Yuen Man-Fung, Locarnini Stephen, Lim Tien Huey, Strasser Simone I, Sievert William, Cheng Wendy, Thompson Alex J, Given Bruce D, Schluep Thomas, Hamilton James, Biermer Michael, Kalmeijer Ronald, Beumont Maria, Lenz Oliver, De Ridder Filip, Cloherty Gavin, Ka-Ho Wong Danny, Schwabe Christian, Jackson Kathy, Lai Ching Lung, Gish Robert G, Gane Edward
Department of Medicine, The University of Hong Kong, Hong Kong, China.
Victorian Infectious Diseases Reference Laboratory, Victoria, Australia.
J Hepatol. 2022 Nov;77(5):1287-1298. doi: 10.1016/j.jhep.2022.07.010. Epub 2022 Jul 20.
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.
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.
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 log 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 log 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 log IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose.
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.
NCT03365947.
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.
在临床前模型中，RNA干扰疗法已显示可降低乙肝表面抗原（HBsAg）水平，这可能为慢性乙型肝炎患者带来功能性治愈。这项IIa期试验（ClinicalTrials.gov标识符：NCT03365947）评估了小干扰RNA JNJ-73763989（JNJ-3989）联合核苷（酸）类似物（NA），加或不加衣壳组装调节剂JNJ-56136379（JNJ-6379）治疗慢性乙型肝炎患者的安全性和疗效。
初治和接受NA治疗的患者每周皮下注射3剂JNJ-3989（每周一次；100、200或300毫克），每2周一次（每两周一次；100毫克）或每4周一次（每四周一次；25、50、100、200、300或400毫克），或JNJ-3989每四周一次（200毫克）加口服JNJ-6379每日250毫克，共12周。患者全程接受NA治疗。
招募了84名患者。所有治疗耐受性良好，所有5例严重不良事件均被认为与研究药物无关。JNJ-3989每四周一次100至400毫克使39/40（97.5%）患者的HBsAg从基线水平降低≥1 log IU/ml，最低值时达到这一效果。所有接受三联疗法（n = 12）的患者在最低值时HBsAg从基线水平降低≥1 log IU/ml。在所有JNJ-3989每四周一次治疗组，包括三联疗法组（n = 68），HBeAg阳性（n = 21）和HBeAg阴性（n = 47）患者的HBsAg降低情况相似。25毫克（n = 8）和50毫克（n = 8）组的HBsAg降低幅度小于100至400毫克组（n = 40）。与每四周一次给药相比，较短的给药间隔（每周一次[n = 12]和每两周一次[n = 4]）并未改善疗效。在最后一剂JNJ-3989给药336天后，38%的患者HBsAg从基线水平降低≥1 log IU/ml的情况仍持续存在。
JNJ-3989联合NA，加或不加JNJ-6379，耐受性良好，在最后一剂JNJ-3989每四周一次给药后长达336天可使HBsAg降低。
NCT03365947。
乙型肝炎病毒会影响人们的肝脏，并产生称为乙肝表面抗原（HBsAg）的颗粒，这些颗粒会损害人的肝脏，并可能帮助病毒长期感染人，即慢性乙型肝炎（CHB）。在这项研究中，评估了一种名为JNJ-3989的新疗法（与称为核苷（酸）类似物的常规治疗联合使用）对降低CHB患者HBsAg颗粒数量的安全性和有效性。这项研究的结果表明，JNJ-3989治疗对CHB患者可能是安全的，可降低他们的HBsAg水平，并且在38%的患者接受最后一剂JNJ-3989后336天内使HBsAg水平保持降低。
