包括小干扰 RNA JNJ-3989 在内的联合治疗可在 CHB 患者中诱导快

StephenW

包括小干扰 RNA JNJ-3989 在内的联合治疗可在 CHB 患者中诱导快速且有时延长的病毒反应

    袁文峰
    斯蒂芬·洛卡尼尼
    田惠林
    清龙礼
    罗伯特·G·吉什
    爱德华·盖恩
    显示所有作者

开放存取发布时间：2022 年 7 月 20 日 DOI：https://doi.org/10.1016/j.jhep.2022.07.010


强调

    •
    小干扰 RNA (siRNA) 可降低慢性乙型肝炎患者的 HBsAg 水平。
    •
    研究了 3 种 siRNA JNJ-3989 剂量 + 核苷（酸）类似物的安全性和有效性。
    •
    在本研究中，所有 JNJ-3989 剂量在 CHB 患者中均具有良好的耐受性。
    •
    许多患者的 HBsAg 从基线下降≥1 log10 IU/ml。
    •
    许多患者在最后一次 JNJ-3989 给药后 336 天后 HBsAg 持续下降。

背景与目标
RNA 干扰疗法已被证明可以降低临床前模型中的乙型肝炎表面抗原 (HBsAg) 水平，这可以使慢性乙型肝炎患者获得功能性治愈。这项 IIa 期试验（ClinicalTrials.gov 标识符：NCT03365947）评估了用于慢性乙型肝炎患者的小干扰 RNA JNJ-73763989 (JNJ-3989) 和核苷（酸）类似物 (NA)，加/不加衣壳组装调节剂 JNJ-56136379 (JNJ-6379)。
方法
初治和 NA 抑制患者每周接受 3 次皮下 JNJ-3989 剂量（QW；100、200 或 300 mg）、2 周（Q2W；100 mg）或 4 周（Q4W；25、50、100、200 、300 或 400 毫克），或 JNJ-3989 Q4W（200 毫克）加口服 JNJ-6379 250 毫克每日 12 周。患者自始至终接受 NA。
结果
招募了八十四名患者。所有治疗均具有良好的耐受性，所有 5 种严重不良事件均被认为与研究药物无关。 JNJ-3989 100 至 400 mg Q4W 导致 39/40 (97.5%) 处于最低点的患者 HBsAg 从基线降低≥1 log10 IU/ml。接受三联疗法的所有患者（n = 12）在最低点时 HBsAg 从基线降低≥1 log10 IU/ml。在所有 JNJ-3989 Q4W 治疗组中，包括三联疗法 (n = 68)，HBeAg 阳性 (n = 21) 和 HBeAg 阴性 (n = 47) 患者的 HBsAg 降低相似。与 100 至 400 mg (n = 40) 相比，25 mg (n = 8) 和 50 mg (n = 8) 的 HBsAg 降低幅度较小。与 Q4W 给药相比，较短的给药间隔（QW [n = 12] 和 Q2W [n = 4]）并未改善反应。在最后一次 JNJ-3989 给药后 336 天，38% 的患者 HBsAg 从基线降低 ≥1 log10 IU/ml 持续存在。
结论
JNJ-3989 加 NA，有/无 JNJ-6379，耐受性良好，在最后一次 JNJ-3989 Q4W 剂量后长达 336 天导致 HBsAg 降低。
临床试验编号
NCT03365947。
总结
乙型肝炎病毒会影响人的肝脏并产生称为乙型肝炎表面抗原 (HBsAg) 的颗粒，这种颗粒会损害人的肝脏，并可以帮助病毒长期感染人，称为慢性乙型肝炎 (CHB)。在这项研究中，评估了一种称为 JNJ-3989 的新疗法（与称为核苷（酸）类似物的正常疗法相结合），评估其在减少慢性乙型肝炎患者 HBsAg 颗粒数量方面的安全性和有效性。这项研究的结果表明，使用 JNJ-3989 治疗对于 CHB 患者来说是安全的，降低了他们的 HBsAg 水平，并且在接受最后一剂 JNJ-3989 后，38% 的患者的 HBsAg 水平降低了 336 天。

StephenW

Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB

    Man-Fung Yuen
    Stephen Locarnini
    Tien Huey Lim
    Ching Lung Lai
    Robert G. Gish
    Edward Gane
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Open AccessPublished:July 20, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.010


Highlights

    •
    Small-interfering RNA (siRNA) lowers HBsAg levels in patients with CHB.
    •
    Safety and efficacy of 3 siRNA JNJ-3989 doses + a nucleos(t)ide analogue was studied.
    •
    All JNJ-3989 doses were well tolerated in patients with CHB in this study.
    •
    Many patients experienced HBsAg declines ≥1 log10 IU/ml from baseline.
    •
    HBsAg reduction persisted 336 days after the last JNJ-3989 dose in many patients.

Background & Aims
RNA interference therapy has been shown to reduce hepatitis B surface antigen (HBsAg) levels in preclinical models, which could confer functional cure in patients with chronic hepatitis B. This phase IIa trial (ClinicalTrials.gov Identifier: NCT03365947) assessed the safety and efficacy of the small-interfering RNA JNJ-73763989 (JNJ-3989) plus a nucleos(t)ide analogue (NA), with/without the capsid assembly modulator JNJ-56136379 (JNJ-6379) in patients with chronic hepatitis B.
Methods
Treatment-naïve and NA-suppressed patients received 3 subcutaneous JNJ-3989 doses every week (QW; 100, 200, or 300 mg), 2 weeks (Q2W; 100 mg) or 4 weeks (Q4W; 25, 50, 100, 200, 300, or 400 mg), or JNJ-3989 Q4W (200 mg) plus oral JNJ-6379 250 mg daily for 12 weeks. Patients received NAs throughout.
Results
Eighty-four patients were recruited. All treatments were well tolerated, with all 5 serious adverse events considered unrelated to study drugs. JNJ-3989 100 to 400 mg Q4W resulted in HBsAg reductions ≥1 log10 IU/ml from baseline in 39/40 (97.5%) patients at the nadir. All patients receiving the triple combination (n = 12) had HBsAg reductions ≥1 log10 IU/ml from baseline at the nadir. HBsAg reductions were similar for HBeAg-positive (n = 21) and HBeAg-negative (n = 47) patients in all JNJ-3989 Q4W treatment arms, including the triple combination (n = 68). Smaller HBsAg reductions were seen with 25 mg (n = 8) and 50 mg (n = 8) than with 100 to 400 mg (n = 40). Shorter dosing intervals (QW [n = 12] and Q2W [n = 4]) did not improve response vs. Q4W dosing. HBsAg reductions ≥1 log10 IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose.
Conclusions
JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose.
Clinical trial number
NCT03365947.
Lay summary
Hepatitis B virus affects people’s livers and produces particles called hepatitis B surface antigen (HBsAg) that damage a person’s liver and can help the virus infect a person for a long time, known as chronic hepatitis B (CHB). In this study, a new treatment called JNJ-3989 was assessed (in combination with normal treatment known as nucleos(t)ide analogues), for its safety and effectiveness in reducing the number of HBsAg particles in people with CHB. The results of this study showed that treatment with JNJ-3989 could be safe for people with CHB, lowered their HBsAg levels, and kept HBsAg levels lowered for 336 days in 38% of patients after receiving their last dose of JNJ-3989.

StephenW

http://www.journal-of-hepatology.eu/article/S0168827822029415/pdf