− Demonstrates PPARG inhibition as a potential strategy to overcome immune resistance in advanced UC
− Supports the planned Phase 1 cohort of FX-909 in combination with pembrolizumab; initiating in the first quarter of 2026
CAMBRIDGE, Mass., Nov. 07, 2025 (GLOBE NEWSWIRE) -- Flare Therapeutics Inc. (FlareTx), a clinical-stage biotechnology company targeting transcription factors to discover precision medicines for oncology and other therapeutic areas, today announced the presentation of a correlative biomarker analysis from the Phase 1A clinical study of FX-909, a first-in-class orally available small molecule inhibitor of peroxisome proliferator-activated receptor gamma (PPARG), the master regulator of the luminal lineage, in locally-advanced or metastatic urothelial cancer (UC). This analysis includes novel insights regarding FX-909’s immune modulatory mechanism of action and demonstrate that FX-909 exerts immune-modulatory activity as a single agent, supporting the rationale for combination with an anti-PD-1 inhibitor in advanced UC.
Matthew L. Milowsky, M.D., Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, will present these results in a poster presentation titled “Phase 1 Clinical Data Show FX-909, a First-in-Class Oral PPARG Inhibitor, Drives Immune Modulation and Pro-Inflammatory Cytokine Induction in IO-Experienced Patients with Advanced Urothelial Carcinoma” on Saturday, November 8, 2025 from 10:00 a.m. to 6:35 p.m. ET at the Society for Immunotherapy of Cancer (SITC) 2025 40th Anniversary Annual Meeting in National Harbor, MD.
“Along with the recently presented clinical activity data for FX-909, it is particularly exciting to now present this correlative data showing the induction of pro-inflammatory cytokines and chemokines and the promotion of T-cell expansion. This analysis supports PPARG inhibition as a potential strategy to overcome immune resistance and provides a rationale for the planned cohort evaluating FX-909 in combination with pembrolizumab. I look forward to seeing this cohort initiate early in 2026,” commented Dr. Milowsky.
“Having recently disclosed that FX-909 has achieved clinical proof of concept as a monotherapy, we are very pleased to now share IO-experienced patient level evidence that support our translational hypothesis regarding the immune modulatory mechanism of action of FX-909. We look forward to generating data from our planned cohort of FX-909 in combination with pembrolizumab and believe this approach could provide a “one-two punch” to overcome IO resistance,” said Michaela Bowden, Ph.D., Chief Development Officer of Flare Therapeutics.
Phase 1A Study
Correlative biomarker evaluations were conducted on a subset of IO-experienced advanced UC patients enrolled in the Phase 1A open-label 3+3 dose-escalation study. This analysis evaluated baseline molecular features of archival tumors and longitudinal proteomic and single-cell immune profiles to elucidate the immune-modulatory mechanism of FX-909.
Key highlights include:
- Baseline molecular profiling confirmed that PPARGhigh tumors are of luminal lineage and display a cold immune phenotype consistent with lack of response to anti-PD-1 inhibition
- FX-909 treatment activated IFNy-induced inflammatory pathways in all patients evaluated, including important IO biomarkers of response such as CXCL9, CXCL10 and TNFa amongst others
- FX-909 treatment induces expansion of activated CD4 and CD8 T-cells and a corresponding decrease in circulating monocytes was observed in PPARGhigh tumors with confirmed responses
Taken together these results demonstrate that FX-909 exerts immune modulatory activity as a single agent supporting the rationale for combination with an anti-PD-1 inhibitor in advanced urothelial carcinoma.
FX-909 Next Steps
FX-909 is currently being evaluated in a Phase 1B expansion study evaluating safety and efficacy in second line or beyond to determine the recommended Phase 2 dose in a biomarker-defined PPARGhigh locally advanced (unresectable) or metastatic UC patient population. The Phase 1 Part B study adopts a randomized 2-stage design. A validated immunohistochemistry (IHC)-based test has been developed to identify patients eligible for enrollment in the expansion study. The company expects interim efficacy data in a biomarker-defined population at the recommended Phase 2 dose in the first quarter of 2026.
In the first quarter of 2026, the company expects to initiate enrollment of a Phase 1 combination cohort that will investigate the safety, tolerability, immunologic effects and preliminary efficacy of escalating doses of FX-909 in combination with standard dose KEYTRUDA® (pembrolizumab) in patients with advanced urothelial carcinoma. As announced on October 21, 2025, Merck (known as MSD outside of the United States and Canada) has agreed to provide its anti-PD-1 therapy KEYTRUDA for this combination cohort under the clinical trial collaboration and supply agreement.
More information about the trial is available at clinicaltrials.gov using the identifier NCT05929235.
About Advanced Urothelial Cancer
Advanced urothelial cancer (UC) is an aggressive and challenging form of bladder cancer, representing approximately 25% of all bladder cancers diagnosed each year. In the United States, bladder cancer accounts for approximately 84,000 new cases each year, with urothelial carcinoma being the predominant histologic type. In advanced or metastatic stages, the disease is notably difficult to treat, with over 50% of patients experiencing disease progression within six to nine months of first-line chemotherapy. The five-year survival rate for metastatic UC remains poor, with estimates below 6%. While the introduction of checkpoint inhibitors and targeted therapies has expanded treatment options, clinical outcomes remain suboptimal, underscoring an urgent need for additional and more effective treatment options. Molecular subtyping has revealed that luminal tumors, or tumors that are characterized by high PPARG expression, comprise approximately 65% of advanced urothelial cancers. These luminal tumors are often or invariably characterized by activation of the PPARG (peroxisome proliferator-activated receptor gamma) pathway, which plays a critical role in maintaining tumor identity, promoting tumor growth, and contributing to immune evasion. Novel approaches such as PPARG inhibition are emerging as promising strategies to improve outcomes for patients that have UC with high PPARG expression. It is estimated that the United States alone, there are approximately 14,000 new cases of advanced urothelial cancer with high PPARG expression diagnosed each year, based on the portion of luminal subtypes and overall incidence data.
About Flare Therapeutics Inc.
Flare Therapeutics is a clinical-stage biotechnology company exclusively focused on drugging transcription factors to fully unlock the therapeutic potential of this previously elusive target class. The company’s lead program, FX-909, is a first-in-class orally available small molecule inhibitor of PPARG, the master regulator of the luminal lineage, that is initially being developed for locally advanced or metastatic urothelial cancer. FX-909 has achieved clinical proof-of-concept in a Phase 1A study as a monotherapy and is actively dosing patients in a Phase 1B to determine the recommended Phase 2 dose in a biomarker-defined population. The second lead program, FX-111, is a novel and highly differentiated potent and selective degrader for ARON, the transcriptionally active, hormone-bound androgen receptor. This approach offers the potential to overcome key vulnerabilities of conventional therapies that target AROFF and has broad potential across prostate cancer at all stages. FX-111 is undergoing Investigational New Drug (IND)-enabling studies for initial development for the treatment of metastatic castration-resistant prostate cancer (mCRPC). These two programs, along with an earlier-stage portfolio targeting transcription factors involved in oncology and other therapeutic areas, leverages Flare Therapeutics’ integrated discovery platform of capabilities that identifies novel validated ligands to the undrugged proteome. For more information, please visit www.flaretx.com and follow us on LinkedIn.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Contacts:
Investors:
Sarah McCabe
investorrelations@flaretx.com
Media:
Timothy Cockroft
media@flaretx.com
