Abstract 7094: Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations
Authors: Meissen John K. , Contrepois Kevin , Regan Sophie , Tan Jennifer , Foster Alison J. , Yuan Jiaqi , Sharma Shringi , Williams Dominic , Rosenbaum Anton I. 
Published: March 2024

AZD4573 is a highly potent and selective Cyclin-Dependent Kinase 9 inhibitor. The AZD4573 First-in-Human (FIH) study revealed variable alanine transaminase (ALT) and/or bilirubin elevation and a clear correlation to dose or PK exposure could not be defined. While concurrent ALT elevation ≥3x upper limit of normal (ULN) and bilirubin elevation ≥2x ULN (potential Hy’s law) is a biochemical finding indicating potential drug-induced liver injury, quantitative modeling disconnected ALT and bilirubin elevation demonstrating that the observations were not Hy’s Law cases. Furthermore, we implemented a targeted metabolomics workflow to investigate the ALT and bilirubin elevation mechanism and identify predictive biomarkers to better understand and/or predict any hepatic stress liabilities associated with AZD4573 clinical development. We implemented an established metabolomics methodology to 359 samples from 15 patients yielding 47,000 total data points. Data was separated into 98 different dosing intervals from the 15 patients to identify the ALT and bilirubin-associated metabolic changes conserved across all patients while incorporating metabolic differences in individual patents with ALT and bilirubin elevation in only a fraction of multiple doses. Orthogonal Partial Least Squares modeling identified several metabolites and pathways altered as a function of maximum ALT or bilirubin levels. Post-dose conjugated bile acids were elevated when ALT and bilirubin were elevated. Pre-dose creatine levels were decreased when ALT and bilirubin elevation occurred, and pre-dose glutamate levels were elevated when ALT elevation occurred. Pre-dose decreased total carnitines and kynurenine pathway activation were observed when ALT and bilirubin elevation occurred, but the effect did not reach statistical significance. Elevated bile acids are an established characteristic of cholestasis and suggest cholestasis as a probable mechanism for AZD4573-induced reversible liver stress. Interestingly, decreased creatine, glutamate elevation, decreased total carnitine, and kynurenine pathway activation are all associated with some form of liver stress or disfunction which may explain the irregular ALT and bilirubin elevations observed in patients receiving AZD4573; while ALT itself is a biomarker of liver damage, these pre-dose biochemical changes may illuminate potential preceding liver stress. Dosing patients already experiencing higher liver stress levels may be more susceptible to drug-induced ALT and bilirubin elevation, and patients with increasing in-study liver stress may only present at later doses. This work demonstrates metabolomics utility to elucidate possible mechanisms of liver toxicity as well as to identify potential predictive biomarkers for further investigation to explore individual patient risk in clinical studies.

Citation Format: John K. Meissen, Kevin Contrepois, Sophie Regan, Jennifer Tan, Alison J. Foster, Jiaqi Yuan, Shringi Sharma, Dominic Williams, Anton I. Rosenbaum. Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7094.