTau217R could reduce tau PET scans by 65% at 95% sensitivity. pTau217R model aids in disease staging and monitoring in early AD.