This article has been updated to clarify the difference in druggability between PPAR gamma agonists and inhibitors.
NEW YORK – Flare Therapeutics is preparing to initiate a biomarker-driven clinical trial program for a small molecule candidate targeting the notoriously difficult to drug peroxisome proliferator-activated receptor gamma (PPAR gamma) in patients with urothelial cancer in the first half of 2023.
The nuclear receptor PPAR gamma is well known as a potential therapeutic target in urothelial cancer. It is associated with the luminal lineage subtype, which represents about 65 percent of all advanced cases. Genetic alterations in PPAR gamma, including amplification, missense mutations, and fusions, are commonly found in this subtype. Mutations may also be found in PPAR gamma's binding partner, retinoid X receptor alpha (RXR alpha). With standard chemotherapy, the five-year survival rate for patients with metastatic bladder cancer is about 15 percent. While some approved drugs act as PPAR gamma agonists, development of drugs that inhibit PPAR gamma has proved much more challenging.
The Cambridge, Massachusetts-based Flare launched in 2021 with $82 million in Series A financing led by Third Rock Ventures to advance oncology treatments that are developed by identifying druggable regions within transcription factors that control gene expression, dubbed "switch-site" drug discovery.
Transcription factors have been elusive targets for drug discovery, according to Robert Sims, a cofounder and CSO of Flare. Having spent 25 years working in the area of transcription and gene expression Sims anticipated making a move away from transcription and into another field with his next venture. "I kept coming back to transcription," he said, because, due to their role in gene expression, transcription factors are involved in hundreds of disease processes. "The challenge has been this is a very difficult drug discovery area."
Sims said that although the pharma industry "largely divested" from targeting nuclear receptors 15 years ago, he drew encouragement from the fact that small molecules targeting nuclear receptors comprise 16 percent of all approved medicines, even though the corresponding targeted receptors represent only 1 percent of the family of nuclear receptors. "It's a huge opportunity, with incredibly deep biologic connectivity to human disease," he said.
PPAR gamma represented a "perfect embodiment" of this type of opportunity, Sims said. The company's objective for this program was to study the role of PPAR gamma mutations in bladder cancer and develop drug candidates targeting PPAR gamma.
Flare presented preclinical data for one of those drug candidates, FTX6746, at the EORTC-NCI-AACR Symposium in October, showing that it suppressed PPAR gamma target genes in vitro and drove tumor regression in PPAR gamma-amplified and RXR alpha-mutant urothelial cancer animal models.
Sims said the breakthrough allowing Flare to target PPAR gamma came from investigating the structural biology of the molecule. Various compounds had been in development for two decades that targeted PPAR gamma, but they didn't work, he said. "Even though they bound agnostic to the mutation, they weren't very good at shutting down the pathway," he added.
In contrast, Flare's molecules bind covalently to a region of PPAR gamma that is sequestered from the mutation. That covalent bond turned out to be important. "We found molecules that were more conventional, that were reversible. We could not get those compounds to be as effectual as the covalent permanent [bond]," Sims said.
Sims said that PPAR gamma is more than simply a good potential target in urothelial cancer. "What we're doing with PPAR gamma is we are targeting the identity of that tumor," he said, comparing PPAR gamma in urothelial cancer with the estrogen receptor in breast cancer or the androgen receptor in prostate cancer. "These are therapies that have been backbone treatments for decades. We're doing the same thing, but with a different target in a different cancer type."
Flare has not disclosed the specifics of its lead development candidate, FX-909, for bladder cancer yet. The company aims to file an investigational new drug application with the US Food and Drug Administration in the first half of 2023.
To recruit the patient population most likely to benefit for the Phase Ib expansion cohort, patients will be screened using genomic profiling to identify those whose cancers harbor alterations in PPAR gamma, RXRZ, or FGFR3. "All genetically altered patients also express high levels of the PPAR gamma gene, which reflects a larger cross section of the advanced urothelial cancer population with potential to respond to FX-909," said Michaela Bowden, Flare senior VP of biology and translation. In parallel, Flare is developing biomarkers that select for PPAR gamma-positive patients via an immunohistochemistry assay and intends to conduct an exploratory, retrospective analysis of its Phase I data to examine whether these biomarkers could be adopted in Phase II to prospectively enrich for FX-909 responders.
Flare estimates that about 20,000 patients in the US with advanced urothelial cancer might be eligible for treatment with FX-909 on an annual basis. "Bladder cancer for many decades has been primarily treated with chemotherapy regimens. In the last 10 to 12 years there's been an advent of new drugs coming to market," Bowden said. "Immuno-oncology combination agents are moving up to first-line and chemotherapy is moving back as a last resort. In the middle is a place where our drug would be positioned. Understanding that space is very important."
In a molecular real-world profiling study that Flare carried out in partnership with Tempus, they found that in urothelial cancer patients, PPAR gamma is conserved as the disease progresses. The study also showed that patients with metastatic disease harbor high PPAR gamma expression with genetic changes in PPAR gamma, RXR alpha, and FGFR3 that have been linked to urothelial cancer in the Cancer Genome Atlas (TCGA) and other published datasets. Flare initiated the study in an effort to build a cohort similar to the one that will be enrolled in its Phase I trial. They assembled a cohort of 3,000 patients for the study. "To put that in perspective," said Bowden, "the TCGA datasets are 400-plus locally advanced metastatic patients."