BEPIROVIRSEN 治疗导致乙型肝炎表面抗原 (HBsAg) 减少和细胞因子/

StephenW

BEPIROVIRSEN 治疗导致乙型肝炎表面抗原 (HBsAg) 减少和细胞因子/趋化因子反应与阶段 2a 中的先天性和适应性免疫相关，随机、双盲、安慰剂对照


AASLD 2021 十一月 12-15

Jennifer Singh、Shihyun You、William Jordan、Avijit Ray、Yee Voan Teo、Adam Taylor、Melanie Paff 和 Dickens Theodore、葛兰素史克

背景：Bepirovirsen（bepi，GSK3228836）是一种修饰的反义寡核苷酸，靶向所有乙型肝炎病毒 RNA 共享的区域，包括前基因组 RNA。这项事后分析评估了生物标志物与在 2 期临床试验 (NCT02981602) 中接受 Bepi 的慢性乙型肝炎患者的 Bepi 诱导的免疫反应的相关性。

方法：本研究分析了在第 1、4、8、11、15 和 22 天接受安慰剂或 bepi (3:1) 的初治和核苷（酸）化物 (NA) 治疗患者的血浆和血清。分析包括 30 名患者（未治疗：安慰剂 n=6，bepi 150 mg n=6，300 mg n=12；NA 治疗：安慰剂 n=2，bepi 300 mg n=4）；血浆分析仅包括未治疗组。在给药后 0.5（用作标准化参考的最早时间点）、4、6 和 24 小时 (h) 收集血浆；第 1 天（基线）、第 2、8、15、22、23、36、57、85、113 和 211 天的血清。使用 Olink Target 96 Inflammation panel 评估可溶性蛋白。拟合广义线性混合效应模型以比较每个时间点的基线变化。平均倍数变化 (FC) 和 p 值用于通路分析 (MetaCore)。分析了 bepi 治疗、血清 HBsAg、丙氨酸氨基转移酶 (ALT)、IFNg/CXCL10 信号和可溶性蛋白之间的关联。

结果： 血浆分析：观察到多个显着的 FC 时间进程，一些在 4 小时内很快（例如，CCL11、CCL25）；其他的在给药后 24 小时（例如，IFNg；TNFRSF9）首先变得显着。血清纵向分析：具有最高平均 FC 表达的分析物与适应性免疫、IFNg 信号传导和细胞外基质重塑相关。一些分析物在第 2 天和/或第 23 天给药后 24 小时显示出早期反应（例如，IFNg；CCL19）。从参考时间点开始，在很长一段时间内（例如，CXCL10；IL10RA）到≥第 36 天（ALT 爆发的时间），许多仍然显着；一些（例如，IFNg；CCL19）在血浆和血清中均被上调。 27 种分析物（例如，CXCL11；CXCL9）与 HBsAg、ALT、IFNg/CXCL10 反应的相关系数 >0.8。 ALT 爆发与下游 IFNg 信号传导的蛋白质相关。

结论：Bepi 触发了与免疫反应相关的生物标志物水平的改变，这可能与 HBsAg 降低、ALT 升高和 IFNg/CXCL10 信号传导相关。这些生物标志物关联和在接受 Bepi 治疗的患者中观察到的免疫反应将在 2 期研究中进行调查。资金来源：葛兰素史克（205695）。

StephenW

TREATMENT WITH BEPIROVIRSEN LEADS TO HEPATITIS B SURFACE ANTIGEN (HBsAg) REDUCTION AND CYTOKINE/ CHEMOKINE RESPONSES LINKED TO INNATE AND ADAPTIVE IMMUNITY IN A PHASE 2a, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY


AASLD 2021 Nov 12-15

Jennifer Singh, Shihyun You, William Jordan, Avijit Ray, Yee Voan Teo, Adam Taylor, Melanie Paff and Dickens Theodore, GlaxoSmithKline

Background: Bepirovirsen (bepi, GSK3228836) is a modified antisense oligonucleotide targeting regions shared by all hepatitis B virus RNAs, including pregenomic RNA. This post hoc analysis evaluated the correlation of biomarkers with bepi-induced immune responses in patients with chronic hepatitis B receiving bepi in a Phase 2 clinical trial (NCT02981602).

Methods: This study analyzed plasma and serum from treatment-naïve and nucleos(t)ide (NA)-treated patients receiving placebo or bepi (3:1), administered on Days 1, 4, 8, 11, 15, and 22. Analysis included 30 patients (treatment-naïve: placebo n=6, bepi 150 mg n=6, 300 mg n=12; NA-treated: placebo n=2, bepi 300 mg n=4); the plasma analysis included only treatment-naïve groups. Plasma was collected at 0.5 (earliest time point used as reference for normalization), 4, 6, and 24 hours (h) post dose; serum on Days 1 (baseline), 2, 8, 15, 22, 23, 36, 57, 85, 113, and 211. Soluble proteins were evaluated using the Olink Target 96 Inflammation panel. A generalized linear mixed effects model was fit to compare changes from baseline at each time point. Mean fold changes (FC) and p-values were used for pathway analyses (MetaCore). Associations between bepi treatment, serum HBsAg, alanine aminotransferase (ALT), IFNg/CXCL10 signaling, and soluble proteins were analyzed.

Results: Plasma analysis: Multiple significant FC time courses were observed, some quickly at 4 h (eg, CCL11, CCL25); others first became significant at 24 h (eg, IFNg; TNFRSF9) post dose. Serum longitudinal analysis: Analytes with the greatest average FC expression were associated with adaptive immunity, IFNg signaling, and extracellular matrix remodeling. Some analytes showed an early response 24 h post dose at Day 2 and/or Day 23 (eg, IFNg; CCL19). Many remained significant, from reference time point, over prolonged periods (eg, CXCL10; IL10RA) to ≥Day 36 (timing of an ALT flare); some (eg, IFNg; CCL19) were upregulated in both plasma and serum. 27 analytes (eg, CXCL11; CXCL9) had a correlation coefficient >0.8 to HBsAg, ALT, IFNg/CXCL10 responses. ALT flare correlated with proteins involved in downstream IFNg signaling.

Conclusion: Bepi triggered altered levels of biomarkers associated with immunological responses that may correlate with HBsAg reduction, ALT flare, and IFNg/CXCL10 signaling. These biomarker associations and the immunological response seen in bepi-treated patients will be investigated in Phase 2 studies. Funding: GSK (205695).