GSK3389404在接受稳定核苷（酸）治疗的慢性乙型肝炎患者中的

StephenW

GSK3389404在接受稳定核苷（酸）治疗的慢性乙型肝炎患者中的 IIa 期随机双盲研究
Man-Fung Yuen 1 , Jeong Heo 2 , Hiromitsu Kumada 3 , Fumitsu Suzuki 3 , Yoshiyuki Suzuki 4 , 庆谢 5 , Jidong Jia 6 , Yoshiyasu Karino 7 , Jinlin Ho 8 , Kazuaki Chayama 9 , Michio Imamura 10 , Judy Y Lao- Tan 11 , Seng Gee Lim 12 , Yasuhito Tanaka 13 , Wen Xie 14 , Jung-Hwan Yoon 15 , Zhongping Duan 16 , Masayuki Kurosaki 17 , Sung-Jae Park 18 , Madalinee Eternity Labio 19 , Rajneesh Kumar 20 , Young-Oh Kweon 21 , Hyung Joon Yim 22 , Yu Tao 23 , Jennifer Cremer 24 , Robert Elston 25 , Matt Davies 26 , Sharon Baptiste-Brown 27 , Kelong Han 27 , Fiona M Campbell 25 , Melanie Paff 27 , Dickens Theodore 24
隶属关系

    PMID: 35714812 DOI: 10.1016/j.jhep.2022.05.031

抽象的

背景与目的：GSK3389404 是一种针对乙型肝炎病毒 (HBV) 前基因组和 mRNA 转录物的反义寡核苷酸，可与 N-乙酰半乳糖胺偶联以增强肝细胞递送。这项剂量探索研究首次评估了 GSK3389404 在慢性 HBV 感染中的作用。

方法：这项 2a 期、随机、双盲、安慰剂对照、两部分研究在亚洲的 22 个中心进行（NCT03020745）。第 1 部分的药代动力学 (PK) 结果为第 2 部分的给药提供了依据。在第 2 部分中，接受核苷（酸）类似物治疗的慢性乙型肝炎患者以 11:2 的比例随机分配至 GSK3389404（每周 30、60、120 毫克或每两周 120 毫克）或安慰剂组，直至第 85 天。共同终点包括 HBsAg 反应（从基线降低≥1.5 log10 IU/mL）率、安全性和 PK。

结果：第 1 部分和第 2 部分分别包括 12 名（9 GSK3389404，3 名安慰剂）和 66 名患者（56 名 GSK3389404，10 名安慰剂）。在第 2 部分中，每周 60 mg、每周 120 mg 和每两周 120 mg 组中的一名患者获得了 HBsAg 反应。 HBsAg 降低是剂量依赖性的（第 85 天：平均 0.34 [60 mg 每周] 至 0.75 log10 IU/mL [120 mg 每周]）并且发生在乙型肝炎 e 抗原阳性和阴性患者中。没有患者达到 HBsAg 血清学清除。 43/56 (77%) GSK3389404 治疗和 9/10 (90%) 安慰剂患者报告了不良事件。没有死亡报告。两名接受 GSK3389404 治疗的患者（每周 120 毫克，每两周 120 毫克）发生丙氨酸氨基转移酶发作（> 正常上限的 2 倍）；两者都与 HBsAg 降低有关，但都没有被认为是反应者。 GSK3389404 血浆浓度在给药后 2-4 小时达到峰值；平均血浆半衰期为 3-5 小时。

结论：GSK3389404 显示出可接受的安全性和靶点参与度，HBsAg 呈剂量依赖性降低。然而，没有确定有效的给药方案。

临床试验编号：NCT03020745 LAY 摘要：乙型肝炎病毒（HBV）可导致慢性HBV感染，最终可能导致慢性肝病、原发性肝癌和死亡； HBV 蛋白可能会阻止免疫系统成功控制病毒。 GSK3389404 是一种针对 HBV RNA 的研究药物，可减少病毒蛋白的产生。本研究评估了 GSK3389404 的安全性及其降低慢性 HBV 感染患者病毒蛋白的能力。 GSK3389404 表现出乙型肝炎表面抗原的剂量依赖性降低，具有可接受的安全性。虽然没有确定明确的最佳剂量，但这项研究的结果可能有助于为慢性 HBV 感染患者开发改进的治疗方案。

关键词：GSK3389404； HBeAg;乙肝表面抗原；反义寡核苷酸；慢性乙型肝炎；药代动力学；安全;病毒学反应。

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StephenW

Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy
Man-Fung Yuen  1 , Jeong Heo  2 , Hiromitsu Kumada  3 , Fumitaka Suzuki  3 , Yoshiyuki Suzuki  4 , Qing Xie  5 , Jidong Jia  6 , Yoshiyasu Karino  7 , Jinlin Hou  8 , Kazuaki Chayama  9 , Michio Imamura  10 , Judy Y Lao-Tan  11 , Seng Gee Lim  12 , Yasuhito Tanaka  13 , Wen Xie  14 , Jung-Hwan Yoon  15 , Zhongping Duan  16 , Masayuki Kurosaki  17 , Sung-Jae Park  18 , Madalinee Eternity Labio  19 , Rajneesh Kumar  20 , Young-Oh Kweon  21 , Hyung Joon Yim  22 , Yu Tao  23 , Jennifer Cremer  24 , Robert Elston  25 , Matt Davies  26 , Sharon Baptiste-Brown  27 , Kelong Han  27 , Fiona M Campbell  25 , Melanie Paff  27 , Dickens Theodore  24
Affiliations

    PMID: 35714812 DOI: 10.1016/j.jhep.2022.05.031

Abstract

Background & aims: GSK3389404, an antisense oligonucleotide targeting hepatitis B virus (HBV) pregenomic and mRNA transcripts, is conjugated to N-acetyl galactosamine for enhanced hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 in chronic HBV infection.

Methods: This Phase 2a, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic (PK) findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/mL reduction from baseline) rate, safety and PK.

Results: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg biweekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/mL [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404-treated and 9/10 (90%) placebo patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in two GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours.

Conclusions: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified.

Clinical trial number: NCT03020745 LAY SUMMARY: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.

Keywords: GSK3389404; HBeAg; HBsAg; antisense oligonucleotide; chronic hepatitis B; pharmacokinetics; safety; virological response.

Copyright © 2022. Published by Elsevier B.V.