Lecanemab in patients with early Alzheimer's disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

Abstract

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 .

Fig. 1

Results for A amyloid PET SUVr and B Centiloid scale assessments from study 201 core

Fig. 2

Correlation between adjusted mean differences (+/− standard error) from placebo in amyloid PET and clinical efficacy endpoints (A CDR-SB; B ADCOMS; C ADAS-Cog) at 18 months

Fig. 3

Time courses of predicted change from baseline in A CDR-SB, B ADCOMS, and C ADAS-Cog14 by PET SUVr change from baseline

Fig. 4

Change in A plasma Aβ42/40 ratio and B p-tau181 by treatment group in study 201 core based on standardized value

Fig. 5

Population correlations between amyloid PET using Centiloids and plasma A Aβ42/40 ratio and B p-tau181 based on standardized value

Fig. 6

Time course of predicted change from baseline in clinical endpoints by plasma A Ab42/40 ratio and B p-tau181 change from baseline

Fig. 7

Imaging, biomarker, and cognitive effects during and after treatment with lecanemab in the study 201 core and gap period for A amyloid PET SUVr, B amyloid Centiloid, C plasma Aβ42/40 ratio (standardized value), D p-tau181 (standardized value), E CDR-SB, F ADCOMS, and G ADAS-cog. F/up = 90-day follow-up period following study 201 core

Fig. 8

Observed mean change from baseline in A amyloid PET SUVr, B amyloid Centiloid, C plasma Aβ42/40 ratio (standardized value), and D Plasma p-tau181 (standardized value) during study 201 core, gap period, and OLE phase (OLE enrolled set). F/up = 90-day follow-up period following study 201 core

Fig. 9

Adjusted mean change from baseline in A CDR-SB, B ADCOMS, and C ADAS-Cog14 during study 201 core, gap period, and OLE phase (OLE enrolled set excluding those who progressed beyond early AD). F/up = 90-day follow-up period following study 201 core