GSK3915393: An In-Depth Analysis of a Novel Transglutaminase 2 Inhibitor for Idiopathic Pulmonary Fibrosis

Executive Summary

This report provides an exhaustive analysis of GSK3915393, an investigational small molecule inhibitor of transglutaminase 2 (TG2) developed by GlaxoSmithKline (GSK). The drug represents a novel therapeutic approach for Idiopathic Pulmonary Fibrosis (IPF), a chronic, progressive, and fatal lung disease with a significant unmet medical need. GSK3915393 works by targeting the TG2 enzyme, a key driver of the fibrotic process through its role in extracellular matrix (ECM) cross-linking and myofibroblast activation.

Initially acquired through the 2019 buyout of Sitari Pharmaceuticals, GSK3915393 was first evaluated for the treatment of celiac disease. However, in early 2023, GSK strategically discontinued the celiac disease program, citing a disciplined approach to capital allocation and R&D prioritization rather than any reported failure of the drug's mechanism or safety. The development program was subsequently pivoted to focus entirely on IPF, an indication with a more severe prognosis and a well-defined regulatory pathway.

The clinical development of GSK3915393 has been characterized by a meticulous and strategically de-risked approach. A comprehensive Phase 1 program has been completed, assessing the drug's safety, tolerability, and pharmacokinetics (PK) in healthy volunteers of diverse ethnic backgrounds. Crucially, these early studies also proactively investigated potential drug-drug interactions (DDIs) with CYP3A4 inhibitors and with nintedanib, a current standard-of-care therapy for IPF. This early focus on combination potential and metabolic pathways underscores a sophisticated, long-term development strategy aimed at positioning GSK3915393 as both a potential monotherapy and an add-on treatment.