Flare Therapeutics has initiated dosing in a Phase 1B clinical trial (NCT05929235) evaluating FX-909, a first-in-class orally available small molecule inhibitor of PPARG, for patients with locally advanced or metastatic urothelial carcinoma. The announcement marks a significant advancement in targeting transcription factors for cancer treatment, with the company focusing on a biomarker-defined patient population.
Clinical Proof-of-Concept Achieved
FX-909 has achieved clinical proof-of-concept in a Phase 1A study as a monotherapy, based on pre-specified criteria. The company expects to present these data at a scientific conference in 2025, following positive proof-of-concept results from the earlier-phase study.
"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.
Biomarker-Driven Patient Selection
The Phase 1B trial employs a precision medicine approach by prospectively screening for patients with high expression of PPARG, the hallmark of the luminal lineage. According to Flare Therapeutics, this biomarker-defined population accounts for approximately 65% of cases of advanced urothelial cancer.
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. 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.
Trial Design and Timeline
The open-label study plans to enroll approximately 40 patients with locally advanced or metastatic urothelial carcinoma through clinical trial sites in the United States. Patients enrolled in the study will take FX-909 once orally daily, administered in 28-day cycles.
The study will assess two dose levels of FX-909—30 mg and 50 mg—in a 2-stage design. The Phase 1B study will evaluate safety and efficacy to determine the recommended Phase 2 dose in the biomarker-defined population. Following the determination of a recommended Phase 2 dose, phase 2 of the trial is expected to proceed as a single-arm study.
The company expects to report efficacy data in a biomarker-defined population at the recommended Phase 2 dose in the first quarter of 2026. Final completion of the Phase 1B study is anticipated for January 2027.
Mechanism of Action and Clinical Rationale
According to the company, FX-909 works by inhibiting basal- and ligand-activated transcription by PPARG, which is described as a "master regulator of the luminal lineage." This approach represents a novel nuclear hormone receptor therapy, similar to the critical roles that androgen receptor (AR) and estrogen receptor (ER) play in prostate and breast cancers, respectively.
Addressing Unmet Medical Need
Advanced urothelial cancer represents an aggressive and challenging form of bladder cancer, accounting for approximately 25% of all bladder cancers diagnosed each year. In the United States, bladder cancer accounts for approximately 84,000 new cases annually, with urothelial carcinoma being the predominant histologic type.
The disease presents significant treatment challenges, with over 50% of patients experiencing disease progression within six to nine months of first-line chemotherapy. The five-year survival rate for metastatic urothelial cancer remains poor, with estimates below 6%. While checkpoint inhibitors and targeted therapies have expanded treatment options, clinical outcomes remain suboptimal.
Molecular subtyping has revealed that luminal tumors, characterized by high PPARG expression, comprise approximately 65% of advanced urothelial cancers. These luminal tumors are characterized by activation of the PPARG pathway, which plays a critical role in maintaining tumor identity, promoting tumor growth, and contributing to immune evasion. It is estimated that in the United States alone, there are approximately 14,000 new cases of advanced urothelial cancer with high PPARG expression diagnosed each year.
"We believe our PPARG inhibitor approach in this defined patient population represents a significant step toward addressing the disease at its source," Manion concluded. "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."
