EASL2019 PS-052 LIMT HDV研究结果：36％持久病毒学 用聚乙二醇化

StephenW

PS-052
End of study results from LIMT HDV study: 36% durable virologic
response at 24 weeks post-treatment with pegylated interferon
lambda monotherapy in patients with chronic hepatitis delta
virus infection
Ohad Etzion1, Saeed Sadiq Hamid2, Yoav Lurie3, Edward Gane4,
Nimrah Bader2, David Yardeni2, a Nevo-Shor1, sm channa5,
Minaz Mawani2, Om Parkash2, Kyunghee Yang6, Diane Longo6,
Robert G. Gish7, Jeffrey Glenn7, David Apelian8. 1Soroka University
Medical Center, Beer-Sheva, Israel; 2Aga Khan University Hospital,
Karachi, Pakistan; 3Shaare Zedek, Jerusalem, Israel; 4Auckland City
Hospital, Auckland, New Zealand; 5Ghulam Mohammad Mahar Medical
College Sukkur, Sukkur, Pakistan; 6Dilisym, Research Triangle Park,
United States; 7Stanford University, Stanford, United States; 8Eiger
BioPharmaceuticals, Inc, Palo Alto, United States
Email: [email protected]
Background and aims: Hepatitis Delta Virus (HDV) infection leads to
the most aggressive form of human viral hepatitis. There is noapproved therapy. Worldwide prevalence of HDV infection is 15-20
million. PEG IFN-lambda-1a (Lambda) has previously demonstrated a
good tolerability profile in >3000 HBV and HCV patients, with fewer
cytopenias, flu-like and psychiatric symptoms compared to PEG IFNalfa
(Alfa). The goal of LIMT was to evaluate safety and efficacy of
Lambda monotherapy in patients with HDV.
Method: Randomized, open-label study of Lambda 120 or 180 μg,
weekly SC injections for 48 wks follow by 24 wks post-tx in patients
with chronic HDV, conducted in Pakistan, Israel, and New Zealand.
Major inclusion criteria: positive HDV RNA by qPCR (Robogene® 2.0,
BLQ 14 IU/ml), ALT<10×ULN, and compensated liver disease.
Tenofovir or entecavir were started at baseline (BL).
Results: 33 patients were randomized to Lambda 180 μg (n = 14) or
120 μg (n = 19). BL mean values: HDV RNA 4.1 log IU/ml (SD±1.4); ALT
106 IU/L (35-364) and bilirubin 0.5 mg/dL (0.2-1.2).
48 Wk On-Treatment   24 Wk  Post-Treatment
Dose,   N ,  Mean Wk 48 Log HDV RNA Decline,    2 Log Decline or  BLQ ,   BLQ,  2 Log Decline or BLQ , BLQ
180μg All, 14, ,9/14 64%,5/14 36%, 7/14 50%, 5/14 36%
High BL VL, 8,-2.3 ,7/8 88%, 3/8 38%, 4/8 50%, 2/8 25%
Low BL VL, 6, ,2/6 33%, 2/6 33%, 3/6 50%, 3/6 50%

ITT rates of durable virologic response (DVR = BLQ at 24 wks post-tx)
for Lambda 180 μg (5 of 14, 36%) compare favorably to historic rates
for Alfa 180 μg (28%) (Wedemeyer, NEJM, 2011). 50% DVR in low BL
viral load (VL) patients (≤4log10). Common on-treatment AEs
included mild to moderate flu-like symptoms and elevated transaminase
levels. Patients previously treated with Alfa noted significantly
less side effects on Lambda. Cases of jaundice and increased
incidences of bilirubin elevations were observed in the Pakistani
cohort. No patients showed symptoms of decompensation, and all
responded favorably to dose reduction or dose discontinuation.
DILIsym® modeling of ALT and bilirubin dynamics indicate a
transporter-based mechanism for the observed bilirubin elevations.
Conclusion: Lambda 180 μg had comparable antiviral activity with
better tolerability, compared to historical data for Alfa. Durable BLQ
virologic responses have been observed 24 weeks post-treatment.
Lambda is a promising agent for mono or combo treatment of HDV.
The LIFT study with Lambda + Lonafarnib is on-going at NIH.

StephenW

PS-052
LIMT HDV研究结果：36％持久病毒学
用聚乙二醇化干扰素治疗后24周的反应
慢性肝炎三角洲患者的lambda单药治疗
病毒感染
Ohad Etzion1，Saeed Sadiq Hamid2，Yoav Lurie3，Edward Gane4，
Nimrah Bader2，David Yardeni2，Nevo-Shor1，sm channa5，
Minaz Mawani2，Om Parkash2，Kyunghee Yang6，Diane Longo6，
Robert G. Gish7，Jeffrey Glenn7，David Apelian8。 1索罗卡大学
以色列Beer-Sheva医疗中心; 2Aga Khan大学医院，
巴基斯坦卡拉奇; 3 Shaare Zedek，耶路撒冷，以色列; 4 Auckland市
医院，新西兰奥克兰; 5Ghulam Mohammad Mahar Medical
巴基斯坦Sukkur的Sukkur学院; 6Dilisym，三角研究园，
美国; 7斯坦福大学，斯坦福，美国; 8Eiger
BioPharmaceuticals，Inc，Palo Alto，United States
电子邮件：[email protected]
背景和目的：肝炎病毒（HDV）感染导致
最具攻击性的人类病毒性肝炎。没有批准的治疗方法。全球HDV感染率为15-20
百万。 PEG IFN-λ-1a（Lambda）先前已经证明了a
在> 3000 HBV和HCV患者中具有良好的耐受性，较少
与PEGIFNα相比，血细胞减少，流感样和精神症状
（阿尔法）。 LIMT的目标是评估安全性和疗效
HDV患者的Lambda单药治疗。
方法：Lambda 120或180μg的随机，开放标签研究，
每周SC注射48周，患者后24周后进行
患有慢性HDV，在巴基斯坦，以色列和新西兰进行。
主要入选标准：qPCR阳性HDV RNA（Robogene®2.0，
BLQ 14 IU / ml），ALT <10×ULN和补偿性肝病。
替诺福韦或恩替卡韦在基线（BL）开始。
结果：33名患者被随机分配到180μg（n = 14）或
120μg（n = 19）。 BL平均值：HDV RNA 4.1log IU / ml（SD±1.4）; ALT
106 IU / L（35-364）和胆红素0.5 mg / dL（0.2-1.2）。
48周治疗24周后处理
剂量N均值Wk 48 Log HDV RNA下降2 LogDecline或
BLQ
BLQ 2日志
下降
或BLQ
BLQ
180
微克
全部14
-2.3
9/14
64％
5/14
36％
7/14
50％
5/14
36％
高
BL VL
8 7/8
88％
3/8
38％
4/8
50％
2/8
25％
低
BL VL
6 2/6
33％
2/6
33％
3/6
50％
3/6
50％
ITT耐久性病毒学应答率（DVR = tx后24周时的BLQ）
Lambda180μg（14％中的5％，36％）与历史价格相比有利
阿尔法180μg（28％）（Wedemeyer，NEJM，2011）。低BL中50％DVR
病毒载量（VL）患者（≤4log10）。常见的治疗中的AE
包括轻度至中度流感样症状和转氨酶升高
水平。之前接受过阿法治疗的患者显着
对Lambda的副作用较小。黄疸病例增多
巴基斯坦人观察到胆红素升高的发生率
队列。没有患者出现失代偿症状，全部
对减少剂量或停止剂量反应良好。
ALT和胆红素动态的DILIsym®模型表明a
基于转运蛋白的观察胆红素升高的机制。
结论：Lambda180μg具有可比较的抗病毒活性
与阿尔法的历史数据相比，耐受性更好。持久的BLQ
治疗后24周观察到病毒学应答。
Lambda是一种有前途的HDV单一或组合治疗药物。
Lambda + Lonafarnib的LIFT研究正在美国国立卫生研究院进行。