Systematic Analysis and Threshold Synthesis for |G*| as a Diagnostic Biomarker for NAFLD and NASH Clinical Trials - DDT-BMQ-000099

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Higher incidence of metabolic disease and obesity have fueled a rise in non-alcoholic fatty liver disease (NAFLD), which has in turn contributed to increased prevalence of non-alcoholic steatohepatitis (NASH). Despite the increasing prevalence of NAFLD and NASH, drug development in this area has faced several challenges – notably the lack of validated, noninvasive biomarkers to enroll patients based on the stage of fibrosis. This is a critical enrollment step, as regulatory bodies have identified two specific cohorts of NASH patients for clinical study: NASH with fibrosis (F2-F3) and NASH with cirrhosis (F4). A validated diagnostic biomarker for enrolling subjects in the correct cohort of interest in a timely and cost-effective way would replace the need for liver biopsy and greatly propel the field forward. The overall goal of this work is to document an evidence base to support the use of an MR elastography-based measurement of the magnitude of the complex shear modulus (|G*|) as a diagnostic pre-screening biomarker. |G*| is proposed for use to screen for subjects with NAFLD/NASH with high risk of having histopathologic findings of significant fibrosis. This biomarker has an accepted Letter of Intent (DDTBMQ000099). While |G*| and its corresponding measurement method, magnetic resonance elastography (MRE), is recognized as a reliable and established biomarker of liver fibrosis in the clinical radiology and hepatology communities, there are minor gaps that must be filled for this diagnostic Context of Use. The objective for this proposal is to conduct a retrospective analysis of the diagnostic performance of this biomarker for staging liver fibrosis and to establish standardized thresholds for |G*| for use as a diagnostic screening drug development tool. Aim 1: Establish cutoffs for |G*| for the diagnosis of significant (≥F2), advanced fibrosis (≥F3) or cirrhosis (F4) for subjects with NAFLD and determine evidence-based diagnostic performance summaries of |G*| compared with the reference standard of liver biopsy for a pre-screening context of use. Aim 2: Validate optimal cutoffs in a test cohort of subjects with NAFLD and biopsy determine the diagnostic performance (sensitivity, specificity, PPV, NVP, and AUROC). The completion of Aim 1 and Aim 2 will provide critical evidence to further the development of |G*| as a pre-screening biomarker for fibrotic NAFLD/NASH, fulfilling an unmet need in NAFLD drug development. Completion of this work will inform our Qualification Plan for |G*| as a pre- screening biomarker to the FDA’s Biomarker Qualification Program.