Feed

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are an established treatment for management of type 2 diabetes mellitus (T2DM) and obesity. While these agents provide clinical benefits, chronic rodent bioassays have shown a consistent increase in thyroid C-cell tumors, raising regulatory concerns for human carcinogenicity risk and resulting in a boxed warning for medullary thyroid carcinoma (MTC). However, the human relevance of the rodent tumors is unclear due to species differences in GLP-1 receptor (GLP-1R) biology. Carcinogenicity testing of pharmaceuticals is described in ICH S1 guidelines. ICH S1B(R1) outlines experimental approaches to carcinogenicity evaluation including a weight-of-evidence (WoE) framework to determine whether long-term rat carcinogenicity studies add value to human cancer risk assessments. This manuscript applies that framework across seven approved GLP-1RAs: lixisenatide, exenatide, liraglutide, dulaglutide, semaglutide, tirzepatide, and albiglutide, to evaluate the relevance of rodent thyroid tumors and the utility of 2-year bioassays for this drug class. Across all six WoE domains, the evidence supports concluding that GLP1-RAs are tumorigenic in rats via a known human-irrelevant mechanism. Thus, within the S1B(R1) WoE framework, future carcinogenicity testing in rats is unlikely to provide additional value for regulatory decision-making for this class of pharmaceuticals.