Phase 1B trial of PPARG inhibitor launches in urothelial carcinoma

The first patients have been dosed in a phase 1B trial (NCT05929235) evaluating FX-909, an investigational small molecule PPARG inhibitor for patients with locally advanced or metastatic urothelial carcinoma (la/mUC), Flare Therapeutics announced in a news release.¹

“The initiation of the phase 1b expansion study marks an important milestone as we seek to improve the treatment of advanced urothelial cancer with our lead program FX-909,” said Doug Manion, MD, FRCP (C), Chief Executive Officer and Board Member of Flare Therapeutics, in the news release.¹ “We are prospectively screening for patients with high expression of PPARG, the hallmark of the luminal lineage, which accounts for approximately 65% of cases of advanced UC.”

According to the company, FX-909 works by inhibiting basal- and ligand-activated transcription by PPARG, which is a “master regulator of the luminal lineage.”

The initiation of the phase 1B trial of FX-909 follows positive proof-of-concept data from a phase 1A study, the company reported. Data from the phase 1A trial are expected to be shared at an upcoming medical meeting in 2025.

In the phase 1B portion of the trial, investigators will evaluate the safety, tolerability, and preliminary clinical activity of FX-909 and determine a recommended phase 2 dose (RP2D) in a biomarker-defined population.

In total, the open-label study plans to enroll approximately 40 patients with la/mUC through clinical trial sites in the US.² To be eligible for enrollment, patients need to have an ECOG performance score of 0 to 2, measurable disease per RECIST v1.1, and high levels of PPARG protein expression.

According to Flare Therapeutics, “A validated immunohistochemistry (IHC)-based test is being deployed to prospectively select patients with the lineage determining transcription factor that drives the initiation and progression of these tumor types.”

Patients enrolled in the study will be asked to take FX-909 once orally daily, administered in 28-day cycles. The study will assess 2 dose levels of FX-909—30 mg and 50 mg—in a 2-stage design. Following the determination of a RP2D, phase 2 of the trial is expected to proceed as a single-arm study.

The company expects to report on the efficacy of FX-909 in the RP2D in a biomarker-defined population in the first quarter of 2026. Final completion of the phase 1B study is anticipated for January 2027.

Manion concluded in the news release,¹ “We believe our PPARG inhibitor approach in this defined patient population represents a significant step toward addressing the disease at its source. By introducing a novel nuclear hormone receptor therapy—akin to the critical roles AR and ER play in prostate and breast cancers, respectively—we are expanding the therapeutic landscape to directly target the cell of origin and address the underlying disease biology.”

REFERENCES:

1. Flare Therapeutics announces initiation of phase 1B study of FX-909 for treatment of metastatic urothelial cancer. News release. Flare Therapeutics. August 5, 2025. Accessed August 5, 2025. https://www.flaretx.com/flare-therapeutics-announces-initiation-of-phase-1b-study-of-fx-909-for-treatment-of-metastatic-urothelial-cancer/

2. A study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma. ClinicalTrials.gov. Last updated June 17, 2025. Accessed August 5, 2025. https://clinicaltrials.gov/study/NCT05929235