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

作者：Man‐Fung Yuen, Stephen Locarnini, Tien Huey Lim, Simone I. Strasser, William Sievert, Wendy Cheng, Alexander Thompson, Bruce D. Given, Thomas Schluep, James Hamilton, Michael Biermer, Ronald Kalmeijer, Maria Beumont, Oliver Lenz, Filip De Ridder, Gavin Cloherty, Danny Ka‐Ho Wong, Christian Schwabe, Kathy Merlock Jackson, Ching‐Lung Lai, Robert G. Gish, Edward Gane · 发表于：Journal of Hepatology · 年份：2022 · DOI：10.1016/j.jhep.2022.07.010 · 被引用次数：106 · 研究领域：Hepatitis B Virus Studies、RNA Interference and Gene Delivery、Virus-based gene therapy research

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 log 10 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 10 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 ...