Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
Université de Paris-Cité, Department of Hepatology, AP-HP Hôpital Beaujon, Clichy, INSERM UMR1148, France.
Lancet Gastroenterol Hepatol. 2023 Sep;8(9):790-802. doi: 10.1016/S2468-1253(23)00148-6. Epub 2023 Jul 10.
JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B.
The REEF-1 multicentre, double-blind, active-controlled, randomised, phase 2b study was done at 108 hospitals or outpatient centres across 19 countries in Asia, Europe, and North and South America. We included patients aged 18-65 years with chronic hepatitis B (defined as HBsAg positivity at screening and at least 6 months before screening or alternative markers of chronicity [eg, HBV DNA]), including those not currently treated, virologically suppressed, HBeAg positive, and HBeAg negative. Patients were randomly assigned (1:1:2:2:2:2) via permuted block randomisation according to a computer-generated schedule to receive oral nucleos(t)ide analogues once per day plus placebo (control group); oral JNJ-6379 250 mg daily plus nucleos(t)ide analogues (JNJ-6379 dual group); nucleos(t)ide analogues plus subcutaneously injected JNJ-3989 at doses of 40 mg (JNJ-3989 dual 40 mg group), 100 mg (JNJ-3989 dual 100 mg group), or 200 mg (JNJ-3989 dual 200 mg group) every 4 weeks; or JNJ-6379 250 mg plus JNJ-3989 100 mg every 4 weeks plus nucleos(t)ide analogues (triple group) for 48 weeks followed by a follow-up phase. An interactive web response system provided concealed treatment allocation, and investigators remained masked to the intervention groups until the primary analysis at week 48. The primary endpoint was the proportion of patients meeting predefined nucleos(t)ide analogue-stopping criteria (alanine aminotransferase <3 × upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg negative, and HBsAg <10 IU/mL) at week 48. All patients who received at least one dose of study drug were included in the analysis population used for primary efficacy assessment, excluding those who withdrew because of COVID-19-related reasons, withdrew before week 44, or had no efficacy data (ie, the modified intention-to-treat population). Safety was assessed in all participants who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, NCT03982186. The study has been completed.
Between Aug 1, 2019, and April 26, 2022, 470 patients (310 [66%] male and 244 [52%] White) were randomly assigned: 45 to the control group, 48 to the JNJ-6379 dual group, 93 to the JNJ-3989 dual 40 mg group, 93 to the JNJ-3989 dual 100 mg group, 96 to the JNJ-3989 dual 200 mg group, and 95 to the triple group. At week 48, five (5%; 90% CI 2-11) of 91 patients in the JNJ-3989 dual 40 mg group, 15 (16%; 10-24) of 92 in the JNJ-3989 dual 100 mg group, 18 (19%; 13-27) of 94 in the JNJ-3989 dual 200 mg group, eight (9%; 4-15) of 94 in the triple group, and one (2%; 0-10) of 45 in the control group met nucleos(t)ide analogue stopping criteria. No patients in the JNJ-6379 dual group met stopping criteria. 38 (81%) patients who met nucleos(t)ide analogue-stopping criteria at week 48 were virologically suppressed and HBeAg negative at baseline. Ten (2%) of 470 patients had serious adverse events during the treatment phase, and two patients (one each from the JNJ-3989 dual 200 mg group [exercise-related rhabdomyolysis] and the triple group [increase in ALT or AST]) had serious adverse events related to study treatment. During follow-up, 12 (3%) of 460 patients had a serious adverse event; one (<1%), a gastric ulcer, was considered to be related to nucleos(t)ide analogues and occurred in a patient from the JNJ-3989 dual 200 mg group. 29 (6%) of 460 patients in the treatment phase and in ten (2%) of 460 patients in the follow-up phase had grade 3 or 4 adverse events. Five (1%) of 470 patients discontinued treatment due to adverse events, and there were no deaths.
Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies.
Janssen Research and Development.
JNJ-73763989（JNJ-3989）是一种小干扰 RNA，可靶向所有乙型肝炎病毒（HBV）RNA，从而降低所有 HBV 蛋白。JNJ-56136379（JNJ-6379；也称为 bersacapavir）是一种衣壳组装调节剂，可抑制 HBV 复制。我们旨在评估这些治疗药物联合核苷（酸）类似物在慢性乙型肝炎患者中的疗效（即抗病毒活性）和安全性。
REEF-1 是一项多中心、双盲、活性对照、随机、2b 期临床试验，在 19 个国家/地区的 108 家医院或门诊中心进行，包括年龄在 18-65 岁之间的慢性乙型肝炎患者（定义为筛选时和筛选前至少 6 个月的 HBsAg 阳性或替代慢性标志物[例如，HBV DNA]），包括目前未治疗、病毒学抑制、HBeAg 阳性和 HBeAg 阴性的患者。患者根据计算机生成的方案通过区组随机化（1:1:2:2:2:2）随机分配接受每日一次口服核苷（酸）类似物加安慰剂（对照组）；每日口服 JNJ-6379250mg 加核苷（酸）类似物（JNJ-6379 双药组）；核苷（酸）类似物加皮下注射 JNJ-3989 剂量为 40mg（JNJ-3989 双药 40mg 组）、100mg（JNJ-3989 双药 100mg 组）或 200mg（JNJ-3989 双药 200mg 组）每 4 周一次；或 JNJ-6379250mg 加 JNJ-3989100mg 每 4 周一次加核苷（酸）类似物（三联组），持续 48 周，然后进行随访阶段。交互式网络应答系统提供隐藏的治疗分配，调查人员在主要分析时（第 48 周）之前保持对干预组的盲态。主要终点是符合核苷（酸）类似物停药标准的患者比例（丙氨酸氨基转移酶 <3×正常值上限、HBV DNA 低于定量下限、HBeAg 阴性和 HBsAg<10IU/mL）在第 48 周。所有接受至少一剂研究药物的患者均被纳入主要疗效评估的分析人群，排除因 COVID-19 相关原因退出、在第 44 周前退出或无疗效数据的患者（即修改后的意向治疗人群）。所有接受至少一剂研究药物的患者均进行安全性评估。该试验在 ClinicalTrials.gov 上注册，编号为 NCT03982186。该研究已完成。
2019 年 8 月 1 日至 2022 年 4 月 26 日期间，470 名患者（310 名[66%]男性和 244 名[52%]白人）被随机分配：45 名至对照组、48 名至 JNJ-6379 双药组、93 名至 JNJ-3989 双药 40mg 组、93 名至 JNJ-3989 双药 100mg 组、96 名至 JNJ-3989 双药 200mg 组和 95 名至三联组。第 48 周时，JNJ-3989 双药 40mg 组 91 名患者中有 5 名（5%；90%CI2-11）、JNJ-3989 双药 100mg 组 92 名患者中有 15 名（16%；10-24）、JNJ-3989 双药 200mg 组 94 名患者中有 18 名（19%；13-27）、三联组 94 名患者中有 8 名（9%；4-15）和对照组 45 名患者中的 1 名（2%；0-10）符合核苷（酸）类似物停药标准。JNJ-6379 双药组无患者符合停药标准。第 48 周时，符合核苷（酸）类似物停药标准的 38 名（81%）患者在基线时病毒学抑制且 HBeAg 阴性。470 名患者中有 10 名（2%）在治疗期间发生严重不良事件，两名患者（JNJ-3989 双药 200mg 组[运动相关横纹肌溶解症]和三联组[ALT 或 AST 升高]各 1 名）发生与研究治疗相关的严重不良事件。在随访期间，460 名患者中有 12 名（3%）发生严重不良事件；1 名（<1%），即胃溃疡，被认为与核苷（酸）类似物有关，发生在 JNJ-3989 双药 200mg 组的一名患者中。治疗阶段的 29 名（6%）和随访阶段的 10 名（2%）患者发生 3 级或 4 级不良事件。5 名（1%）患者因不良事件停止治疗，无死亡。
尽管 JNJ-3989 的治疗导致符合核苷（酸）类似物停药标准的比例呈剂量依赖性，但很少导致 HBsAg 血清学清除。然而，大多数接受 JNJ-3989 治疗的患者的 HBsAg 有显著降低，这可能有助于形成有利于更好免疫控制的肝脏环境，进而可能改善对免疫调节治疗的反应。
Janssen 研究与开发。
