一项 2 期、开放标签、随机、多剂量研究评估 Inarigivir 在初

StephenW

一项 2 期、开放标签、随机、多剂量研究评估 Inarigivir 在初治慢性乙型肝炎患者中的疗效
Man-Fung Yuen 1 , C Y Chen 2 , C J Liu 3 , W J Jeng 4 , M Elkhashab 5 , C S Coffin 6 , W Kim 7 , S Greenbloom 8 , A Ramji 9 , Y S Lim 10 , Yoon Jun Kim 11 , Scott K Fung 12, D J Kim, Jeong Won Jang 13, K S Lee 14, R P Iyer 15, C Macfarlane 16, K Jackson 17, S Locarnini 17, H L Y Chan 18, N H Afdhal 19
隶属关系
隶属关系

    1
    香港大学临床医学院玛丽医院内科及肝脏研究国家重点实验室。
    2
    台湾嘉义市迪特曼森医学基金会嘉义基督教医院内科肠胃肝病科。
    3
    台湾大学医学院内科及肝炎研究中心，台湾。
    4
    台湾长庚大学林口医学中心长庚纪念医院肠胃肝病科。
    5
    加拿大多伦多大学北约克总医院多伦多肝脏中心。
    6
    加拿大卡尔加里大学卡明医学院。
    7
    首尔国立大学医学院内科，首尔市政府 Boramae 医疗中心首尔，韩国。
    8
    多伦多消化疾病协会，加拿大伍德布里奇。
    9
    胃肠道研究所，加拿大。
    10
    韩国首尔蔚山大学医学院牙山医疗中心。
    11
    韩国首尔国立大学医学院内科和肝脏研究所。
    12
    多伦多大学多伦多总医院医学系，加拿大多伦多； 13 韩国春川翰林大学医学院。
    13
    韩国天主教大学首尔圣玛丽医院，韩国首尔。
    14
    韩国首尔延世大学卫生系统江南 Severance 医院。
    15
    RIGImmune, Inc.，美国纽黑文。
    16
    Spring Bank Pharmaceuticals，霍普金顿，美国。
    17
    澳大利亚彼得多尔蒂感染与免疫研究所皇家墨尔本医院维多利亚传染病参考实验室。
    18
    香港中文大学威尔斯亲王医院内科及治疗学系。
    19
    美国波士顿贝丝以色列女执事医疗中心胃肠病学和肝病学部。

    PMID：36300646 DOI：10.1111/liv.15465

抽象的

背景/目的：需要新的抗乙型肝炎病毒 (HBV) 药物来提高 HBsAg 血清学清除率或称为“功能性治愈”率。 Inarigivir（视黄酸诱导基因 I 激动剂）对 HBV 具有免疫调节和直接抗病毒作用。我们旨在确定 Inarigivir 治疗 HBV 感染的安全性和有效性。

患者/方法：80 名初治患者被随机分配到 4 个递增剂量队列中，以 4:1 的比例接受为期 12 周的 Inarigivir 25、50、100、200 mg 或安慰剂。然后所有患者都接受了替诺福韦治疗 12 周。

结果： HBV DNA 从基线的最小二乘 (LS) 平均减少随着 Inarigivir 剂量的增加而增加（25 mg 组为 0.6116，200 mg 组为 1.5774，安慰剂组为 0.0352）（95% CI 分别为 0.9518-0.2011 和 1.921-1.1634 ）。在 Inarigivir 治疗组和安慰剂组中， HBV RNA 和 HBsAg 从基线的 LS 平均变化范围分别为 -0.3856 至 -0.5794 和 -0.1474 和 -0.0956 至 -0.1818 和 +0.0026。在替诺福韦治疗期间，Inarigivir 治疗组的 LS 平均 HBsAg 降低范围为 0.1709 至 0.3529，而安慰剂组为 0.1984。 Inarigivir 治疗组显示 ALT 从基线平均降低 23.3 至 33.8 U/L，而安慰剂组为 0.7 U/L。与 Inarigivir 和安慰剂相关的治疗中出现的不良事件分别发生在 4.7% 和 6.3% 的患者中。

结论：长达 200 mg 剂量的 12 周 Inarigivir 与 HBV DNA、HBV RNA 和抗原水平的降低有关。 Inarigivir 预处理患者在改用替诺福韦后观察到 HBsAg 降低的趋势。

关键词：HBV DNA抑制； HBsAg 水平；伊那吉韦；视黄酸诱导基因1；替诺福韦。

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StephenW

A phase 2, open-label, randomized, multiple dose study evaluating Inarigivir in treatment-naïve patients with chronic hepatitis B
Man-Fung Yuen  1 , C Y Chen  2 , C J Liu  3 , W J Jeng  4 , M Elkhashab  5 , C S Coffin  6 , W Kim  7 , S Greenbloom  8 , A Ramji  9 , Y S Lim  10 , Yoon Jun Kim  11 , Scott K Fung  12 , D J Kim, Jeong Won Jang  13 , K S Lee  14 , R P Iyer  15 , C Macfarlane  16 , K Jackson  17 , S Locarnini  17 , H L Y Chan  18 , N H Afdhal  19
Affiliations
Affiliations

    1
    Department of Medicine & State Key Laboratory of Liver Research, Queen Mary Hospital, School of Clinical Medicine, The University of Hong Kong, Hong Kong.
    2
    Division of Gastroenterology and Hepatology, Department of Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan.
    3
    Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taiwan.
    4
    Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Chang Gung University, Taiwan.
    5
    Toronto Liver Centre, North York General Hospital, University of Toronto, Canada.
    6
    Cumming School of Medicine, University of Calgary, Canada.
    7
    Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center Seoul, Korea.
    8
    Toronto Digestive Disease Associates, Woodbridge, Canada.
    9
    Gastrointestinal Research Institute, Canada.
    10
    Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
    11
    Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
    12
    Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Canada; 13Hallym University College of Medicine, Chuncheon, Korea.
    13
    Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
    14
    Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea.
    15
    RIGImmune, Inc., New Haven, USA.
    16
    Spring Bank Pharmaceuticals, Hopkinton, USA.
    17
    Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Australia.
    18
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.
    19
    Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, USA.

    PMID: 36300646 DOI: 10.1111/liv.15465

Abstract

Background/aims: Novel agents acting against hepatitis B virus (HBV) are needed to improve HBsAg seroclearance or termed as "functional cure" rate. Inarigivir (retinoic acid-inducible gene I agonist) has immunomodulatory and direct antiviral actions against HBV. We aimed to determine the safety and efficacy of Inarigivir for the treatment of HBV infection.

Patients/methods: 80 treatment-naïve patients were randomized in 4 ascending dose cohorts to receive 12-week of Inarigivir 25, 50, 100, 200 mg or placebo in a ratio of 4:1. All patients were then given tenofovir for another 12 weeks.

Results: Least squares (LS) mean reductions in HBV DNA from baseline increased with higher doses of Inarigivir (0.6116 in 25 mg and 1.5774 in 200 mg groups vs. 0.0352 in placebo group)(95% CI 0.9518-0.2011 and 1.921-1.1634 respectively). LS mean changes in HBV RNA and HBsAg from baseline ranged from -0.3856 to -0.5794 vs. -0.1474 and -0.0956 to -0.1818 vs. +0.0026 in Inarigivir-treated vs. placebo groups respectively. During the tenofovir-treated period, LS mean reductions in HBsAg in the Inarigivir-treated groups ranged from 0.1709 to 0.3529 vs. 0.1984 in placebo group. Inarigivir-treated groups showed mean reductions in ALT from baseline between 23.3 and 33.8 U/L vs. 0.7 U/L in placebo group. Treatment-emergent adverse events related to Inarigivir and placebo occurred in 4.7% and 6.3% patient respectively.

Conclusions: 12-week Inarigivir up to 200 mg dose was associated with reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir.

Keywords: HBV DNA suppression; HBsAg level; Inarigivir; retinoic acid-inducible gene 1; tenofovir.

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