ARO-HIF2

ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC)...Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.

Referring herein to both first- and second-generation (ARO-HIF2) siRNA drugs, siHIF2 is specifically taken up by human ccRCC tumors transplanted in mice, where it depletes HIF2a inhibiting target gene expression and tumor growth...siHIF2 has activity against both wild-type and drug-resistant mutant HIF2a and is expected to be active in patients progressing on PT2977 (belzutifan), a PT2399-related drug recently approved by the FDA. To our knowledge, this is the first example of functional inactivation of an oncoprotein with a tumor-directed siRNA in humans. In summary, these studies provide unique insight into HIF2a (the only known core dependency in ccRCC), illustrate how it can be effectively inhibited by an siRNA drug, and establish a paradigm for the development of tumor directed siRNA-based therapeutics.

One pt (cohort 2, with prior sunitinib, nivolumab, axitinib) experienced a partial response with 66% reduction in sum of longest diameters. HIF2a is a clinically validated driver of ccRCC which can be targeted with a RNAi therapeutic. This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2a expression as well as a favorable safety profile in response to escalating doses of ARO-HIF2.