Flare Therapeutics Presents Preclinical Data that Show Potential of Novel PPARG Inhibitors to Treat Urothelial Cancer at 2022 EORTC-NCI-AACR Symposium

Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, today presented new preclinical data in a poster presentation titled, "Novel inhibitors of the luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) durably eradicate tumors in urothelial cancer (UC) animal models" at the 34th EORTC-NCI-AACR Symposium in Barcelona, Spain. The data presented by Robert Sims, Ph.D., Chief Scientific Officer and Co-founder of Flare, show that FTX-6746, a potent, selective, small molecule PPARG inhibitor (inverse agonist), drives robust PPARG target gene silencing in UC cell lines and drives tumor regression in PPARG-amplified and RXRA-mutant UC xenograft models.

"Targeting cell lineage-defined transcription factors with small molecules is a proven and effective therapeutic strategy, as demonstrated by estrogen and androgen receptor therapies for breast and prostate cancers. Our goal is to add PPARG to that list, to potentially enable treatment of urothelial cancers. Leveraging our deep expertise in transcription factor biochemistry, we engineered compounds capable of driving a powerful repressive conformation of PPARG with high specificity, thereby inducing significant pharmacological effects," said Dr. Sims. "In preclinical models, FTX-6746 demonstrated a favorable therapeutic profile, suppressing PPARG target genes with durable tumor regression at well-tolerated doses. We are currently advancing a novel PPARG inhibitor through IND-enabling studies and plan to advance that therapeutic candidate into the clinic in 2023 in locally advanced or metastatic UC."

Data highlights:

• FTX-6746 drives an enhanced repressive conformation to overcome UC mutations
• FTX-6746 counteracts the activating effects of recurrent PPARG and RXRA missense mutations in preclinical models of UC
• FTX-6746 treatment results in robust PPARG target gene silencing in cells (average 50% maximal inhibitor concentration (IC50) ~5 nM); in vitro growth inhibition is preferentially observed in cell lines with activated PPARG signaling
• Tumor growth inhibition or regression was observed in PPARG-amplified and RXRA-mutant UC xenograft models, with no tumor regrowth upon cessation of treatment

"Today's data presentation demonstrates the strength and depth of Flare's research platform and our teams' ability to rapidly advance a first in class molecule in precision oncology," said Amit Rakhit, M.D., Chief Executive Officer of Flare Therapeutics. "Flare is poised to transition to a clinical-stage company early next year with our lead molecule in the PPARG program. Given the high unmet medical need with poor survival in advanced stages of disease, novel approaches that provide alternative therapeutic options are needed for people living with bladder cancer."

About Urothelial Cancer

Muscle-invasive UC is a common type of bladder cancer, with about 20,000 individuals diagnosed each year in the United States alone, and significantly higher incidence rates in other regions of the world. This disease has high rates of recurrence and the five-year survival rate is approximately 5% 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 patients. 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 pioneering a new therapeutic space with a novel approach to decipher the biology of transcription factors to develop small molecule medicines. Based on insights from the seminal work of its scientific founders, Flare's team has uncovered ?switch sites,' druggable regions that are key targets for transcription factor regulation, to address mutations that cause disease. Flare's drug discovery efforts to target switch sites has rapidly advanced, resulting in an emerging pipeline of research programs that address well-validated genetically-defined transcription factors, initially focused on precision oncology with future potential in neurology, rare genetic disorders, immunology and inflammation. Flare Therapeutics was launched in 2021 and is backed by founding investor Third Rock Ventures, as well as Boxer Capital, Nextech Invest, Casdin Capital, Invus Financial Advisors and Eventide Asset Management. For more information, please visit www.flaretx.com.