Agarwal K, Ahn S H, Elkhashab M, Lau A H, Gaggar A, Bulusu A, Tian X, Cathcart A L, Woo J, Subramanian G M, Andreone P, Kim H J, Chuang W L, Nguyen M H
Institute of Liver Studies, Kings College Hospital, London, UK.
Brain Korea 21 Project of Medical Science, Yonsei University College of Medicine, Seoul, Korea.
J Viral Hepat. 2018 Nov;25(11):1331-1340. doi: 10.1111/jvh.12942. Epub 2018 Aug 22.
Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.
维萨特利莫德是一种 toll 样受体 7 的口服激动剂，旨在尽量减少全身暴露和副作用。我们在一项 2 期、多中心、双盲、随机、安慰剂对照研究中，评估了维萨特利莫德对目前未接受口服抗病毒治疗（OAV）的病毒血症慢性乙型肝炎（CHB）患者的安全性和疗效。共有 192 例按 HBeAg 状态和丙氨酸氨基转移酶水平分层的患者，以 2:2:2:1 的比例随机分组，接受口服维萨特利莫德（1 毫克、2 毫克或 4 毫克）或安慰剂，每周一次，共 12 周；富马酸替诺福韦二吡呋酯（每日 300 毫克）每日给药 48 周。通过第 24 周时血清 HBsAg 较基线的定量下降来评估疗效。除安全性评估外，还探讨了全血干扰素刺激基因（ISG）转录本和血清细胞因子的变化。大多数患者基线时为男性（64.1%）且 HBeAg 阴性（60.9%）。在接受维萨特利莫德治疗的患者中，大多数（60.4%-69.1%）经历了≥1 次治疗中出现的不良事件；大多数为轻度或中度严重程度。治疗组之间未观察到 HBsAg 较基线变化的临床意义上的差异。没有患者出现 HBsAg 消失，而 3 例患者在第 48 周出现 HBeAg 消失和乙肝 e 抗体血清学转换。在第 24 周时，所有治疗组的 HBV DNA 抑制率相似。ISG15 的诱导呈剂量依赖性，且与 HBsAg 变化无关。一小部分患者表现出剂量依赖性的干扰素-α 诱导，这与流感样不良事件的分级相关。总体而言，维萨特利莫德在 CHB 患者中安全且耐受性良好。尽管证实了 ISG 存在一致的剂量依赖性药效学诱导，但这并未导致临床上显著的 HBsAg 下降。
