FX-909 is a first-in-class PPARG inverse agonist. PPARG is a transcription factor and core determinant of luminal lineage in the normal urothelium. There are multiple lines of evidence that support PPARG hyperactivated signalling as a driver of luminal urothelial cancers and this includes the finding that PPARG amplifications are enriched in luminal urothelial cancers and RXRα mutations, the obligate heterodimer partner for PPARG, are also enriched in luminal urothelial cancers. So this evidence together really suggests that pharmacologic approaches to inhibit PPARG signalling could hold therapeutic utility in the treatment of urothelial cancers where PPARG signalling is hyperactivated, however attempts previously to antagonise PPARG have been unsuccessful, largely because PPARG antagonists that have been developed have been unable to completely inhibit ligand-activated PPARG signalling and have been unable to inhibit basal PPARG transcriptional activity. FX-909 is a first-in-class PPARG inverse agonist and upon binding the PPARG this induces a confirmational change that biases the structure towards co-repressor binding, thereby potently inhibiting PPARG transcriptional activity, both ligand-activated signalling and basal transcriptional activity.
So this study, FX-909 clinical phase I, is a phase I study that’s really comprised of two parts, a phase Ia and a phase Ib. The phase Ia is the dose escalation phase and that’s the phase of the study that was presented at ASCO GU. This portion of the study was a dose escalation phase that enrolled patients with advanced solid tumours, however, the study was enriched for patients with advanced urothelial cancer via backfill cohort, so 46 of the 56 patients enrolled had advanced urothelial cancer. A dose escalation design was proceeded with in a 3+3 fashion and a dose was determined to test further, or two doses, rather, were determined to test further in an ongoing phase Ib expansion study.
The study demonstrated safety and tolerability with FX-909 but also demonstrated preliminary evidence of anti-tumour activity. That anti-tumour activity was actually enriched in patients with tumours that had high PPARG immunohistochemical expression based on an assay that was developed and a threshold that was defined in parallel with dose escalation of this phase Ia cohort.
What were the key findings?
The study demonstrated preliminary evidence of anti-tumour activity, monotherapy activity with this first-in-human approach in the treatment of patients with urothelial cancers where PPARG expression was increased based on an immunohistochemical assay. Really these findings credential PPARG as a therapeutic target in luminal urothelial cancer, really established proof of concept that targeting PPARG with an inverse agonist can translate into clinical responses and really provide a robust rationale for ongoing clinical development of FX-909 in luminal urothelial cancers.
