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EASL2017:Arbutus公布乙肝新药ARB-1467 phase 2a期临床部分结果

2017-04-19  来源:肝脏巴士(HeparBus)微信  作者:无聊的猫  编辑:放下
导读
ARB-1467 是 Arbutus 生物制药公司众多 RNAi 产品线中的一个,是含有三个双链小干扰RNA(siRNA)的脂质纳米颗粒(LNP)制剂,其靶向病毒基因组中的三个不同位点,以实现由
 
ARB-1467 是 Arbutus 生物制药公司众多 RNAi 产品线中的一个,是含有三个双链小干扰RNA(siRNA)的脂质纳米颗粒(LNP)制剂,其靶向病毒基因组中的三个不同位点,以实现由cccDNA和整合DNA产生的HBV蛋白的转录后基因抑制,包括乙肝表面抗原(HBsAg)。在临床前试验中表现出了降低乙肝病毒抗原如 cccDNA 和 HBV DNA 水平的能力。
 
在此次的2017欧洲肝病学会年会上Arbutus公司公布的是该药用于HBeAg阳性和阴性病毒已受控制慢乙肝患者的多剂量 phase 2a 期临床研究结果。该研究为一项单盲、安慰剂对照、多剂量研究,受试对象为无肝硬化的病毒已受控制的慢乙肝患者,主要评估在为期12周的疗程中该药的安全性和有效性。
 
24名使用核苷(酸)类似物治疗病毒已获得稳定控制的慢乙肝患者分为3组队列:Cohort 1, HBeAg(−) 0.2 mg/kg;Cohort 2, HBeAg(−) 0.4 mg/kg; Cohort 3, HBeAg(+)  0.4 mg/kg。受试对象被按照3:1 (实验 vs 安慰剂)比例随机接受为期3个月用药的安全性、药代动力学和乙肝病毒标志物的研究。
 
3组队列的基线情况相似。24名受试对象中19(79%)名为男性,平均年龄为45.5岁, Cohorts 1, 2, 3 和对照组基线平均HBsAg (log10 IU/mL)水平分别为: 3.46; 3.38; 3.62 和 3.43 。
 
两个无关的不良反应为:在3剂用药后的筛选中发现HCC和左耳前庭功能降低。1名对象由于急性 HEV 感染和肝炎(Grade 3 ALT)。Cohorts 1, 2和安慰剂组中均有5(83.3%) 名对象出现不良反应,Cohorts 3有1名(16.7%)。Cohorts 1 和 3 均有3名(50%)对象出现独立的3级实验室检测结果异常,Cohorts 2和 安慰剂组均有2 (33.3%)名。连续剂量使用的 HBsAg 下降幅度更大,而 Cohorts 2中 3/5受试者实现下降大于 1 log,如下图。


 
ARB-1467治疗一般耐受良好。单剂量和多剂量后均观察到 HBsAg 下降; 三个月 0.4mg / kg 剂量之后的下降大于 0.2mg / kg。这些结果支持进一步对 ARB-1467 在慢乙肝的治疗开发。
 
 
编号:SAT-155
 
A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBeAg positive and negative virally suppressed subjects with hepatitis B
 
A. Streinu-Cercel1, E. Gane2, W. Cheng3, W. Sievert4, S. Roberts5,S.H. Ahn6, Y.J. Kim7, K. Agarwal8, D. Niforos9, B. Symonds9, P. Mendez9.1Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases “Prof. Dr. Matei Balș”, Bucharest, Romania;2Auckland Clinical Studies Limited, Auckland, NewZealand; 3Royal Perth Hospital and Linear Research, Perth; 4Monash Health; 5The Alfred,Melbourne, Australia; 6Yonsei University College of Medicine; 7Seoul National University College of Medicine, Seoul, Korea, South; 8Institute of Liver Studies, King’s College Hospital Foundation Trust, London,United Kingdom; 9Arbutus Biopharma, Burnaby, Canada
E-mail: mbates@arbutusbio.com 
 
Background and Aims: ARB-1467 is a lipid nanoparticle (LNP)formulation containing three double-stranded small interfering RNAs (siRNA) which target three distinct sites in the viral genome to achieve post-transcriptional gene suppression of HBV proteins generated from both cccDNA and integrated DNA, including surface antigen (HBsAg).
 
Methods: This is a single-blind, placebo-controlled, multi-dose study in non-cirrhotic, virally suppressed subjects to evaluate safety and efficacy of ARB-1467 over 12 weeks. 24 subjects on stable nucleoside therapy were enrolled in 3 cohorts: Cohort 1, HBeAg(−) at 0.2 mg/kg;Cohort 2, HBeAg(−) at 0.4 mg/kg; Cohort 3, HBeAg(+) at 0.4 mg/kg.Subjects were randomized 3:1 (active vs placebo) to 3 monthly doses and monitored for safety, PK and HBV markers.
 
Results: Baseline characteristics were similar for the 3 cohorts. Of 24 subjects, 19 (79%) were male, mean age was 45.5 years and mean baseline HBsAg (log10 IU/mL) levelswere: 3.46; 3.38; 3.62 and 3.43 in Cohorts 1, 2, 3 and placebo, respectively.Two unrelated SAEs were: HCC at screening and left cochleovestibular deficit after Dose 3. 1 subject discontinued due to acute HEV suprainfection and hepatic flare (Grade 3 ALT). AEswere reported in 5 (83.3%) subjects each in Cohorts 1, 2 and placebo, and 1 (16.7%) in Cohort 3. Isolated grade 3 lab abnormalities occurred in 3 (50%)subjects in Cohort 1 and 3, and 2 (33.3%) in Cohort 2 and placebo.HBsAg reductions were greater with successive doses and 3/5 subjects in Cohort 2 achieved reductions >1 log as summarized below.
 
Conclusions: Treatment with ARB-1467was generallywell tolerated. HBsAg reductions were observed following single and multiple doses; reductions after three monthly 0.4 mg/kg doses were greater than at 0.2 mg/kg. These results support further investigation with ARB-1467 in treatment of CHB.
 
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