捷书夜半到长安: ARO-HIF2 更新

Arrowhead日前披露了RNAi治疗药物ARO-HIF2用于治疗ccRCC的Ph1b剂量探索研究AROHIF21001的前2个剂量队列的初期结果，ARO-HIF2是首个基于TRiM™平台的靶向治疗的临床阶段研究药物，Arrowhead 正计划入组第三个队列的患者并将在将来的医学会议上披露结果

Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced positive interim results from the first two cohorts of AROHIF21001, a Phase 1b dose-finding clinical study of ARO-HIF2, the company’s investigational RNA interference (RNAi) therapeutic being developed as a treatment for patients with clear cell renal cell carcinoma (ccRCC). ARO-HIF2 is the first tumor-targeted investigational medicine to utilize Arrowhead’s proprietary Targeted RNAi Molecule (TRiM™) platform in a clinical trial. Arrowhead is currently enrolling the third planned patient cohort of AROHIF21001 and the company intends to present additional data at an appropriate medical congress.

AROHIF21001 旨在评估在晚期ccRCC患者中的安全性、初步PD和有效性，前两个剂量队列的结果也显示了靶点结合的清晰信号以及至少1例患者中观察到了早期有效性的信号，这是一个令人鼓舞的开始。在17例接受ARO-HIF2治疗的患者中，9例接受组织活检可进行评估，7/9的患者样本中HIF2a蛋白表达下降（IHC检测），平均降幅48%（range 9-82%）。Cohort 2中1例患者肿瘤缩小65%获得PR，另有4例患者持续SD。该研究的患者在包括免疫检查点抑制剂和anti-VEGF抑制剂在内的多线治疗后失败，肿瘤高度异质性，所以在重度治疗的群体中取得这样的结果对于ARO-HIF2和TRiM™平台来说都是令人鼓舞的。最后ARO-HIF2整体上可耐受性很好，期待继续剂量递增。

James Hamilton, M.D., MBA, senior vice president of discovery and translational medicine at Arrowhead, said: “The AROHIF21001 Phase 1b study is designed to evaluate safety as well as preliminary pharmacodynamics and efficacy in an advanced ccRCC patient population. We believe that in the first two dose cohorts investigational ARO-HIF2 is showing clear signs of meaningful target engagement and some potentially early signs of efficacy in at least one patient. This is an encouraging start for the study. Specifically, in seventeen patients treated with investigational ARO-HIF2, nine had tumor biopsy material that could be evaluated. Seven of these nine tumor samples demonstrated reductions in HIF2α protein, as measured by immunohistochemistry H-score. The mean of these reductions was -48% with a range from -9% to -82%. In addition, one patient achieved a partial response with tumor shrinkage of approximately 65% and four additional patients in cohort 2 remain on study drug with stable disease. Tumors typically have a high level of heterogeneity and the patients in AROHIF21001 have advanced ccRCC and have failed multiple lines of treatment including checkpoint inhibitors and anti-VEGF regimens, so these early results in a heavily pre-treated population are encouraging for investigational ARO-HIF2 and our tumor-targeted platform broadly. ARO-HIF2 has been generally well-tolerated and we look forward to continued dose escalation.”

AROHIF21001关键结果汇总

  • 17例患者分别接受ARO-HIF2 225mg  IV QW（Cohort 1，n=7）和525mg  IV QW（Cohort 1，n=10）

  • 目前已经爬到1050mg  IV QW（Cohort 3），目前正在入组

  • IHC检测得到HIF2a蛋白H-score：9例患者样本可评估，其中7例HIF2a降低，平均降幅48%（range 9%-82%）

  • 疗效评估基于RECIST标准，Cohort 2中1例患者获得PR肿瘤缩小65%另有5例SD，治疗持续12-24wks的时候，仍有4例SD的患者在组

  • 安全性方面，目前为止所有剂量下ARO-HIF2 的可耐受性很好，没有报道药物相关的贫血

回顾下ARO-HIF2 的临床前开发

下载链接：

https://ir.arrowheadpharma.com/index.php/static-files/524a179b-0082-4663-8ada-1e0172891280

肾癌相关

  • 肾癌每年新发7.38w，其中70-80%属于ccRCC

  • 正常情况下VHL泛素化氧感知通路中的缺氧诱导因子（HIFs），从而导致HIF降解，而在ccRCC中VHL基因突变失活引起HIF聚积，诱导肿瘤产生过量的VEGF促进血管生成

  • 从这个角度看抑制剂HIF可能比VEGFR 抑制剂提供更强的疗效

ARO-HIF2是Arrowhead的首个肝外靶向的全身性RNAi疗法，基于TRiM™平台开发，通过连接的配体特异性识别在多个肿瘤类型中高度表达的整合素受体αvβ3来增强递送，最终特异性地靶向肿瘤中编码HIF2α的mRNA，将脱靶效应最小化，其他的化学修饰也增强了效价强度也组织了对免疫系统的激活

肿瘤组织中的有效递送依赖于Ligand（红色代表 ARO-HIF2）

看下小鼠模型，A498属于已建立的ccRCC细胞株：VHL突变、HIFα过表达且αvβ4阳性，而SEAP-A498模型可稳定表达SEAP且SEAP水平与肿瘤大小有显著相关性，这样就有了一个监测肿瘤生长的血清标志物

A498小鼠模型接受单剂ARO-HIF2后在Day8 观察到基因表达的敲低，6mpk以上观察到剂量反应

单剂ARO-HIF2 13mpk在Day8将HIFα敲低82.2%并保持一周左右

接受单剂10mpk后，mRNA还是蛋白水平，都观察到80%以上水平的下调

在多剂次的TGI研究中，连续接受ARO-HIF2每周13或26mpk x 8周的治疗

基于SEAP水平评估：均能显著抑制SEAP的分泌，也就是抑制了肿瘤的增长，但26mpk组有1只小鼠有治疗脱逸的迹象——其SEAP水平在7wk后飙升

基于肿瘤体积和基因沉默评估：不管安全性好，而且两个剂量下肿瘤生长都受到强抑制，也观察到HIF2α mRNA的深度敲低

组织学染色看，Day57的时候两个剂量组都显示了广泛的肿瘤破坏，透明细胞的肿瘤特征也消失了，有明显的凋亡及坏死区域，也观察到巨噬细胞的浸润

ARO-HIF2临床前总结

  • 配体增强了ARO-HIF2向肿瘤的递送：证明了可以深度的敲低肿瘤细胞中的HIF2α mRNA并因此降低HIF2α 蛋白；在肿瘤模型中可以抑制肿瘤生长并延长生存

  • 单剂及多剂可以爬到26mpk

  • 大鼠及NHP中毒理试验可以爬到120mpk：没有发现药物相关毒性也没有影响体重；最高剂量下肝功能监测升高极少；EPO水平未下降；80mpk下NHP肝肾脾及肾上腺中HIF2α mRNA水平未见显著敲低

展望中提到默克收的HIF2α抑制剂观察到EPO的降低（任意Gr 75%，其中Gr 3 20%）

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