Galunisertib (DB11911): A Comprehensive Oncological and Pharmacological Review from Preclinical Promise to Clinical Discontinuation

Executive Summary

This report provides an exhaustive analysis of Galunisertib (LY2157299), a first-in-class, orally bioavailable, small molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor I kinase (TGF-βRI/ALK5), developed by Eli Lilly and Company. Galunisertib emerged from a strong preclinical rationale, demonstrating potent, on-target inhibition of the canonical TGF-β/SMAD signaling pathway. This mechanism conferred broad anti-tumor, anti-fibrotic, and critically, immunomodulatory effects in a range of preclinical models, positioning it as a promising agent against cancers where TGF-β is a key driver of progression, such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. A significant early success of the development program was the proactive mitigation of a severe preclinical cardiac toxicity signal through the implementation of a sophisticated pharmacokinetic/pharmacodynamic (PK/PD)-driven intermittent dosing regimen (14 days on/14 days off). This strategy proved effective in clinical trials, rendering the drug safe and tolerable for human administration.