PT2977, a Novel HIF-2a Antagonist, Affords Potent Anti-Tumor Activity and Remodels the Immunosuppressive Tumor Microenvironment in Clear Cell Renal Cell Cancer

Hypoxia-inducible factor 2a (HIF-2a), a transcription factor, has been established as an oncogenic driver in clear cell renal cell cancer (ccRCC). The first HIF-2a antagonist being evaluated in clinical development, PT2385, has demonstrated clinical activity in ccRCC patients who had previously been treated with multiple lines of therapy. There is continuing effort to characterize additional HIF-2a antagonists possessing attributes that may enhance clinical activity. PT2977 is a novel HIF-2a antagonist with improved potency in preclinical tumor models compared to PT2385. This improvement arises from augmented biochemical and cellular potency, reduced plasma protein binding, and diminished metabolic clearance in vivo relative to PT2385. PT2977 exhibits favorable metabolic stability and pharmacokinetic characteristics when dosed orally in multiple preclinical species. Allometric scaling of the preclinical data predicts PT2977 to be suitable for oral once daily dosing in humans. PT2977 inhibits expression of HIF-2a target genes in tumor cells and induces complete stasis or regression in ccRCC xenografts. A strong pharmacokinetics/pharmacodynamics correlation is observed in tumors from xenograft models treated with PT2977. Gene expression analyses of ccRCC xenografts treated with PT2977 reveal extensive modulation of genes in the tumor cells as well as in tumor associated immune cells. Immune phenotyping of tumors treated with PT2977 confirms that HIF-2a antagonism results in a reduction in the number of immunosuppressive myeloid-derived cells, including neutrophils and macrophages. Treatment with PT2977 also results in an influx of mature dendritic cells. These observations are consistent with aberrant HIF-2a activity exerting an immunosuppressive effect on the tumor microenvironment, in addition to driving angiogenesis and the proliferation and viability of tumor cells. With its favorable preclinical profile, PT2977 is well-positioned to further reveal the broader therapeutic potential of HIF-2a antagonism for the treatment of cancer, as a single agent or in combination with other immune modulating agents.