December 12, 2022
Sysmex Corporation【Overview presentation】
15th Clinical Trials on Alzheimer’s Disease (CTAD)

Three group classification of participants based on fully automated plasma
β-amyloid measurements to achieve high positive and negative predictive
valuesAuthors

Kazuto Yamashita1, Masahiro Miura1, Kota Nagai2, David Verbel3, Shigeki Iwanaga1,Toshiyuki Sato1, Tomokazu Yoshida4, and Atsushi Iwata5

1Central Research Laboratories, Sysmex Corporation
2Japan and Asia Clinical Development Department, Eisai Co., Ltd.
3Biostatistics, Eisai Inc.
4Sysmex Corporation
5Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of gerontology

Overview

Backgrounds

presentation

Blood-based biomarkers that can predict brain β-amyloid (Aβ) status are in highdemand not only for the recruitment of participants into Alzheimer’s disease (AD)clinical trials but also for ensuring that appropriate AD patients can receive diseasemodifying therapies in the future as they become available. Recently, we reported thatplasma Aβ1-42 (Aβ42) to Aβ1-40 (Aβ40) ratio measured by our fully automatedimmunoassay platform (HISCLTM series) predicted brain Aβ status defined by amyloid
positron emission tomography (PET) as assessed by Centiloids (CL). Area under thecurves of 0.932 and 0.922 were obtained in two clinical studies (discovery andvalidation studies). In the previous analysis, we determined a cut-off value of 0.102
using the Youden index in the discovery study. Using this cut-off value, we achieved
high negative predictive value (NPV) of 97.6% and 94.0%, and moderate positive
predictive value (PPV) of 80.6% and 79.6% in the discovery and validation studies,respectively. Considering use in the screening of participants for clinical trials, higher
PPV would be preferable. In this study, we combined discovery and validation studies
to one dataset, and classified participants into three groups (positive, intermediate,and negative Aβ groups) depending on their plasma Aβ42/Aβ40 ratio, in order toimprove PPV of our plasma Aβ assay.

Objectives
To evaluate the performance of our plasma Aβ42/Aβ40 ratio in predicting amyloid
PET status upon classifying participants into three groups.
Methods
Plasma Aβ40 and Aβ42 were measured using a fully automated immunoassay
platform in a set of plasma samples sourced from participants in the screening phaseof the elenbecestat Phase 3 program. Participants were clinically diagnosed with mild
cognitive impairment and mild dementia. In this analysis, we combined datasets frompreviously reported discovery and validation studies to make one dataset that
included 172 amyloid PET positive participants and 199 negative participants. Brain
Aβ status was determined by amyloid PET scans as assessed by the Centiloid
method (cut-off value defined previously as 32.21 CL). Here, we determined the cutoff value of our plasma Aβ42/Aβ40 ratios that would result in a PPV of 90% or more.
We then utilized this cut-off value and the prior reported cut-off value as the thresholds
to divide participants into positive, intermediate, and negative Aβ groups.
Results
A cut-off value was determined based on the criteria to achieve a PPV of at least
90%, and we used this cut-off value and the prior reported cut-off value to classify
participants into positive, intermediate, and negative Aβ groups. In this analysis, PPV
in positive Aβ group and NPV in the negative Aβ group were both more than 90%.
Conclusion
Our Aβ assay achieved PPV and NPV ≥ 90% by classifying participants into thethree groups. Majority of participants were classified as positive or negative Aβ groups
by plasma Aβ42/Aβ40 ratio, indicating that our assay may contribute to reduce
amyloid PET scan or CSF Aβ testing, which could be helpful in applications such as
the recruitment step of clinical trials.
SessionPoster, Clinical Trials: Biomarkers including plasma（LP84A）