APASL2017 [PL012] 安全性，耐受性，药代动力学和抗病毒活性 的A

StephenW

APASL2017[PL012]
Safety, tolerability, pharmacokinetics and antiviral activity
of AL-3778, a first-in-class, HBV core assembly modulator alone
and in combination with peginterferon-alpha 2A, in treatment
naive HBeAg-positive chronic hepatitis B patients
William Kennedy1, Man-fung Yuen2, D J Kim3, F Weilert4,
Henry L.y. Chan5, Jay Lalezari6, S G Hwang 7, T Nguyen8, Chris
Westland1, Thomas Kakuda1, Nathaniel Brown9, Klaus Klumpp9,
Lalo Flores9, Willem Talloen10, Oliver Lenz11, Edward Gane12,
Pieter van Remoortere11, Sushmita Chandra1, John Fry1
1Alios BioPharma, Inc., A Janssen Pharmaceutical Company of
Johnson & Johnson; 2Queen Mary Hospital, University of Hong
Kong, Pok Fu Lam; 3Hallym University, Chuncheon Sacred Heart
Hospital; 4Waikato Hospital, Hamilton, New Zealand; 5The Chinese
University of Hong Kong, Pok Fu Lam; 6Quest Clinical Research,
San Francisco, CA, USA; 7CHA Bundang Medical Center, Gyeonggido,
Republic of Korea; 8Research and Education, Inc., San Diego,
CA, USA; 9Novira Therapeutics; 10Janssen Pharmaceutical Company
of Johnson & Johnson; 11Janssen Pharmaceutical Company of
Johnson & Johnson; 12Auckland Clinical Studies, Auckland, New
Zealand
Background: AL-3778 is an orally-administered, first-in class hepatitis
B (HBV) capsid assembly modulator (CAM). We report the
safety, tolerability, pharmacokinetic (PK) and antiviral activities of
AL-3778 alone and in combination with peginterferon-alpha-2a
(PegIFN) in a 28 day Phase 1b study with treatment-naı¨ve CHB
patients.
Methods: Safety and efficacy were assessed in HBeAg + non-cirrhotic
CHB patients with HBV DNA[20,000 IU/mL and elevated
ALT. Patients were treated for 28 days and followed off-treatment for
28 days. Patients were randomized to receive AL-3778 or matching
placebo at doses of 100 and 200 mg QD (5:1 active:placebo), 400 mg
and 600 mg BD (4:1) in the first four cohorts. Patients were randomized
to receive 1000 mg BD or placebo (7:2) in the highest
monotherapy dose cohort. Patients were randomized (10:10) to separate
treatment arms to receive PegIFN (180 lg SQ weekly 9 4) in
combination with AL-3778 (600 mg BD) or PegIFN plus placebo. PK
sampling was done after the first dose in each cohort followed by
trough measures (C0h) on Days 3, 7, 14, 21 and 29. Serum HBV DNA
was quantified using the TaqmanTM HBV Test v2.0 (Roche). Quantification
of HBV RNA was developed using the QuantigeneTM
hybridization-based assay format (Affymetrix).
Result: 73 HBeAg+ CHB patients were enrolled. They were predominantly
Asian with HBV genotype B and C, and mean HBV viral
load between 7.23–8.39 log10 IU/mL. AL-3778 was generally welltolerated
with no discontinuations. One patient in the 100 mg cohort
developed an SAE of palmar-plantar dysesthesia related to AL-3778
administration. Mean steady-state. AL-3778 trough concentrations
were two to fourfold above the protein-binding adjusted EC90 with
BD dosing but below this threshold with QD dosing. Dose-related
HBV DNA and HBV RNA reductions were observed but no statistically
significant changes in HBV serology parameters were observed
after 28 days of dosing. The largest mean HBV DNA reduction was
observed with the 600-mg BD AL-3778/PegIFN combination
(1.97 log IU/mL) which was greater than AL 3778 alone (1.72 log10)
or PegIFN alone (1.06 log10). After 28 days’ treatment, mean HBV
RNA (log10 copies/ml) changes from baseline were 0.00 in untreated,
-0.73 in PegIFN treated, -0.82 in 600-mg BD AL-3778 treated and
-1.5 in 600-mg BD AL-3778/PegIFN combination treated patients.
Changes in HBsAg levels were negligible, as expected from the short
treatment duration.
Conclusion: AL-3778 was well tolerated in CHB patients, with
predominantly Grade 1 and Grade 2, transient AEs. There was a nonlife
threatening rash SAE. Dose-related HBV DNA reductions and
HBV RNA reductions were observed, with evidence of additive
antiviral effects in combination with Peg-IFN. Reduction of serum
HBV RNA is consistent with the novel mechanism of action of AL-
3778, to disrupt efficient HBV RNA encapsidation.
Hepatol Int (2017) 11 (Suppl 1):S1–S1093 S7

StephenW

APASL2017 [PL012]
安全性，耐受性，药代动力学和抗病毒活性
的AL-3778，单独的第一类，HBV核心组装调制器
并与聚乙二醇干扰素-α2A联合治疗
原初HBeAg阳性的慢性乙型肝炎患者
William Kennedy1，Man-fung Yuen2，D J Kim3，F Weilert4，
亨利L. Chan5，Jay Lalezari6，S G Hwang 7，T Nguyen8，Chris
Westland1，Thomas Kakuda1，Nathaniel Brown9，Klaus Klumpp9，
Lalo Flores9，Willem Talloen10，Oliver Lenz11，Edward Gane12，
Pieter van Remoortere11，Sushmita Chandra1，John Fry1
1Alios BioPharma，Inc.，A Janssen Pharmaceutical Company of
强生公司香港大学2Queen Mary医院
孔福林; 3Hallym大学，春川神圣的心
醫院; 4Waikato Hospital，Hamilton，New Zealand; 5中国人
香港大学，薄扶林; 6临床研究，
San Francisco，CA，USA; 7CHA Bundang医疗中心，Gyeonggido，
大韩民国; 8 Research and Education，Inc.，San Diego，
CA，USA; 9Novira治疗; 10扬森制药公司
约翰逊11扬森制药公司
强生公司12Auckland Clinical Studies，Auckland，New
西兰
背景：AL-3778是一种口服，首发型肝炎
B（HBV）衣壳组装调节剂（CAM）。我们报告
安全性，耐受性，药代动力学（PK）和抗病毒活性
AL-3778单独和与聚乙二醇干扰素-α-2a组合
（PegIFN）在28天的1b期研究中与治疗前的CHB相比
耐心。
方法：在HBeAg +非肝硬化患者中评估安全性和有效性
CHB患者HBV DNA [20,000 IU / mL和升高
ALT。患者治疗28天，随后进行关闭治疗
28天。患者随机接受AL-3778或匹配
安慰剂，剂量为100和200mg QD（5:1活性剂：安慰剂），400mg
和600mg BD（4:1）的前四个队列。患者随机化
接受1000mg BD或安慰剂（7：2）在最高
单药治疗剂量组。患者随机分组（10：10）
治疗臂接受PegIFN（180μgSQ每周9±4）
与AL-3778（600mg BD）或PegIFN加安慰剂组合。 PK
在每个队列中在第一次剂量后进行取样
在第3,7,14,21和29天的血清HBV DNA水平（C0h）
使用Taqman TM HBV Test v2.0（Roche）进行定量。定量
的HBV RNA是使用QuantigeneTM开发的
基于杂交的测定形式（Affymetrix）。
结果：73例HBeAg + CHB患者入组。他们主要是
亚型与HBV基因型B和C，和平均HBV病毒
负荷在7.23-8.39log10IU / mL之间。 AL-3778通常耐受性良好
没有中断。一个病人在100毫克队列
开发了与AL-3778相关的掌跖感觉迟钝的SAE
行政。平均稳态。 AL-3778谷浓度
是蛋白质结合调节的EC90的2至4倍
BD给药但低于此阈值与QD给药。剂量相关
观察HBV DNA和HBV RNA降低，但无统计学意义
观察到HBV血清学参数的显着变化
28天给药后。最大的平均HBV DNA减少
用600-mg BD AL-3778 / PegIFN组合观察
（1.97log IU / mL），其大于单独的AL 3778（1.72log 10）
或单独的PegIFN（1.06log10）。经过28天的治疗，平均HBV
相对于基线的RNA（log 10拷贝/ ml）变化为0.00，
在PegIFN处​​理的-0.73，在600-mg BD AL-3778处理的-0.82，
-1.5在600-mg BD AL-3778 / PegIFN组合治疗的患者中。
HBsAg水平的变化是可以忽略的，如从短期的预期
治疗持续时间。
结论：AL-3778在CHB患者中耐受性良好
主要为1级和2级，短暂性AE。有一个非生活
威胁性皮疹SAE。剂量相关的HBV DNA减少和
观察到HBV RNA减少，具有加性的证据
抗病毒效应与Peg-IFN联合。血清减少
HBV RNA与新型AL-
3778，以破坏有效的HBV RNA衣壳化。
Hepatol Int（2017）11（Suppl 1）：S1-S1093 S7

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