Matthew Galsky, MD, on the mechanism of action of FX-909 in advanced UC

In an interview at the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Matthew D. Galsky, MD, discussed the mechanism of action for FX-909, a first-in-class agent targeting peroxisome proliferator-activated receptor gamma (PPARγ) in advanced urothelial carcinoma. Galsky is a professor of medicine at the Icahn School of Medicine at Mount Sinai and the director of GU medical oncology at the Tisch Cancer Center in New York, New York.

Galsky explained that PPARγ is a transcription factor that plays a central role in luminal differentiation within normal urothelium and emerging data suggests a role as a key driver in luminal urothelial cancer as well. Genomic analyses have demonstrated enrichment of PPARγ amplifications and RXRα mutations in this disease subtype, supporting the notion that the PPARγ signaling pathway is hyperactivated in luminal tumors. RXRα functions as an obligate heterodimeric partner of PPARγ, further underscoring the biologic relevance of this axis. Together, these findings provide a strong rationale for therapeutically targeting PPARγ signaling in urothelial carcinoma.

Historically, transcription factors such as PPARγ have been considered difficult to target pharmacologically. Prior attempts to develop PPARγ antagonists were limited by incomplete inhibition of ligand-dependent activity and minimal impact on basal transcriptional activity, which is necessary for meaningful clinical efficacy. FX-909 represents a novel approach as a PPARγ inverse agonist. Rather than simply blocking receptor activation, the agent induces a conformational change that promotes binding of corepressors over coactivators, thereby suppressing both ligand-induced and basal PPARγ transcriptional activity. This mechanistic distinction may enable more effective pathway inhibition compared with earlier strategies.

Results from the phase 1a study of FX-909 were presented at ASCO GU 2026, demonstrating evidence of target engagement and early signs of antitumor activity in heavily pretreated patients with advanced urothelial carcinoma, particularly those with PPARγ^high tumors.¹ The therapy exhibited an acceptable safety profile, supporting continued clinical development. The investigators are pursuing development of a companion diagnostic to better identify patients most likely to benefit. An ongoing phase 1b expansion study (NCT05929235) is also evaluating daily doses of 30 mg and 50 mg and limiting prior lines of therapy to further define the role of PPARγ inverse agonism in this setting. Collectively, the data position PPARγ as a promising therapeutic target in luminal urothelial carcinoma, alongside other successfully drugged nuclear receptors in oncology.

REFERENCE
1. Galsky MD, Bellmunt J, Mantia C, et al. Updated clinical results and associated biomarkers from an ongoing phase 1 study of FX-909, a first-in-class peroxisome proliferator-activated receptor gamma (PPARG) inhibitor, in patients (pts) with advanced urothelial carcinoma (adv UC). Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract LBA639. https://www.asco.org/abstracts-presentations/256844/abstract