Industry Perspective on Nonclinical Approaches for Hepatotoxicity Risk Assessment: Insights from Two Longitudinal...

The Nonclinical Translation Working Group of the IQ Drug-Induced Liver Injury (DILI) Consortium conducted two surveys in 2023 and 2017 to canvas member companies on approaches and experiences in the preceding 5-year periods that inform how DILI risk assessment has evolved in the past decade. Surveys comprised 53 detailed questions to understand the current status, temporal changes, and future direction and to gain insights. Focusing on the 2023 survey for the most contemporary data, responses indicated that DILI still remains a problem during drug development, with 41% of companies in the 2023 survey (50% in 2017) filing at least one clinical expedited safety report in the last 5 years. Most companies have common nonclinical screening approaches, with the majority of companies incorporating target safety assessments, considering physicochemical properties and dose, and using multiple in vitro approaches including cytotoxicity, mitotoxicity, BSEP inhibition, and various reactive metabolite assays, with the utilization of many of these being increased in the 2023 survey compared to the 2017 survey. The impact of in vivo toxicology studies on clinical study design and compound progression is also reviewed in both the 2023 and 2017 surveys. A large majority of companies now report having new modality drugs in their portfolios, including antibody-based and oligonucleotide-based modalities, cell therapies, protein degraders, and peptide-based medicines; yet only 1 or 2 companies report having modality-specific approaches to assess DILI risk despite these modalities having very different mechanisms of causing DILI compared to small molecules. This is a key area for growth in the nonclinical assessment of hepatotoxicity to support these emerging modalities and the tremendous potential that they offer for unmet clinical needs. Collaborative partnerships will be key to driving new capabilities forward in this area, contributing to the development of safer novel therapeutics for patients.