Flare Therapeutics Presents First Preclinical Data on Lead Asset FX-909, a Novel Small Molecule PPARG Inhibitor to Potentially Treat Urothelial Cancer, at the 2023 AACR Annual Meeting

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Apr 17, 2023, 15:00 ET

--FX-909 is highly potent and selective for the PPARG transcription factor, and demonstrates tumor eradication in preclinical animal models of urothelial cancer at low oral doses--

--Therapeutic efficacy of FX-909 assessed through gene expression profiling of normal skin tissue, potentially offers a less invasive surrogate biospecimen collection method compared to a traditional tumor biopsy--

CAMBRIDGE, Mass., April 17, 2023 /PRNewswire/ -- Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, today highlighted the first preclinical data from its lead compound FX-909, a novel, small molecule peroxisome proliferator-activated receptor gamma (PPARG) inhibitor to potentially treat patients with advanced urothelial cancer (UC), in an oral presentation and poster format at the AACR Annual Meeting being held in Orlando, FL from April 14-19, 2023.

"These initial findings suggest that FX-909 could become a backbone therapy for patient populations harboring the luminal subtype of UC, much like ER therapies in the luminal subtype of breast cancer," said Rob Sims, Ph.D., Chief Scientific Officer and Co-founder of Flare. "We are eager to continue advancing FX-909, which will be further evaluated in a Phase 1 trial that will begin later in the year. This will be a milestone moment for Flare, as we are the first company slated to enter the clinic with a small molecule inhibitor targeting the PPARG transcription factor for advanced UC."

Flare is building a pipeline of potentially first-in-class therapies against genetically validated transcription factor targets, initially focused on cancer. Although challenging to drug, elusive transcription factors remain high-value targets across numerous disease categories, most notably oncology. Treatments that target cell lineage have become mainstay therapies in breast and prostate cancer, through the successful inhibition of the estrogen receptor (ER) and androgen receptor (AR) transcription factors. Similar to ER and AR, PPARG drives luminal cell identity and accounts for two thirds of all advanced UC, highlighting its potential as a therapeutic target.

The oral presentation, titled, "Discovery of FX-909, a first-in-class inverse agonist of the peroxisome proliferator-activated receptor gamma (PPARG) lineage transcription factor, to potentially treat patients with the luminal subtype of advanced urothelial cancer (UC)," shows that administration of FX-909 elicited durable tumor regressions in animal models of UC. The projected human starting dose of 50 mg/kg is also anticipated to be pharmacologically active.

Additional key takeaways are as follows:

FX-909 is a highly selective and potent covalent small molecule inhibitor of PPARG (cellular EC₅₀, 1 nM), showing >2000-fold selectivity for PPARG over PPARA/PPARD (related transcription factors) – acting through a mechanism that promotes a repressive conformation of PPARG.
FX-909 inhibited cell growth in UC cell lines with activated PPARG signaling but had no effect on cell lines without activated PPARG.
FX-909 administered orally twice a day caused tumor regression in PPARG-amplified and RXRA-mutant UC xenograft models at 1 mg/kg doses, and tumor eradication at 3 mg/kg doses.
FX-909 demonstrated predictable, on-target and reversible pharmacology in normal tissues at supra-pharmacologic doses, mimicking PPARG loss-of-function mutations with notable remodeling in adipose tissue and the normal urothelium.

The poster presentation titled, "Development of a surrogate tissue pharmacodynamic (PD) assay for potential clinical use with FX-909, a novel inhibitor of the urothelial luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG)," outlines the FX-909-dose dependent expression of PPARG target genes as markers of PD response in tumor, adipose and skin tissue from mouse xenograft, and normal rat and normal human skin preclinical models.

"Based on our observation of the consistent correlation of PPARG target gene expression patterns in tumor and normal tissues, we have elected to develop a normal skin PD biomarker assay to support early assessment of FX-909 biological activity in our Phase 1 study," said Michaela Bowden, Ph.D., Chief Development Officer of Flare. "These findings reinforce the importance of uncovering valuable translational insights and applying them to further guide our drug development process, potentially enabling us to reduce the burden of repeated, invasive tumor biopsy collections for patients with late-stage cancer by offering surrogate skin biopsies as a viable alternative."

Additional key takeaways are as follows:

In a rat pharmacology study, 30% of all genes that responded to FX-909 treatment in skin displayed a similar dose-dependent response profile in fat.
PPARG target genes including FABP4/Fabp4, AGT/Agt, IVT/Ivd and ARG1/Arg1 are repressed across different species and/or tissues, exemplified by dose-dependent suppression of FABP4/Fabp4 (a target gene for PPARG) and showing a strong correlation (r=0.98, p value=0.003) between tumor and skin tissues.
Skin explant models bridge the interspecies translational gap for studying FX-909-mediated effects, where preliminary evidence shows on-target regulation of genes involved in known PPARG-mediated processes.

About Urothelial Cancer
Bladder cancer is the third most common cancer in men in the United States alone. Each year, there are more than 83,000 new cases diagnosed among men and women, and about 25% of those cases are classified as muscle-invasive UC. This disease has high rates of recurrence and the five-year survival rate is approximately 15% in metastatic cases. The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is associated with the luminal lineage subtype reflecting approximately 65% of all advanced UC cases. Recurrent genetic alterations in PPARG, including focal amplification, missense mutations, and fusions, as well as hotspot mutations in its binding partner, retinoid X receptor alpha (RXRA) are characteristic of this molecular subtype.

About Flare Therapeutics
Flare Therapeutics is a biotechnology company changing the paradigm in drugging transcription factors with an initial focus in precision oncology. Flare's proprietary engine is founded on the identification of novel druggable pockets, or 'switch sites', within transcription factor complexes that solve for where to drug and how to tune gene expression to discover small molecule precision medicines for cancer and other diseases. The team has rapidly advanced an emerging pipeline of assets and plans to advance its lead precision oncology program, FX-909, a small molecule inhibitor targeting PPARG into the clinic in 2023 in individuals with locally advanced or metastatic urothelial cancer. For more information, please visit www.flaretx.com.

SOURCE Flare Therapeutics