PD-1抑制剂西瑞利单抗治疗慢性乙型肝炎的随机、双盲、安慰剂对照研究。
完整摘要 · 中文译文
乙型肝炎病毒（HBV）诱导的T细胞耗竭可能通过程序性死亡受体1（PD-1）抑制剂逆转，例如西瑞利单抗（cetrelimab），这是一种靶向PD-1的在研全人源单克隆抗体。旨在评估低剂量（即低于肿瘤领域所用剂量）西瑞利单抗在病毒学抑制（VS）且稳定使用核苷（酸）类似物（NA）的慢性乙型肝炎（CHB）参与者中的安全性、活性和药代动力学。采用随机、双盲、安慰剂对照、多队列、单次剂量递增研究设计，西瑞利单抗经皮下或静脉给药。由于战略性决策而非任何安全性问题，仅执行了一个队列（45 mg皮下给药）。参与者维持NA治疗以避免HBV再激活。在24周内收集血清西瑞利单抗浓度、HBV生物标志物、PD-1受体占有率（RO）和安全性数据。共入组并随机化11名参与者，8名接受西瑞利单抗，3名接受安慰剂，全部11名完成研究。西瑞利单抗平均半衰期为16.3天，给药后达到最大西瑞利单抗浓度的中位时间为10.4天。给药后6小时达到接近最大的RO，随后随时间减弱。HBV生物标志物或实验室指标（包括肝功能检查和促甲状腺激素）无临床相关变化。未报告临床相关不良事件。在VS的CHB参与者中单次皮下给予45 mg西瑞利单抗是安全且耐受良好的。HBV生物标志物无变化，西瑞利单抗用于HBV的进一步开发 被放弃。临床试验注册：ClinicalTrials.gov：NCT05242445；EudraCT编号：2021-004857-21。
完整摘要 · 英文原文
Hepatitis B virus (HBV)-induced T-cell exhaustion may be reversed using a programmed death receptor 1 (PD-1) inhibitor such as cetrelimab, an investigational fully human monoclonal antibody targeting PD-1. To evaluate the safety, activity and pharmacokinetics of low-dose (i.e., a dose lower than that used in oncology) cetrelimab in participants with chronic hepatitis B (CHB) virologically suppressed (VS) on a stable nucleos(t)ide analog (NA). Randomized, double-blind, placebo-controlled, multi-cohort, single-dose escalation study of cetrelimab administered subcutaneously or intravenously. Due to a strategic decision, and not to any safety concern, only one cohort (45 mg subcutaneous) was executed. Participants maintained their NA treatment to avoid HBV reactivation. Serum cetrelimab concentrations, HBV biomarkers, PD-1 receptor occupancy (RO) and safety were collected over 24 weeks. Eleven participants were enrolled and randomized, eight to cetrelimab and three to placebo and all 11 completed the study. Mean cetrelimab half-life was 16.3 days with median time to maximum cetrelimab concentration 10.4 days post-dose. Near-maximal RO was achieved 6 h post-dose which waned over time. There were no clinically relevant changes in HBV biomarkers or laboratory values including liver function tests and thyroid-stimulating hormone. No clinically relevant adverse events were reported. A single 45 mg dose of cetrelimab administered subcutaneously in VS participants with CHB was safe and well tolerated. There was no change in HBV biomarkers and further development of cetrelimab for HBV was abandoned. Clinical Trial Registration: ClinicalTrials.gov: NCT05242445; EudraCT Number: 2021-004857-21.