New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
Chung-Ang University Hospital, Seoul, South Korea.
Hepatology. 2021 Oct;74(4):1737-1749. doi: 10.1002/hep.31795. Epub 2021 Sep 14.
In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment.
In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity.
Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
在慢性乙型肝炎（CHB）感染患者中，Toll 样受体 8 的激活可能诱导抗病毒免疫并促进功能性治愈。Selgantolimod 是一种 Toll 样受体 8 激动剂，已在接受口服抗病毒治疗病毒抑制或病毒血症且未接受口服抗病毒治疗的 CHB 患者中进行了评估。
在这项 1b 期研究中，患者按 4:1 的比例随机接受 selgantolimod 或安慰剂每周一次。病毒抑制的患者接受 1.5mg（2 周）或 3mg（2 周或 4 周）。病毒血症患者接受 3mg 治疗 2 周。主要终点是安全性，通过不良事件（AE）、实验室异常和生命体征检查进行评估。通过血浆分析评估药代动力学和药效学参数。共从澳大利亚、新西兰和韩国的六个地点招募了 38 名患者（28 名病毒抑制，10 名病毒血症）。20 名患者（53%）发生 AE，32 名（84%）出现实验室异常，均为轻度或中度。最常见的 AE 是头痛（32%）、恶心（24%）和头晕（13%）。多次给药后，selgantolimod 的半衰期为 5 小时，未观察到药物蓄积。Selgantolimod 诱导了血清细胞因子的短暂、剂量依赖性增加，包括 IL-12p40 和 IL-1RA，这对于多种 T 细胞亚群和固有免疫的扩张和活性很重要。
Selgantolimod 在病毒抑制和病毒血症的 CHB 患者中安全且耐受良好，并引起了与靶点结合一致的细胞因子反应。需要进行更长时间的 selgantolimod 治疗研究来评估疗效。
