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本帖最后由 StephenW 于 2014-10-9 11:22 编辑
AASLD Late-breaking abstract
Final ID: B-21
PhaseII, dose ranging study of ARC-520,a siRNA-based therapeutic, in patients with chronic hepatitis B virus infection
M. Yuen;1;
H. Chan;2;
B. Given;3;
J. Hamilton;3;
T. Schluep;3;
D. L. Lewis;3;
C. Lai;1;
S. Locarnini;4;
J. Y.Lau;5;
R. G. Gish;6, 7;
1. The University of Hong Kong, Hong Kong, China.
2. The Chinese University of Hong Kong, Hong Kong, China.
3. Arrowhead Research Corp., Pasadena, CA, United States.
4. Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia.
5. Hong Kong Polytechnic University, Hong Kong, China.
6. Stanford University, Palo Alto, CA, United States.
7. Hepatitis B Foundation, Doylestown, PA, United States.
Abstract Body:
ARC-520 is a novel, short interfering RNA (siRNA)-containing, liver-targeted therapeutic for treatment of chronic hepatitis B virus (HBV) designed to reduce all HBV transcripts via RNA interference, with an observed reduction of viral particles and decreased expression of viral proteins in an HBV-infected chimpanzee and HBV mouse models. Viral proteins, in particular HBeAg and HBsAg, have been implicated in immune tolerance, sustained infection and disease progression. Therapies targeting viral proteins might allow host immune reconstitution, thereby promoting HBsAg seroclearance. A Phase I study in healthy subjects has demonstrated the safety profile of ARC-520. This phase IIa, randomized, double blind, placebo controlled study a t two centers assesses depth and duration of HBsAg reduction and safety after a single, intravenous dose of ARC-520 in HBeAg negative adult patients with chronic HBV infection receiving long-term entecavir. Patients meeting the inclusion-exclusion criteria are randomized to placebo or ARC-520 at a ratio of 1:3 and continue daily entecavir. Escalating, single doses of ARC-520 at 1 mg/kg (Cohort 1, 8 patients), 2 mg/kg (Cohort 2, 8 patients) and 3 mg/kg (Cohort 3, 6 patients) have been evaluated. Cohorts 1 and 2 have been evaluated through Day 85 and are unblinded. Cohort 3 is enrolling and remains blinded. In all three cohorts there have been no SAEs, no AEs rated as severe, no signs of hypersensitivity, no dose limiting toxicities and no discontinuations due to AEs. There were no treatment emergent changes in vital signs, physical exams or ECGs rated clinically significant by the investigator.
There have been few abnormal laboratory values, with no clinically significant, treatment emergent, changes in ALT, AST, GGT, LDH, bilirubin, BUN or creatinine or apparent trends. All AEs reported to date (n=4) have been mild or moderate and rated as unrelated to study drug by the investigator.
ARC-520 activity is assessed by measuring percent change of quantitative HBsAg decline from baseline. For patients receiving ARC-520 in cohort 1, mean nadir HBsAg was -39% (range-22 to -57) with a mean change on day 85 of -31% (range -14 to -39). For patients receiving ARC-520 in cohort 2, mean nadir HBsAg was – 51% (range -46 to -59) with a mean change on day 85 of -22% (range -7 to -40). For cohort 2, the percent reduction in HBsAg was statistically significant vs placebo for Days 3 through 43 post dose. This is the first time that a reduction in HBsAg mediated through RNA interference has been shown in chronic HBV patients.
AASLD的最新摘要
最终编号:LB-21
PhaseII,ARC-520的剂量范围研究中,基于siRNA的治疗,在慢性乙型肝炎病毒感染
M.元; 1;
H·陈; 2;
B.考虑; 3;
J·汉密尔顿; 3;
T. Schluep先生; 3;
D. L.刘易斯; 3;
三丽; 1;
S. Locarnini; 4;
J. Y.Lau; 5;
R. G.吉什;6,7;
香港,中国香港1。大学。
二,中国香港大学,香港,中国。
3,慈姑研究公司,帕萨迪纳,加利福尼亚,美国。
4,维多利亚传染病参考实验室,墨尔本,澳大利亚。
5,香港理工大学,香港,中国。
6,斯坦福大学,加州帕洛阿尔托,美国。
7,B型肝炎基金会,多伊尔斯敦,宾夕法尼亚州,美国。
摘要正文:
ARC-520是一种新型的,短干扰RNA(siRNA)基,肝靶向治疗用于治疗慢性乙型肝炎病毒(HBV)的设计,以减少经由RNA干扰所有的HBV转录物,与所观察到的减少的病毒颗粒的和减少的表达在一个HBV感染的黑猩猩和HBV小鼠模型中的病毒蛋白。病毒蛋白质,特别是HBeAg和HBsAg的,有牵连的免疫耐受性,持续感染和疾病的进展。针对病毒蛋白的治疗可能会允许宿主的免疫重建,从而促进乙肝表面抗原转阴。我研究在健康受试者进行的第一阶段已经证明ARC-520的安全性。这IIa期,单一的,静脉注射的ARC-520在HBeAg阴性患者的成年慢性HBV感染者长期接受恩替卡韦后,随机,双盲,安慰剂对照的两个中心研究评估的深度和降低乙肝表面抗原和安全工期。符合纳入,排除标准的患者被随机分为安慰剂组或ARC-520在1:3的比例,并继续每天的恩替卡韦。升级,单剂量的ARC-520在1毫克/公斤(组1,8名患者),2毫克/千克(组群2,8名患者)和3毫克/公斤(组群3,6名患者)进行了评价。队列1和2已经通过85天进行评价,并且非盲法。队列3招收并保持蒙蔽。在所有三个同伙没有出现过严重不良事件,无不良评为严重,过敏的迹象,没有剂量限制性毒性,无停药由于不良事件。有生命体征,体检或心电图没有治疗突发变化额定临床显著由研究者。
已经有一些实验室检查异常,没有任何临床显著,处理突发的变化,ALT,AST,GGT,LDH,胆红素,尿素氮肌酐或或明显的趋势。迄今报告的所有不良事件(N=4)已经轻度或中度,评为无关系的调查研究药物。
ARC-520的活性是通过测量从基线定量HBsAg的下降百分比变化进行评估。对于第1组接受ARC-520例,平均低潮乙肝表面抗原为-39%(区间22〜-57),与在-31%(范围-14〜-39)85日平均变化。对于世代2接收ARC-520例,平均最低点为乙肝表面抗原 - 51%(范围-46至-59)与-22%,85日平均变化(范围为-7〜-40)。对于队列2,在HBsAg的减少百分比有统计学显著组比安慰剂组为3天到43后的剂量。这是第一次在HBsAg的减少通过RNA干扰介导的已经在慢性HBV患者中所示。
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