ARC-520是治疗慢性乙肝病毒感染的一种新型的、包含小分子干扰RNA (siRNA)的肝脏靶向治疗方法。其目的是通过干扰RNA来减少所有HBV的转录。在HBV感染的黑猩猩和小鼠模型中，我们观察到病毒颗粒和病毒蛋白质表达的减少。病毒蛋白（尤其是HBeAg 和HBsAg）与免疫耐受、持续感染和疾病进展有关。靶向作用于病毒蛋白的治疗方法能重建宿主的免疫，从而促进HBsAg的血清清除。
这项II期、剂量调整试验旨在评估应用ARC-520（siRNA为基础的疗法）治疗慢性乙肝病毒感染的疗效和安全性。研究结果将在AASLD2014上发布。
研究方法
一个在健康受试者中进行的I期试验证实了ARC-520的安全性。这一在两个中心进行的IIa期、随机、双盲、安慰剂对照试验评估了长期应用恩替卡韦的、HBeAg阴性的慢性HBV感染的患者在单纯静脉应用ARC-520后HBsAg下降的程度和持续时间及其安全性。符合纳入-排除标准的患者被按1：3的比例随机分配到安慰剂组或ARC-520组，并继续每天应用恩替卡韦。
我们评估了ARC-520 单次剂量1 mg/kg (1组，8位患者), 2 mg/kg (2组，8位患者) 和3 mg/kg (3组，6位患者)的疗效。1组和2组在85天内进行评估，是非盲的。3组正在入组阶段，仍未揭盲。
研究结果
所有3个小组都没有严重不良事件、没有严重不良反应、没有过敏的迹象、没有剂量限制性毒性，也没有因为不良反应而终止治疗。没有出现治疗所致的生命体征、体格检查和心电图改变。很少出现实验室异常结果，没有出现明显的临床改变、治疗意外、ALT, AST, GGT, LDH,胆红素,肌酐改变或明显的趋势。到目前为止，报道的不良反应(n=4)都是轻中度的，并且研究者们认为与研究药物无关。
通过测量HBsAg比基础状态下降的程度来评估ARC-520的疗效。1组应用ARC-520的患者，HBsAg最低时降低39% (范围 -22 至 -57)，第85天时平均下降31% (范围-14至-39)。2组应用ARC-520的患者，HBsAg最低时降低51% (范围 -46至 -59)，第85天时平均下降22% (范围 -7 至 -40)。2组中，与安慰剂组相比，HBsAg降低的百分比有统计学意义。这是首个通过干扰RNA使慢性乙肝患者的HBsAg降低的案例。
英文原文
Phase II, dose ranging study of ARC-520, a siRNA-based therapeutic, in patients with chronic hepatitis B virus infection（摘要号：LB-21）
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 sero clearance.
A Phase I study in healthy subjects has demonstrated the safety profile of ARC-520. This phase IIa, randomized, double blind, placebo controlled study at 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.
