随机 2 期研究（JADE）：HBV 衣壳组装调节剂 JNJ-56136379 联合或不联合核苷（酸）类似物治疗慢性乙型肝炎感染患者。

Randomised phase 2 study (JADE) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection.

机构信息

Toronto General Hospital, Toronto, Ontario, Canada.

Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands.

出版信息

Gut. 2023 Jul;72(7):1385-1398. doi: 10.1136/gutjnl-2022-328041. Epub 2023 Jan 25.

OBJECTIVE

We present the final analysis results of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956).

DESIGN

232 patients with chronic hepatitis B (CHB) not currently treated at study start (NCT) at study start or virologically suppressed were randomised to receive 75 mg (part 1) or 250 mg (part 2) JNJ-56136379, a hepatitis B virus (HBV)-capsid assembly modulator, one time per day or placebo with nucleos(t)ide analogue (NA) (tenofovir disoproxil fumarate/entecavir) or JNJ-56136379 alone (NCT-only) for ≥24 and ≤48 weeks.

RESULTS

In patients who are NCT hepatitis B e-antigen (HBeAg) positive, JNJ-56136379 75 mg+NA and 250 mg+NA showed limited mean (SE) hepatitis B surface antigen (HBsAg) declines (0.14 (0.10) and 0.41 (0.15), respectively) from baseline at Week 24 (primary endpoint; placebo+NA: 0.25 (0.11) log international unit (IU)/mL).In patients who are NCT HBeAg positive, mean (SE) HBV DNA declines at Week 24 were 5.53 (0.23) and 5.88 (0.34) for JNJ-56136379 75 mg+NA and 250 mg+NA, respectively, versus 5.21 (0.42) log IU/mL for placebo+NA. In NCT patients, mean (SE) HBV RNA declines were 2.96 (0.23) and 3.15 (0.33) versus 1.33 (0.32) log copies/mL, respectively.Patients with HBsAg declines had HBeAg and hepatitis B core-related antigen (HBcrAg) declines and some early on-treatment isolated alanine aminotransferase flares. Viral breakthrough occurred with JNJ-56136379 monotherapy with the emerging resistant-variant T33N, but not with JNJ-56136379+NA. JNJ-56136379 treatment beyond Week 24 had a generally small additional effect on viral markers.No study treatment-related serious adverse events or clinically significant changes in laboratory parameters occurred.

CONCLUSIONS

In patients with non-cirrhotic CHB, JNJ-56136379+NA showed pronounced reductions in HBV DNA and HBV RNA, limited HBsAg or HBeAg declines in patients who are NCT HBeAg positive, and was well tolerated, but no clear benefit with regards to efficacy of JNJ-56136379 over NA was observed.

目的

我们呈现了 2 期 JADE 研究（ClinicalTrials.gov 标识符：NCT03361956）的最终分析结果。

设计

232 名未接受治疗的慢性乙型肝炎（CHB）患者（NCT）在研究开始时或病毒学抑制时开始接受 75mg（第 1 部分）或 250mg（第 2 部分）JNJ-56136379，一种乙型肝炎病毒（HBV）衣壳组装调节剂，每天一次或安慰剂联合核苷（酸）类似物（NA）（富马酸替诺福韦二吡呋酯/恩替卡韦）或 JNJ-56136379 单药治疗，持续≥24 周且≤48 周。

结果

在 NCT 乙型肝炎 e 抗原（HBeAg）阳性的患者中，JNJ-56136379 75mg+NA 和 250mg+NA 分别显示出有限的平均（SE）乙型肝炎表面抗原（HBsAg）从基线下降（分别为 0.14（0.10）和 0.41（0.15））在第 24 周（主要终点；安慰剂+NA：0.25（0.11）国际单位（IU）/mL）。在 NCT HBeAg 阳性的患者中，JNJ-56136379 75mg+NA 和 250mg+NA 在第 24 周时的平均（SE）HBV DNA 下降分别为 5.53（0.23）和 5.88（0.34），而安慰剂+NA 为 5.21（0.42）IU/mL。在 NCT 患者中，平均（SE）HBV RNA 下降分别为 2.96（0.23）和 3.15（0.33），而安慰剂+NA 为 1.33（0.32）log 拷贝/mL。HBsAg 下降的患者 HBeAg 和乙型肝炎核心相关抗原（HBcrAg）下降，一些患者在治疗早期出现丙氨酸氨基转移酶孤立性升高。JNJ-56136379 单药治疗时出现了耐药变异 T33N 导致的病毒突破，但 JNJ-56136379+NA 没有。在第 24 周之后继续 JNJ-56136379 治疗对病毒标志物通常只有较小的额外作用。