Treatment with FX-909 resulted in selective growth inhibition in PPARγ-activated MIUC cell lines and durable regressions in xenograft models of MIUC. FX-909 is capable of recapitulating PPARG genetic knockout phenotypes in vivo and is currently in clinical development for the treatment of intractable MIUC.

FX-909 demonstrated acceptable safety and tolerability with preliminary antitumor activity, supporting further clinical development in urothelial cancer. ClinicalTrials.gov identifier: NCT05929235 .

P1, N=120, Recruiting, Flare Therapeutics Inc. | N=75 --> 120 | Trial completion date: Jan 2027 --> Jan 2028 | Trial primary completion date: Sep 2026 --> Oct 2027

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.

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