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.

中文翻译：

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针对 HIF2α 的肿瘤定向 RNA 干扰药物治疗晚期透明细胞肾细胞癌患者的首次人体 1 期研究

目的：ARO-HIF2 是一种 siRNA 药物，旨在选择性靶向缺氧诱导因子 2α (HIF2α)，干扰透明细胞肾细胞癌 (ccRCC) 的下游促癌信号传导。这项 1 期研究 (AROHIF21001) 的目的是评估安全性、耐受性、药代动力学，并确定推荐的 2 期剂量。患者和方法：接受至少 2 种包括 VEGF 和免疫检查点抑制剂在内的既往治疗后患有 ccRCC 且疾病进展的受试者被逐步纳入 ARO-HIF2 剂量递增队列，每周静脉注射 225、525 或 1,050 mg。结果：26 名受试者接受了 ARO-HIF2。无论因果关系如何，最常见的治疗紧急不良事件 (AE) 包括疲劳 (50.0%)、头晕 (26.9%)、呼吸困难 (23.1%) 和恶心 (23.1%)。四名受试者 (15.4%) 出现与治疗相关的严重 AE。特别令人感兴趣的 AE 包括神经病变、缺氧和呼吸困难。 ARO-HIF2 在 48 小时内几乎从血浆循环中完全清除，肾脏清除率极低。在给药前和给药后的肿瘤活检中观察到 HIF2α 的减少，但幅度差异很大。客观缓解率为7.7%，疾病控制率为38.5%。副肿瘤性红细胞增多症患者的反应伴随着肿瘤细胞中 ARO-HIF2 的摄取、HIF2α 的下调以及肿瘤产生的促红细胞生成素 (EPO) 的快速抑制。结论：ARO-HIF2 下调晚期 ccRCC 中的 HIF2α，从而抑制部分受试者的肿瘤生长。脱靶神经毒性和低反应率阻碍了进一步的发展。这项研究提供了 siRNA 可以以特定方式靶向肿瘤的概念证明。