A novel inhibitor of the protein PPARG, which is overexpressed in most cases of advanced urothelial carcinoma, led to tumor shrinkage in most patients with high PPARG expression who received the drug FX-909. In addition, some responding patients had elevated levels of CD4+ T cells and circulating chemokines and cytokines, suggesting that the drug attenuates PPARG-mediated immune suppression.

The crystal structure of PPARγ LBD cobound to FX-909 and the NCoR1 corepressor peptide reveals a repressive conformation shared by other covalent inverse agonists. These findings build on recent studies highlighting the pharmacological significance and clinical relevance of transcriptionally repressive PPARγ inverse agonists.

The crystal structure of PPARγ LBD cobound to FX-909 and NCoR1 corepressor peptide reveals a repressive conformation shared by other covalent inverse agonists. These findings build on recent studies highlighting the pharmacological significance and clinical relevance of transcriptionally repressive PPARγ inverse agonists.

The first-in-class PPARγ inverse agonist, FX-909, is currently being studied in clinical trials for cancer treatment...These findings inform the development of anticancer agents that act as PPARγ inverse agonists. Furthermore, our discussion of the complex biological functions of PPARγ provides insights into the exploration of its role in various diseases.

The study is currently enrolling patients in the US. Clinical trial information: NCT05929235.

FX-909, a first-in-class covalent PPARG inverse agonist that will be evaluated in a Ph1 trial this year, will offer an opportunity to investigate the impact of PPARG inhibition on the TME of MIUC patients. FX-909 combination with ICI therapy potentially provides a ‘one-two punch’ strategy to overcome resistance to immunotherapy in MIUC patients with high PPARG expression.

P1, N=75, Recruiting, Flare Therapeutics Inc. | Not yet recruiting --> Recruiting

P1, N=75, Not yet recruiting, Flare Therapeutics Inc.

Sponsored by Pharmaceutical/Biotech Company

Based on these preclinical data and confirmatory experiments in the ex vivo setting, a novel FX-909 signature is under development to predict target modulation in the tumor. The consistent correlation of PPARG target gene suppression in tumor and normal tissues across species provide a strong rationale for a surrogate biospecimen collection, such as a skin punch biopsy, to establish the PK/PD relationship between the dose and response to FX-909 in the clinic.

Predictable, on-target and reversible pharmacology was observed at FX-909 doses above 1 mg/kg, mimicking PPARG loss-of-function mutations with notable tissue remodeling in adipose tissue and the normal urothelium. These collective findings corroborate the role of PPARG as a key UC survival oncogene and suggest that FX-909 will be an effective therapy for patients with advanced UC harboring the luminal subtype.

Material and The PPARG inhibitor FTX-6746 was evaluated in UC cell lines including UMUC9 (PPARG amplification) and HT1197 (RXRA-S427F hotspot mutation), which activate PPARG by different genetic mechanisms... These collective results suggest that PPARG is a lineage-defining transcription factor in UC and small molecule PPARG inhibition will be an effective therapy for patients with advanced urothelial cancer harboring the luminal subtype. Model Dose (mg/kg) Schedule %Tumor Growth Inhibition %Target Gene Suppression (D2) UMUC9 3 BID*20 59 16 UMUC9 10 BID*20 70 ND UMUC9 30 BID*20 83 73 UMUC9 30 BID*21 105 80 UMUC9 60 BID*21 108 ND HT1197 30 BID*42 85 46 HT1197 60 BID*42 112 59