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长效PCSK9靶向RNAi治疗性抑制剂
A Highly Durable RNAi Therapeutic Inhibitor of PCSK9


Kevin Fitzgerald ... 心脑血管疾病 • 2017.01.05
相关阅读
• inclisiran治疗LDL胆固醇升高的心血管高危患者 • 一种新型PCSK9抑制剂inclisiran通过了2期试验

核酸干扰药物的长效抑制作用展示独特优势


唐盛高†,陆阳‡*

† 广州纳泰生物医药技术有限公司和苏州圣诺生物医药技术有限公司;‡ SIRNAOMICS, INC.

* 通讯作者


体内过高的低密度脂蛋白(LDL)胆固醇已被确认是引发心脏病的主要危险因素。尽管已有的他汀类药物得以广泛使用并有很好的疗效,但仍然有相当数量病患用药后低密度脂蛋白胆固醇水平居高不下。因此,针对这类病患研制不同作用机制的药物已经成为亟待解决的临床需求。在本期《新英格兰医学杂志》发表的一篇应用核酸干扰(RNAi)药物来控制低密度脂蛋白胆固醇水平的研究报道,详细介绍了其临床试验的设计与实施及其不同寻常的结果。这是一个以PCSK9为药物靶点,并通过健康人群来评价核酸干扰药物inclisiran(ALN-PCS)的安全性和有效性的Ⅰ期临床试验。结果显示,没有严重不良的安全性问题出现。而在单升序剂量组和多剂量组参与者中都观察到持续长效地对PCSK9和低密度脂蛋白胆固醇水平的降低。如在300、500和800 mg等单剂量组和每月累积剂量高于300 mg的多剂量组中,对PCSK9和低密度脂蛋白胆固醇水平的降低可以维持180日甚至更长。而相对低的剂量,如100 mg单次给药以上剂量组,可观察到在第84日时低密度脂蛋白胆固醇水平降至基线的50.6%。inclisiran是由美国专注核酸干扰药物研发的Alnylam Pharmaceuticals研制的、采用一种多糖基团修饰并具有肝细胞靶向的小干扰核酸(siRNA)药物。这项随机单盲的临床研究由Alnylam Pharmaceuticals和Medicine Company共同资助,并委托两家CRO研究机构在英国实施。在本文介绍的这项临床Ⅰ期研究的基础上,该药物目前已经进入临床Ⅱ期的试验。

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摘要


背景

前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin-kexin type 9,PCSK9)是降低低密度脂蛋白(LDL)胆固醇的治疗靶点之一。inclisiran(ALN-PCSsc)是一种长效的、通过RNA干扰(RNAi)方式抑制PCSK9合成的治疗制剂。


方法

在本Ⅰ期试验中,我们将LDL胆固醇水平不低于100 mg/dL的健康志愿者,按比例3∶1随机分配至两组。两组参与者分别接受inclisiran或安慰剂皮下注射:剂量组分配至单次给药剂量递增阶段(25、100、300、500或800 mg)或多次给药阶段(每周1次125 mg,给药4次;隔周1次250 mg,给药2次;或每月1次300或500 mg,给药2次,联合或不联合他汀类药物治疗);每个剂量组包括4~8名参与者。我们将评估药物的安全性、副作用谱和药效学指标(PCSK9水平、LDL胆固醇水平和探索性脂质变量水平)。


结果

最常见的不良事件为咳嗽、肌肉骨骼疼痛、鼻咽炎、头痛、背痛和腹泻。所有不良事件均为轻或中度。未观察到严重不良事件或因不良事件导致用药中止。其中一例参与者γ-谷氨酰转移酶3度升高,但研究者认为这与他汀药物治疗相关。在单次给药剂量递增阶段,inclisiran给药剂量在300 mg及更高时可降低PCSK9水平(第84日与基线相比最小二乘法平均值降低了74.5%),给药剂量在100 mg或更高时可降低LDL胆固醇水平(最小二乘法平均值较基线降低了50.6%)。在300 mg或更大给药剂量水平下,PCSK9和LDL胆固醇水平的降低可维持至(给药后)180日。多次给药的所有方案均可降低PCSK9水平(第84日与基线相比最小二乘平均值降低了83.8%)和LDL胆固醇的水平(第84日与基线相比最小二乘平均值降低了59.7%)。


结论

在本Ⅰ期(临床)试验中,未观察到inclisiran导致的严重不良事件。给药剂量达到300 mg或更高(单次或多次给药)时,inclisiran可显著降低PCSK9和LDL胆固醇至少6个月(由Alnylam Pharmaceuticals和Medicines Company资助;ClinicalTrials.gov注册号为NCT02314442)。





作者信息

Kevin Fitzgerald, Ph.D., Suellen White, B.S.N., Anna Borodovsky, Ph.D., Brian R. Bettencourt, Ph.D., Andrew Strahs, Ph.D., Valerie Clausen, Ph.D., Peter Wijngaard, Ph.D., Jay D. Horton, M.D., Jorg Taubel, M.D., Ashley Brooks, M.B., Ch.B., Chamikara Fernando, M.B., B.S., Robert S. Kauffman, M.D., Ph.D., David Kallend, M.D., Akshay Vaishnaw, M.D., and Amy Simon, M.D.
From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George’s University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.). Address reprint requests to Dr. Fitzgerald at Alnylam Pharmaceuticals, 300 Third St., Cambridge, MA 02142, or at kfitzgerald@alnylam.com.

 

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