Sample Collection and Analysis to Support the Qualification Plan for Drug Induced Skeletal Muscle Injury Biomarker Panel for DDT-BMQ-000081.

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ABSTRACT This project seeks to increase our understanding of the sensitivity of the four proposed skeletal muscle injury biomarkers to detect drug-induced skeletal muscle injury (DIMI), which will address an unmet need in drug development for detecting and monitoring DIMI. The evidence generated by this project is necessary to support the qualification of four skeletal muscle specific proteins (skeletal troponin I (TNNI2), myosin light chain 3 (MYL3). Fatty acid binding protein 3 (FABP3), and creatine kinase MM (CKM)) as biomarkers of skeletal muscle injury by the Food and Drug Administration’s (FDA’s) Biomarker Qualification Program (BQP). This qualification effort is being led by the Predictive Safety Testing Consortium’s Skeletal Muscle Injury Working Group, for which these four biomarkers serve as safety biomarkers to detect DIMI was accepted into the Biomarker Qualification Program. In order to progress to the next stage of qualification, the Skeletal Muscle Injury Working Group must prepare a Qualification Plan which summarizes the performance of these four biomarkers in the learning phase studies and proposes the confirmatory studies to support the proposed context of use under consideration by the Biomarker Qualification Program. To date, the Skeletal Muscle Injury Working Group has limited clinical data in DIMI or muscle injury populations. To address this gap, the Critical Path Institute (C-Path) proposes the following research aim. Specific Aim 1 will conduct a study to determine the sensitivity of the proposed drug-induced muscle injury biomarkers (TNNI2, MYL3, FABP3, and CKM). The study will collect single samples from 125 subjects at the University of Michigan Hospital with adjudicated skeletal muscle injury due to DIMI, skeletal muscle injury, or skeletal muscle disease and 125 healthy subjects. This study will support the future submission of a Qualification Plan for DDT# DDTBMQ000081 by defining the sensitivity of the proposed drug-induced muscle injury biomarkers in muscle injury patients.