Research & Development

Hypoxia Inducible Factor-2α (HIF-2α)

Peloton is leading the field in developing innovative therapies targeting the regulation of gene expression, including the first antagonist of hypoxia inducible factor-2α (HIF-2α) to enter clinical development.

HIF-2α is a transcription factor that drives the expression of multiple gene products impacting metabolism, angiogenesis, cell proliferation, metastasis, inflammation, and evasion of anti-tumor immune responses. HIF-2α plays a key role in driving disease progression in many pathological disorders affected and propagated by hypoxia and is implicated in the development and progression of several types of cancer.

The role of HIF-2α is particularly important in clear cell renal cell carcinoma (ccRCC). In the majority of patients with ccRCC, the tumor suppressor von Hippel-Lindau protein (pVHL) that targets HIF-2α for degradation is inactivated, leading to the accumulation of HIF-2α and the transcription of genes that drive kidney cancer tumorigenesis.

Peloton’s lead investigational therapy, PT2385, is a selective, potent, orally bioavailable small molecule antagonist of HIF-2α currently being investigated in a Phase 1 clinical trial for the treatment of ccRCC. PT2385 is designed to bind to HIF-2α and disrupt its transcriptional activity.

Preclinical data reveals that disrupting HIF-2α activity in ccRCC suppresses gene expression essential for tumor growth, proliferation, and angiogenesis. Inappropriate activation of HIF-2α has also been implicated in diseases outside of oncology. Peloton is exploring these opportunities as potential additional therapeutic applications.