Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment
Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment
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DOI：
10.1111/jvh.12942
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发表时间：
2018-11-01
影响因子：
2.5
通讯作者：
Nguyen, M. H.
中科院分区：
文献类型：
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作者：
Agarwal, K.;Ahn, S. H.;Nguyen, M. H.
Vesatolimod是一种Toll样受体7的口服激动剂，旨在最大限度地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vesatolimod在目前未接受口服抗病毒治疗（OAV）的病毒血症慢性B型肝炎（CH B）患者中的安全性和疗效。共192例患者按HBeAg状态和丙氨酸氨基转移酶水平分层，按2：2：2：1的比例随机接受口服vesatolimod（1-，2-或4-mg）或安慰剂，每周一次，持续12周;富马酸替诺福韦酯（300-mg每日），持续48周。通过第24周血清HBsAg较基线的定量下降评估疗效。除安全性评估外，还探索了全血干扰素刺激基因（ISG）转录物和血清细胞因子的变化。大多数患者为男性（64.1%），基线时HBeAg阴性（60.9%）。在接受vesatolimod治疗的患者中，大多数（60.4%-69.1%）发生了1起治疗后出现的不良事件;大多数事件的严重程度为轻度或中度。治疗组间未观察到HBsAg较基线变化有临床意义的差异。第48周时，无患者发生HBsAg丢失，而3例患者发生HBeAg丢失和B e型肝炎抗体血清转换。第24周时，所有治疗组的HBV DNA抑制率相似。ISG 15诱导具有剂量依赖性，且与HBsAg变化无关。一小部分患者表现出与流感样不良事件等级相关的剂量依赖性干扰素诱导。总体而言，Vesatolimod在CHB患者中安全且耐受性良好。尽管证实了ISG的一致剂量依赖性药效学诱导，但其未导致具有临床意义的HBsAg下降。
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 12weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48weeks. 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- 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.