DERIVING A CUT-OFF FOR THE ELECSYS® β-AMYLOID (1–42) IMMUNOASSAY FOR USE IN CLINICAL TRIALS SUPPORTED BY ELI LILLY FOR PATIENTS WITH CLINICALLY DEFINED ALZHEIMER’S DISEASE (AD)

Abstract

Amyloid plaque is a histopathological hallmark of AD. In recent trials (EXPEDITION/EXPEDITION2; NCT00905372/NCT00904683) 26% of patients with clinically diagnosed mild-to-moderate AD lacked evidence of amyloid pathology (Siemers, Alzheimers Dement 2016). A subsequent trial, EXPEDITION3 (NCT01900665), was enriched for patients with objective, biomarker-based evidence of amyloid pathologies assessed by (18F)-florbetapir imaging or cerebrospinal fluid (CSF) β-Amyloid (1–42) analysis using the INNO-BIA AlzBio3 immunoassay (Fujirebio) and a 249pg/mL cut-off (Dean, AAIC 2014). The present study established a cut-off for use of the Elecsys®β-Amyloid (1–42) immunoassay (Roche Diagnostics) in future clinical trials, based on exploratory analysis of EXPEDITION/EXPEDITION2 CSF samples. Frozen archived CSF samples collected from a subset of patients with mild-to-moderate AD enrolled in EXPEDITION/EXPEDITION2 (for lumbar puncture addendum analysis) and where AlzBio3 data were available, were analyzed using the Elecsys® β-Amyloid (1–42) immunoassay on a cobas e analyzer. Methods used to estimate a cut-off for Elecsys® β-Amyloid (1–42) were: (a) comparison of results from Elecsys® β-Amyloid (1–42) and AlzBio3 immunoassays (n=206); (b) mixture modeling (n=216) and; (c) concordance with (18F)-florbetapir imaging-based categorical patient classification (n=75 scans). The Elecsys® β-Amyloid (1–42) immunoassay showed good concordance with the AlzBio3 immunoassay (Table). A cut-off estimate of 1065pg/mL was derived, which provided 93.7% (95% CI 89.5–96.6) overall percentage agreement (OPA) and 97.2% (95% CI 93.5–99.1) positive percentage agreement (PPA) with AlzBio3. A comparable cut-off estimate was derived from mixture modeling: 1017pg/mL. A cut-off estimate optimized relative to (18F)-florbetapir visual interpretation was derived as 1198pg/mL and had good concordance: 96.0% (95% CI 88.8–99.2) OPA and 98.4% (95% CI 91.2–100.0) PPA (standard uptake value ratio data were comparable). The cut-off estimates presented are specific to Lilly-sponsored trials and may not be appropriate for other applications. Three methods were used to derive cut-off estimates for the Elecsys® β-Amyloid (1–42) immunoassay in patients with AD in Eli Lilly-sponsored trials; these produced close numerical values with considerable overlap in 95% CIs for all estimates. The Elecsys® β-Amyloid (1–42) immunoassay-based patient classification showed good concordance with classification based on CSF β-Amyloid (1–42) determined by the AlzBio3 immunoassay and (18F)-florbetapir imaging.