Date: 2016-04-18
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans
Company: Arrowhead Research Corporation (USA - CA)
Product: ARC-HIF2
Action
mechanism: RNAi. ARC-HIF2 is designed to inhibit the production of HIF-2alpha, which has been linked to tumor progression and metastasis in ccRCC. ARC-HIF2 employs a novel extrahepatic-targeted DPC™ that comprises a membrane active polymer to promote RNAi trigger endosomal release, an active ligand that targets the DPC™ to tumor cells, reversible masking to prevent polymer activity prior to cellular uptake, and an RNAi trigger to HIF-2alpha conjugated directly to the DPC™. Using ARC-HIF2 in a preclinical ccRCC tumor model, mice treated with weekly injections led to greater than 80% knockdown of HIF-2alpha mRNA in tumors. Furthermore, tumors from treated mice exhibited statistically significant reductions in size and weight, extensive tumor cell death, reduction in the tumor-expressed VEGF-A biomarker, and destruction of the blood vessels feeding the tumors.
Disease: clear cell renal cell carcinoma
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On April 18, 2016, Arrowhead Pharmaceuticals presented a poster on ARC-HIF2, its preclinical development program targeting HIF2-alpha for the treatment of renal cell carcinoma (RCC), at the American Association for Cancer Research Annual Meeting 2016 (AACR16), in New Orleans. The poster titled, "Novel HIF-2alpha targeted RNAi therapeutic for renal cell carcinoma" (abstract 2064), describes data from various stages of development of ARC-HIF2, including RNAi trigger selection, HIF2-alpha target validation, delivery and targeting ligand validation, and multiple RCC tumor models. These data show that important advancements are being made in this program and for Arrowhead's Dynamic Polyconjugate™ (DPC™) delivery platform generally, including the following key findings: * On September 12, 2015, Arrowhead Research Corporation, a biopharmaceutical company developing targeted RNAi therapeutics, announced that it has nominated ARC-HIF2 as its first therapeutic candidate delivered using a new Dynamic Polyconjugate™ (DPC™) designed to target tissues outside of the liver. Arrowhead believes that ARC-HIF2, which uses RNA interference to silence transcription factor hypoxia-inducible factor 2alpha (HIF-2alpha), is a new candidate for the treatment of clear cell renal cell carcinoma (ccRCC). The company will present preclinical data at the European Cancer Congress 2015 (ECC2015) in Vienna on September 27 in a session starting at 16:45 CEST. In a poster titled "HIF-2alpha targeting with a novel RNAi delivery platform as therapy for renal cell carcinoma," (abstract #353), Arrowhead scientists will show data suggesting that HIF-2alpha inhibition through RNA interference may significantly impact late stage ccRCC progression. The company is in the process of manufacturing scale up to allow for initiation of IND-enabling studies. Timing for anticipated regulatory submission will be announced in the future. Therapies for metastatic ccRCC including agents that target the VEGF/VEGFR or mTor signaling pathways, which are validated cancer targets, have become the standard-of-care and have improved patient outcomes. However, since emergence of resistance to these agents is common, novel therapies targeting alternative pathways are needed for patients with resistant tumors. Arrowhead believes that HIF2alpha is an attractive target for intervention because over 90% of ccRCC tumors express a mutant form of the Von Hippel-Landau protein that is unable to degrade HIF-2alpha, leading to its accumulation during tumor hypoxia and promoting tumor growth.
Proof-of-concept ligand dependent, functional delivery was demonstrated using the DPC targeted delivery platform
Silencing HIF2-alpha expression by RNA interference resulted in reduction of HIF-2alpha regulated genes
In two different RCC tumor bearing mouse models, ARC-HIF2 inhibited tumor growth and promoted tumor cell death and structural degeneration.
