P4‐075: LUMIPULSE ^® G TOTAL TAU TO β‐AMYLOID 1‐42 RATIO CUT‐POINT DETERMINATION FOR AMYLOID ELIGIBILITY SCREENING

Contemporary Phase 3 drug intervention clinical trials for Alzheimer's disease (AD) focus on determining efficacy in earlier stages of disease where biomarkers are integral for the execution of such trials. As part of the trial subject screening process, biomarkers are used to identify and confirm the eligibility of trial subjects. Indeed, confirmation of amyloid pathology is a common prerequisite for subjects in AD trials, typically determined using amyloid PET scans. However, since PET analysis requires a complex infrastructure, cerebrospinal fluid (CSF) analysis supporting amyloid positivity is progressing as a more flexible alternative. Here we present a cut-point for amyloid positivity based on measures of CSF using the Lumipulse G Total Tau and β-Amyloid 1-42 assays in samples from PET characterized clinical trial subjects. This cut-point is implemented in the global elenbecestat (E2609) MissionAD Phase 3 trial in early AD to support patient eligibility assessments and biomarkers effects. A total of 138 baseline CSF patient samples from Eisai Inc. with PET status were analyzed on the fully automated Lumipulse G Total Tau and β-Amyloid 1-42 assays. Using ROC curve analysis and Youden index, a cut-point was determined which was checked for trial specific requirements on sensitivity and specificity. All samples were successfully analyzed on a LUMIPULSE G1200 instrument. For the 85 PET positive and 53 PET negative samples, β-amyloid1-42 concentrations were within the assay's measurement range. After statistical analysis, the cut-point was found to be best set using the ratio of total Tau and β-amyloid1-42 and determined to be optimized at a ratio of ≥ 0.37. At this level, a high sensitivity (95%) and specificity (91%) was obtained, with high concordance with PET dichotomous classification of amyloid status (93%). A cut-point with high performance characteristics was identified in this cohort, which aligned well with amyloid PET data. As other studies indicated, the discrimination capacity of β-amyloid1-42 concentrations alone was lower compared to a total Tau to β-amyloid1-42 ratio. Although independent studies are needed to further validate the clinical performance of the chosen cut-point it can be applied in the context of clinical trials for patient eligibility screening.