2015年1月14日讯 /生物谷BIOON/ --总部位于加利福尼亚州帕萨迪纳市的生物技术公司Arrowhead是一家以开发RNAi疗法为核心的生物医药公司。众所周知，RNAi被很多人认为是充满不确定性因素的研究领域，机遇与挑战并存。Arrowhead公司现有三种RNAi药物正处于研发过程，其中ARC-520是走的最远的一个项目。此外Arrowhead公司还有治疗癌症的小分子非RNA药物Cyclosert也正处于临床二期研究过程中。然而，最近FDA对ARC-520提出了新的要求，为ARC-520的前景蒙上了一层阴云。
根据Arrowhead公司透露的消息，FDA要求公司将临床二期研究的剂量由计划的2mg/kg和4mg/kg降低至1mg/kg。此外，FDA还要求公司能够提供更多的关于ARC-520单剂量治疗的数据，这一要求也旨在更全面考虑RNAi疗法潜在的副作用。尽管公司此前已经一再声明，在临床研究中未发现明显的毒副作用。
ARC-520采用了Arrowhead公司独有的Dynamic Polyconjugates输送系统。其原理是通过RNA干扰封闭乙肝病毒某些蛋白的表达，造成病毒无法增殖，然后再利用机体的免疫系统对剩余病毒进行清除。然而，现有数据显示，低剂量的ARC-520对这种蛋白的封闭效果仅为39%，无法达到治疗乙肝的效果。据此，Arrowhead公司也迅速采取措施，公司表示目前正在和FDA进行协商，希望能够将临床二期研究调整为多剂量的研究组。
RNAi现象主要表现为mRNA在细胞质中被切割破坏，从而实现特定基因在转录后水平上的沉默。而最近美国NIH和FDA联合资助用于治疗埃博拉病毒的RNAi疗法也被认为是针对RNAi疗法的一个积极信号。科学家认为肝脏是最适宜接受RNAi疗法的器官，这个器官表面布满了直径在100nm左右的微孔，能够保证装载了RNA药物的脂类纳米颗粒通过。不过，正所谓仁者见仁，最近诺华公司决定退出这一领域则表现出一些生物医药公司所持有的谨慎态度。
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详细英文报道：
Shares of Arrowhead Research ($ARWR) took a beating Monday morning after the biotech revealed that the FDA had made a preliminary call on a partial clinical hold on a Phase IIb trial of its lead drug for hepatitis B.
According to the Pasadena, CA-based Arrowhead, regulators want Arrowhead to start the mid-stage study at a much lower dose than what had been planned: 1 mg/kg of ARC-520 rather than the proposed 2 and 4 mg/kg.
In addition, regulators have come calling for some added info about the experimental therapy. The FDA wanted to find out more about a completed single-dose study of ARC-520 along with some extra input on an ongoing multiple dose trial. The biotech's execs emphasized that they have seen no signs of organ toxicity in either study.
Investors, though, weren't soothed by the assurances. Arrowhead's stock tanked by 28% this morning as rattled investors bailed. And it's not hard to see why. The biotech took a drubbing a few months back after the lower 1 mg/kg dose of the drug failed to trigger the kind of response Wall Street was looking for.
ARC-520 uses a specially designed nano-polymer to deliver an RNA treatment which is supposed to block a key protein the hep B virus needs to stay hidden from the immune system. But at 1 mg/kg, there was only an average 39% reduction in the protein. The stock plunged, lawsuits were filed and Arrowhead set out to go up to 4 mg/kg to see if it could get a much better response.
"Over the next 30 days, Arrowhead will begin preparations for the multiple-dose Phase IIb study," said Arrowhead CEO Dr. Christopher Anzalone. "We will work closely with the FDA throughout this process while we continue to seek approval to proceed with other planned studies in Asia and Europe."