Carcinogenicity Risk Assessment of Targeted Protein Degraders

Targeted protein degraders (TPDs) have recently emerged as a novel drug class. Targeted protein degraders engage E3 ubiquitin ligase complexes to degrade therapeutic proteins of interest via cereblon and other adapter proteins, acting as either molecular glue degraders (MGDs) or proteolysis-targeting chimeras (PROTACs). Several cereblon-based MGDs and PROTACs are in late-stage clinical development for oncology indications. However, as TPD drug discovery includes non-life-threatening indications, carcinogenicity risk assessment will be required. Although there is no regulatory requirement to treat TPDs differently from conventional small molecules in carcinogenesis risk assessment, several properties of TPDs could influence weight of evidence (WoE) assessments and carcinogenicity study design. A series of case studies is presented to provide examples for evolved, modified WoE approaches for carcinogenicity assessment that may be acceptable to health authorities and regulatory agencies. These examples also highlight that the biological assessment of E3 ligase is as critically important to the carcinogenicity and toxicology assessment as is the assessment of the primary target. Finally, drug developers must contend with limitations for early-generation cereblon MGDs related to the translatability of findings that may challenge traditional interpretation paradigms.