LB-9
ARC-520 produces deep and durable knockdown of
viral antigens and DNA in a phase II study in patients
with chronic hepatitis B
Man-Fung Yuen1, Henry Lik-Yuen Chan2
, Sze Hang Kevin Liu1, Bruce Given3, Thomas Schluep3, James Hamilton3, Ching-Lung Lai1, Stephen Locarnini4, Johnson Y. Lau5, Carlo Ferrari6, Robert Gish7,8
; 1The University of Hong Kong, Hong Kong, China;
2The Chinese University of Hong Kong, Hong Kong, China;
3Arrowhead Research Corp., Pasadena, CA;
4Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia;
5Hong Kong Polytechnic University, Hong Kong, China;
6University of Parma, Parma, Italy;
7Stanford University, Palo Alto, CA;
8Hepatitis B Foundation, Doylestown, PA
Chronic hepatitis B (CHB) has become an important target for drug development. ARC-520 (ARC), the first RNA interference-based drug to reach patients (pts), targets ccc-DNA-derived mRNA; herein we report results in CHB.
Methods:
58 CHB pts (48 ARC, 10 placebo (PL), mean age 41 yrs (range 23-59) were included. 38 pts were HBeAg-neg and 20 HBeAg-pos. At entry, 32 of 38 HBeAg-neg and 14 of 20 HBeAg-
pos had taken entecavir (ETV) for mean of 5 yrs (range 2-8) and were on ETV throughout the study. 12 treatment naïve pts
(6 HBeAg-neg, 6 HBeAg-pos) started on ETV during the trial.
All pts received a single dose IV of ARC or PL (6 HBeAg-pos received a divided dose of ARC separated by 2 wks) and had viral parameter knockdown (KD) measured over 85 days [qHBsAg, HB core-related antigen (qHBcrAg) and viral DNA in all, qHBeAg in HBeAg-pos]. Doses were 1-4 mg/kg in HBeAg-neg. All HBeAg-pos received 4 mg/kg. 15 pts are continuing in follow-up.
Results:
ARC therapy was well tolerated - 23%
reported a mild or mod adverse event (AE) with no AE rated serious, severe, drug-related or causing withdrawal from the trial. Viral DNA was below level of quantitation in all chronic ETV pts at study entry. Naïve pts reduced viral DNA up to 4.3
log (mean 2.2 log) after ARC and ETV. ARC reduced viral antigens with qHBeAg best KD of 1.7 log (mean max 1.2 log)
following a single 4 mg/kg dose. In naïve pts, best qHBsAg KD of 1.9 log (mean max 1.1 log) in HBeAg-pos and 0.7 log
(mean max 0.2 log) in HBeAg-neg were observed. qHBcrAg showed a dose response in HBeAg-neg with best KD at 1 mg/kg of 0.18 log (mean max 0.15 log) and 1.1 log (mean max 0.9 log) with 4 mg/kg. HBeAg-pos showed best KD of 1.1 log
(mean max 0.92 log). The qHBsAg dose response was less deep in chronic ETV pts with best observed reduction of 0.3
log (mean max 0.2 log) observed at 1 mg/kg vs 0.5 log (mean max 0.4 log) at 4 mg/kg in HBeAg-neg. Best qHBsAg KD in
chronic ETV treated HBeAg-pos was 0.7 log (mean max 0.3 log). Divided doses at 4 mg/kg did not increase antigen KD.
Duration of qHBsAg KD was typically 8 wks with 2 distinct KD patterns of qHBsAg seen: an immediate, direct ARC antiviral effect (~70% of pts) and a delayed response several weeks after treatment (~30% of pts).
Conclusions:
1) These findings are consistent with more cccDNA-driven antigen production
in HBeAg-pos. 2) ARC was well tolerated 3) ARC effectively inhibited cccDNA-derived mRNA with protein KD up to 1.9
logs (99%) observed 4) These variations in viral protein KD are consistent with ARC data in chimps and previously reported
chronic ETV reductions in pts for cccDNA 5) Chronic ARC studies aimed at producing HBsAg seroclearance are underway.
Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline,
Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer,
GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD, Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and Teaching: Echosens
Bruce Given - Employment: Arrowhead Research Corp; Stock Shareholder: Icon plc
Thomas Schluep - Employment: Arrowhead Research Corp.
James Hamilton - Employment: Arrowhead Research Corp
Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc;
Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc
Stephen Locarnini - Consulting: Gilead, Arrowhead; Employment: Melbourne Health
Johnson Y. Lau - Advisory Committees or Review Panels: Arrowhead Research;
Management Position: Kinex Pharmaceuticals, Avalon BioMedical Management; Speaking and Teaching: Hong Kong Polytechnic University, University of Hong Kong, Southwestern Hospital
Carlo Ferrari - Advisory Committees or Review Panels: Gilead, Roche, Abbvie, BMS, Merck, Arrowhead; Grant/Research Support: Gilead, Roche, Janssen
Robert Gish - Advisory Committees or Review Panels: Gilead, AbbVie, Arrowhead; Consulting: Eiger, Isis, Genentech; Speaking and Teaching: Gilead, AbbVie; Stock Shareholder: Arrowhead
The following people have nothing to disclose: Sze Hang Kevin Liu
1) These findings are consistent with more cccDNA-driven antigen production
in HBeAg-pos. 2) ARC was well tolerated 3) ARC effectively inhibited cccDNA-derived mRNA with protein KD up to 1.9
logs (99%) observed 4) These variations in viral protein KD are consistent with ARC data in chimps and previously reported
chronic ETV reductions in pts for cccDNA 5) Chronic ARC studies aimed at producing HBsAg seroclearance are underway.
今天我也是闲的发慌了。。。这是在网友@zhaoyun810提供的材料中扒出来的一篇2015肝病大会基于ARC-520二期临床数据的研究报告，为了尽量不弄错，也查了很多资料，注解中也有各位关心的所谓降低多少log是什么意思的问题。另外，欢迎转载，但请注明出处。
本研究报告的第一作者是香港大学的Man-Fung Yuen，因为精力问题，就直接将各位作者及单位贴上了，以表示对知识产权的尊重。
Title：ARC-520 produces deep and durable knockdown of viralantigens and DNA in a phase II study in patients with chronic hepatitis B
标题：慢乙患者中进行的ARC-520产品深入并持续性降低病毒抗原与DNA的临床二期研究
作者及单位：
Man-Fung Yuen1, Henry Lik-Yuen Chan2, Sze HangKevin Liu1, Bruce Given3, Thomas Schluep3, James Hamilton3, Ching-Lung Lai1,Stephen Locarnini4, Johnson Y. Lau5, Carlo Ferrari6, Robert Gish7,8;
1The University of Hong Kong, Hong Kong, China;
2The Chinese University of Hong Kong, HongKong, China;
3Arrow-head Research Corp., Pasadena, CA;
4Victorian Infectious Dis-eases ReferenceLaboratory, Melbourne, VIC, Australia;
5Hong Kong Polytechnic University, Hong Kong,China;
6University of Parma, Parma, Italy;
7Stanford University, Palo Alto, CA;
8Hepatitis B Foundation, Doylestown, PA
Chronic hepatitis B(CHB) has become an important target for drug development. ARC-520 (ARC), thefirst RNA interference-based drug to reach patients(pts), targets ccc-DNA-derived mRNA; herein we report results in CHB.
背景：慢性乙肝已经成为药物开发的一个重要目标。ARC-520，首个基于RNA干扰的药物以衍生自共价闭合环状DNA的信使RNA为靶向。（注1：reach patient字面意思是“病患可以接触到”，我猜这里是指针对病人或用于治疗的意思吧；注2：cccDNA是医学术语，在互动百科可以查知，只有消除了细胞核内的cccDNA才能彻底消除乙肝患者的病毒携带状态，是抗病毒治疗的目的。不知道这里可否理解为彻底清除病毒，表抗转阴之类的）
Methods: 58 CHB pts (48 ARC,10 placebo (PL), mean age 41 yrs (range 23-59) were included. 38 pts wereHBeAg-neg and 20 HBeAg-pos. At entry, 32of 38 HBeAg-neg and 14 of 20 HBeAg-poshad taken entecavir (ETV) for mean of 5 yrs (range 2-8) and were on ETVthroughout the study. 12 treatment naïve pts (6 HBeAg-neg, 6 HBeAg-pos) startedon ETV during the trial. All pts received a single dose IV of ARC or PL (6HBeAg-pos received a divided dose of ARC separated by 2 wks) and had viralparameter knockdown(KD) measured over 85 days [qHBsAg, HB core-related antigen (qHBcrAg) and viralDNA in all, qHBeAg in HBeAg-pos]. Doses were 1-4 mg/kg in HBeAg-neg. AllHBeAg-pos received 4 mg/kg. 15 pts are continuing in follow-up.
方法：本研究包括58位慢性乙肝患者，48位使用ARC-520治疗，10人采用安慰剂，年龄在23-59岁之间，平均年龄为41岁。38位病患的乙肝e抗原为阴性但乙肝表面抗原为阳性。参与研究时，38位e抗原阴性的病患中的32位病患与20位表抗阳性的病患中的14位病患已经开始服用恩替卡韦2-8年不等，平均服药年限是5年，并且在研究期间继续服用恩替卡韦。12位初治患者（6人e抗原阴性，6人e抗原阳性）在试验中开始服用恩替卡韦。（就是说，所有的人都在吃恩替卡韦了）所有的病患接受了单倍剂量的ARC-520或安慰剂的静脉注射（6个e抗原阳性的病患接受了间隔两周的均分剂量的ARC-520的静脉注射），85天后，测量病毒参数的降低情况（在全体病患中进行乙肝表面抗原定量，乙肝核相关抗原定量和病毒DNA定量，在e抗原阳性的病患中进行乙肝e抗原定量）。对e抗原阴性的病患的给药剂量是每公斤体重1-4毫克。所有的e抗原阳性的病患接受每公斤体重4毫克的给药。15个病患持续用药中（就是说在本摘要投稿时，还在治疗）。
Results: ARC therapy was welltolerated - 23%reported a mild or mod adverseevent (AE) with no AE rated serious, severe, drug-related or causing withdrawalfrom the trial. Viral DNA was below level of quantization in all chronic ETVpts at study entry. Naïve pts reduced viral DNA up to 4.3 log (mean 2.2 log)after ARC and ETV. ARC reduced viral antigens with qHBeAg best KD of 1.7 log(mean max 1.2 log) following a single 4 mg/kg dose. In naïve pts, best qHBsAg KDof 1.9 log (mean max 1.1 log) in HBeAg-pos and 0.7 log (mean max 0.2 log) in HBeAg-negwere observed. qHBcrAg showed a dose response in HBeAg-neg with best KD at 1mg/kg of 0.18 log (mean max 0.15 log) and 1.1 log (mean max 0.9 log) with 4mg/kg. HBeAg-pos showed best KD of 1.1 log (mean max 0.92 log). The qHBsAg doseresponse was less deep in chronic ETV pts with bestobserved reduction of 0.3 log (mean max 0.2 log) observed at 1 mg/kg vs 0.5 log(mean max 0.4 log) at 4 mg/kg in HBeAg-neg. Best qHBsAg KD in chronic ETVtreated HBeAg-pos was 0.7 log (mean max 0.3 log). Divided doses at 4 mg/kg didnot increase antigen KD. Duration of qHBsAg KD was typically 8 wks with 2distinct KD patterns of qHBsAg seen: an immediate, direct ARC antiviral effect(~70% of pts) and a delayed response several weeks after treatment (~30% ofpts).
结果：ARC-520治疗表现出良好的耐受性，23%的用药者报告了轻微的或中度的不良反应，没有被评估为严重的，剧烈的，与用药相关的或导致病患退出试验的不良反应。乙肝DNA定量值低于全体服用恩替卡韦病患在参与研究时的初始值。初治患者的病毒DNA在接受ARC-520和恩替卡韦联合治疗后最高降低4.3log（平均2.2log）。（注3：1个log就是10的1次幂，因此最高降低4.3log就是说讲了10的4.3次幂。有网友说，降低1个log，就表示DNA降低了90%，如果是4个log，就是降低了99.99%，如果我没理解错的话）在单次按每公斤体重4毫克的给药条件下，ARC-520降低病毒抗原，e抗原最高降低1.7log，平均最大值为1.2log。在初治患者中，e抗原阳性病患的表抗最高降低1.9log，最大均值是1.1log；在e抗原阴性的病患中，表抗最高降低0.7log，最大均值0.2log。乙肝核相关抗原定量表明在e抗原阴性且按每公斤体重1毫克给药的病患中，乙肝核相关抗原最高降低0.18log，平均最大值0.15log；而在e抗原阴性按每公斤体重4毫克给药的病患中，乙肝核相关抗原最高降低1.1log，平均最大值为0.9log。而e抗原阳性的病患（注4：前面方法部分说了，这部分病患也是按每公斤体重4毫克给药）的乙肝核相关抗原最高降低1.1log，平均最大值0.92log。对乙肝表面抗原定量评估给药反应则表现一般，对于服用恩替卡韦的e抗原阴性的按每公斤体重1毫克给药的病患最高降低表抗0.3log，平均最大值0.2log，对于按每公斤体重4毫克给药的服用恩替卡韦且e抗原阴性的病患，表抗最高降低0.5log，平均最大值0.4log。而对于e抗原阳性服用恩替卡韦的病患，表抗最高降低0.7log，平均最高值0.3log。按每公斤体重4毫克标准分开给药不会增加相关抗原的降低。（注5：最后一句专业性强，不太好懂，但应该是解释前一句分开给药和一次给药没差异的，大体意思是在两种不同的给药模式下，同样都有70%的病患表现出即时的抗病毒疗效，而30%的病患表现出延时的抗病毒疗效）
Conclusions: 1) These findings areconsistent with more cccDNA-driven antigen production in HBeAg-pos. 2) ARC waswell tolerated 3) ARC effectively inhibited cccDNA-derived mRNA with protein KDup to 1.9 logs (99%) observed 4) These variations in viral protein KD are consistentwith ARC data in chimps and previously reported chronic ETV reductions in pts forcccDNA 5) Chronic ARC studies aimed at producing HBsAg seroclearance areunderway.
结论：1）这些发现与更多的自共价闭合环状DNA驱动的抗原产品在e抗原阳性病患中的疗效一致。（注6：这里的more...production不太好翻译，感觉很不通顺，可能是我理解不当）2）ARC-520具有良好的耐受性。3）ARC-520能有效地抑制衍生自共价闭合环状DNA的信使RNA，表现为其蛋白质最高降低1.9log（99%）。4）对于变异病毒蛋白质的降低与ARC-520以黑猩猩为试验对象和先前报告的服用恩替卡韦来对抗衍生自共价闭合环状DNA的结果相一致。（注7：自己解读吧）5）长期的意在实现表抗血清清除的ARC-520研究已经到来。作者: qx605 时间: 2015-10-25 16:45
