AASLD2017 [927] 第二期随机临床试验评估 聚乙二醇化干扰素的安

StephenW

AASLD2017[927]
A Phase 2 Randomized Clinical Trial to Evaluate
the Safety and Efficacy of Pegylated Interferon
Lambda Monotherapy in Patients with
Chronic Hepatitis Delta Virus Infection. Interim
Results From the LIMT HDV Study
Saeed S. Hamid2, Ohad Etzion6, Yoav Lurie4, Nimrah Bader2,
David Yardeni6, Saleh M. Channa5, Minaz Mawani2, Om Parkash2,
Eduardo B. Martins1, Edward J. Gane3; 1Clinical Development,
Eiger BioPharmaceuticals, Palo Alto, CA; 2Aga Khan
University and Hospital, Karachi, Pakistan; 3Auckland City Hospital,
Auckland, New Zealand; 4Shaare Zedek Medical Center,
Jerusalem, Israel; 5Department of Gastroenterology, Ghulam
Muhammad Mahar Medical College, Sukkur, Pakistan; 6Gastroenterology
and Liver Disease Institute, Soroka University
Medical Center, Beer-Sheva, Israel
Background and Aims: Globally 15-20 million people are
coinfected with hepatitis delta (HDV) and hepatitis B (HBV)
viruses. Interferon (IFN) or pegylated (PEG) IFN-alfa have
been tested in patients with chronic HDV (CHD). Up to
25% of patients may become HDV PCR-negative, but most
relapse after therapy is discontinued and the tolerability
profile is unsatisfactory. PEG IFN lambda-1a (Lambda) is
a Type III IFN. Based on Lambda’s more limited receptor
distribution and previous data from HBV and HCV studies,
it is postulated that Lambda could induce HDV responses,
but with fewer side effects than IFN-alfa. LIMT HDV is
the first study of Lambda in patients with CHD infection,
including cirrhotics. Methods: Randomized, open-label
study of Lambda 120 or 180 μg subcutaneous injections
administered weekly for 48 weeks in patients with chronic
HDV. Major inclusion criteria were: positive HDV RNA by
qPCR, elevated ALT<10xULN, compensated liver disease
and platelets ≥90,000 cells/μL. HDV RNA (Robogene 2.0,
LLOQ 14 IU/mL), ALT, bilirubin and other parameters were
assessed at each visit. Tenofovir or entecavir were started
at baseline (BL) and will continue through the end of the
study. Results: To date, 20 patients (15 male, 7 cirrhotic),
median age 35 (20-54), have been enrolled; eight randomized
to Lambda 180 μg/week and 12 to 120 μg/week. At
BL, mean lab values were: HDV RNA 4.5 log10 IU/mL (SD
±1.36); ALT 104 IU/mL (47-364 IU/mL) and bilirubin 13
μmol/L (3-20 μmol/L). Mean Fibroscan score was 11.8 kPA
(4.6-27.4 kPA). To date, 13 and 11 patients have reached
Weeks 4 and 8 of therapy, respectively. At Week 4, 3/13
(23%) patients had HDV RNA < LLOQ, one of which was
PCR-negative. At Week 8, 6/11 (55%) had HDV RNA <
LLOQ, 3 of which were PCR-negative. HDV RNA drop from
BL>2 log10 was observed in 31% (4/13) and 46% (5/11) of
patients at Weeks 4 and 8, respectively. Three patients
had grade 3 elevations of ALT. Three patients developed
jaundice (two on 180 μg/week and one on 120 μg); two of
which required permanent drug discontinuation, and one
required temporary drug interruption and resumption at a
reduced dose (peak direct bilirubin 86, 465 and 36 μmol/L,
respectively). In all cases, jaundice was preceded by a rise
in GGT. Constitutional symptoms were less frequent and
milder than historical data with PEG IFN-alfa. Conclusions:
This interim analysis indicates that weekly Lambda – 120
μg or 180 μg – has antiviral activity against HDV, with
some patients already becoming PCR-negative by Week
8 of therapy. Overall, Lambda was well-tolerated, and
hyperbilirubinemia events in three patients responded to
dose reduction or discontinuation. Week 24 data will be
presented.
Disclosures:
Ohad Etzion - Advisory Committees or Review Panels: HepQuant LLC
Eduardo B. Martins - Employment: Eiger Biopharmaceuticals; Stock
Shareholder: Eiger Biopharmaceuticals
Edward J. Gane - Advisory Committees or Review Panels: Alios, Merck,
Janssen, Gilead Sciences; Board Membership: AbbVie; Speaking and
Teaching: Gilead Sciences, Merck, Alnylam, AbbVie
The following people have nothing to disclose: Saeed S. Hamid, Yoav Lurie,
Nimrah Bader, David Yardeni, Saleh M. Channa, Minaz Mawani, Om Parkash

StephenW

AASLD2017 [927]
第二期随机临床试验评估
聚乙二醇化干扰素的安全性和疗效
Lambda单药治疗患者
慢性乙型肝炎病毒感染。临时
LIMT HDV研究结果
Saeed S. Hamid2，Ohad Etzion6，Yoav Lurie4，Nimrah Bader2，
David Yardeni6，Saleh M. Channa5，Minaz Mawani2，Om Parkash2，
Eduardo B. Martins1，Edward J. Gane3; 1临床发展，
Eiger BioPharmaceuticals，Palo Alto，CA; 2Aga汗
巴基斯坦卡拉奇大学医院3A骆驼市医院，
奥克兰，新西兰; 4Shaare Zedek医疗中心，
耶路撒冷，以色列胃肠病学部门，Ghulam
巴基斯坦苏克库穆罕默德马哈尔医学院6Gastroenterology
和索诺卡大学肝病研究所
医疗中心，啤酒舍瓦，以色列
背景与宗旨：全球有一千万到二千万人
与乙型肝炎（HDV）和乙型肝炎（HBV）共感染
病毒。干扰素（IFN）或聚乙二醇化（PEG）IFN-α
在慢性HDV（CHD）患者中进行了测试。取决于
25％的患者可能成为HDV PCR阴性，但大多数
治疗后的复发停止和耐受性
情况不尽人意。 PEG IFNλ-1a（Lambda）是
III型IFN。基于Lambda更有限的受体
分布和以前的HBV和HCV研究数据，
假设Lambda可以诱导HDV反应，
但副作用比IFN-αA少。 LIMT HDV是
Lambda在CHD感染患者中的首例研究，
包括肝硬化。方法：随机，开放标签
研究Lambda 120或180μg皮下注射
每周给予慢性病患者48周
HDV。主要纳入标准是：阳性HDV RNA
qPCR，升高的ALT <10xULN，补偿性肝病
血小板≥90,000细胞/μL。 HDV RNA（Robogene 2.0，
LLOQ 14 IU / mL），ALT，胆红素等参数
每次访问时评估。替诺福韦或恩替卡韦启动
在基线（BL），并将继续通过
研究。结果：迄今为止，20例（15例男性，7例肝硬化）
中位年龄35岁（20-54岁）已入学;八个随机
至180μg/周，12至120μg/周。在
BL，平均实验室值为：HDV RNA 4.5log10 IU / mL（SD
±1.36）; ALT 104IU / mL（47-364IU / mL）和胆红素13
μmol/ L（3-20μmol/ L）。平均Fibroscan评分为11.8 kPA
（4.6-27.4 kPA）。到目前为止，已有13,11例患者达到
第4周和第8周分别进行治疗。在3/13的第4周
（23％）患者有HDV RNA <LLOQ，其中一例为
PCR阴性。在第8周，6/11（55％）有HDV RNA
LLOQ，其中3个为PCR阴性。 HDV RNA从
在31％（4/13）和46％（5/11）中观察到BL> 2 log10
患者分别在第4周和第8周。三名病人
有三级ALT升高。三名患者发展
黄疸（两次180μg/周，一次120μg）;两个
这需要永久停药，一个
要求临时药物中断和恢复
降低剂量（峰值直接胆红素86,465,36μmol/ L，
分别）。在所有情况下，黄疸先于崛起
在GGT。宪法症状较少，
与PEG IFN-α的历史数据比较温和。结论：
这个中期分析表明每周Lambda-120
μg或180μg - 具有抗HDV的抗病毒活性
一些患者本周已经成为PCR阴性
8疗法。总的来说，Lambda具有良好的耐受性
三例患者的高胆红素血症事件反应
减少剂量或停药。第24周的数据将会
呈现。
披露：
Ohad Etzion - 咨询委员会或审查小组：HepQuant LLC
Eduardo B. Martins - 就业：Eiger生物制药;股票
股东：Eiger生物制药
爱德华J. Gane - 咨询委员会或审查小组：Alios，Merck，
甘肃，吉利德科学董事会成员：AbbVie;说话和
教学：Gilead Sciences，Merck，Alnylam，AbbVie
以下人士没有什么可以披露的：Saeed S. Hamid，Yoav Lurie，
Nimrah Bader，David Yardeni，Saleh M. Channa，Minaz Mawani，Om Parkash