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A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced
James Brugarolas1, Gregory Obara2, Kathryn E Beckermann3
1The University of Texas Southwestern Medical Center, Dallas, Texas.
Purpose:
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). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose.
Patients And Methods:
Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly.
Results:
Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia.
Conclusions:
ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. 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.
Insights
ARO-HIF2, an siRNA drug, showed potential by downregulating HIF2α in advanced clear cell renal cell carcinoma. However, development faced challenges due to neurotoxicity and limited response rates.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) is a significant cause of cancer mortality.
- Hypoxia-inducible factor-2α (HIF2α) plays a critical role in ccRCC progression and oncogenic signaling.
- Targeting HIF2α represents a potential therapeutic strategy for advanced ccRCC.
Purpose of the Study:
- To assess the safety, tolerability, and pharmacokinetics of ARO-HIF2, an siRNA targeting HIF2α.
- To determine a recommended Phase 2 dose for ARO-HIF2 in patients with ccRCC.
- To evaluate the preliminary efficacy of ARO-HIF2 in advanced ccRCC.
Main Methods:
- A Phase 1 dose-escalation study (AROHIF21001) enrolled patients with advanced ccRCC.
- ARO-HIF2 was administered intravenously at escalating doses (225, 525, 1,050 mg weekly).
- Safety, adverse events, pharmacokinetics, HIF2α levels, and response rates were assessed.
Main Results:
- Twenty-six patients received ARO-HIF2; common adverse events included fatigue, dizziness, dyspnea, and nausea.
- Four patients (15.4%) experienced treatment-related serious adverse events, including neurotoxicity.
- Objective response rate was 7.7%, with disease control rate of 38.5%; HIF2α downregulation was observed in tumor biopsies.
Conclusions:
- ARO-HIF2 demonstrated proof of concept for siRNA-mediated HIF2α targeting in ccRCC.
- While ARO-HIF2 downregulated HIF2α and inhibited tumor growth in a subset of patients, development was limited by neurotoxicity and low response rates.
- Further investigation into siRNA-based therapies for ccRCC is warranted, potentially with strategies to mitigate toxicity.
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