Auckland City Hospital, Auckland, New Zealand.
School of Biological Sciences, Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
J Hepatol. 2023 Mar;78(3):513-523. doi: 10.1016/j.jhep.2022.09.027. Epub 2022 Oct 29.
BACKGROUND & AIMS: Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment.
Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. The primary efficacy endpoint was the percentage of patients with a ≥1 log10 IU/ml decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued on oral antivirals for 24 weeks.
The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n = 9), only selgantolimod-treated patients (n = 39 total) had HBsAg declines greater than 0.1 log IU/ml at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets.
Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48.
NCT03491553.
The only robust criterion for stopping treatment in chronic hepatitis B is loss of hepatitis B surface antigen (known as functional cure), which is rare during nucleos(t)ide analogue therapy. It is likely that novel antiviral and immunomodulatory therapies will be needed to achieve finite functional cure. Selgantolimod is an oral Toll-like receptor 8 agonist that has shown antiviral activity in vitro as well as safety in a phase I clinical trial with weekly dosing. In this phase II study, selgantolimod therapy was associated with transient increases in serum cytokines, rapid redistribution of circulating immune cell subsets, modest reductions in HBsAg and HBeAg levels, and occasional loss of HBsAg (5%) and HBeAg (16%) among participants with chronic hepatitis B on nucleos(t)ide analogue therapy with viral suppression. Our results support continued development of selgantolimod as a component of a future hepatitis B cure regimen.
Selgantolimod（GS-9688）是一种 Toll 样受体 8（TLR8）激动剂，可在体外抑制 HBV。在一项 II 期研究中，我们评估了每周接受 Selgantolimod 治疗的安全性和疗效，该治疗方案适用于正在接受口服抗病毒治疗且病毒已被抑制的慢性 HBV 患者。
48 名患者被随机分为两组（HBeAg 阳性和阴性[n=24 例]），分别接受口服 Selgantolimod 3mg、1.5mg 或安慰剂（2:2:1），每周一次，共 24 周，同时维持口服抗病毒治疗。主要疗效终点是基线至第 24 周时乙型肝炎表面抗原（HBsAg）下降≥1 log10 IU/ml 的患者比例。治疗结束后，患者继续接受口服抗病毒治疗 24 周。
主要终点由一名 HBeAg 阴性的患者达到，该患者接受 Selgantolimod 1.5mg 治疗。与安慰剂治疗的患者（n=9）相比，仅 Selgantolimod 治疗的患者（n=39）在第 24 周（18%，7/39）和第 48 周（26%，10/39）时 HBsAg 下降大于 0.1 log IU/ml，HBsAg 丢失（5%，通过 48 周）或 HBeAg 丢失（16%，通过 48 周）。Selgantolimod 治疗组最常见的不良事件为恶心（46%）、上呼吸道感染（23%）和呕吐（23%）。胃肠道疾病大多为轻度和短暂的。Selgantolimod 诱导了血清细胞因子的短暂、剂量依赖性增加，包括 IL-12p40、IFN-γ和 IL-1RA，以及某些循环免疫细胞亚群的快速重新分布。
每周口服 Selgantolimod 3mg 一次，持续 24 周，一般安全且耐受良好，并导致两名患者在第 48 周时出现与持续治愈相关的血清学变化。
NCT03491553。
慢性乙型肝炎停止治疗的唯一可靠标准是乙型肝炎表面抗原丢失（称为功能性治愈），这在核苷（酸）类似物治疗期间很少见。很可能需要新型抗病毒和免疫调节疗法来实现有限的功能性治愈。Selgantolimod 是一种口服 Toll 样受体 8 激动剂，在体外具有抗病毒活性，在 I 期临床试验中每周一次给药具有安全性。在这项 II 期研究中，Selgantolimod 治疗与血清细胞因子的短暂增加、循环免疫细胞亚群的快速重新分布、HBsAg 和 HBeAg 水平的适度降低以及偶尔的 HBsAg（5%）和 HBeAg（16%）丢失有关在接受核苷（酸）类似物治疗且病毒抑制的慢性乙型肝炎患者中。我们的研究结果支持继续开发 Selgantolimod，作为未来乙型肝炎治愈方案的一部分。
