Dose response with RNA interference (RNAi) therapy JNJ-3989 combined with nucleos(t)ide analogue (NA) treatment in expanded cohorts of patients (pts) with chronic hepatitis B (CHB).

Abstract

Introduction: JNJ-3989 silences HBV RNA transcripts from episomal cccDNA and integrated HBV DNA. In AROHBV1001 (phase 2a), JNJ-398 and an NA resulted in: >=1 log10 HBsAg reduction; reduction of measurable viral products; was well tolerated. Objective(s): 100-400 mg cohorts were expanded and 2 lower dose cohorts were added. Method(s): HBeAg-positive/-negative, NA-experienced/-naive CHB pts were enrolled, and received 3 subcutaneous JNJ-3989 doses (25, 50, 100, 200, 300, 400 mg; days 1, 27, 57). Pts started/continued with an NA (day 1) and continued throughout. Safety and viral parameters (HBsAg, HBeAg, HBV DNA, RNA, HBcrAg) were assessed. Result(s): No treatment discontinuations or drug-related serious adverse events occurred. At day 113 (typical mean nadir after 3 doses, 56 days after last dose), mean HBsAg (SE) log10 reduction from day 1 (n = 8) was 1.00 (0.18; 25 mg), 1.18 (0.08; 50 mg), 1.54 (0.18; 100 mg), 1.77 (0.18, n = 7, 200 mg), 1.48 (0.11; 300 mg) and 1.75 (0.16; 400 mg) (Figure). 4/8 (25 mg), 5/8 (50 mg), 7/8 (100 mg), 8/8 (200 mg), 8/8 (300 mg) and 8/8 (400 mg) patients achieved >=1.0 log10 reduction in HBsAg from day 1 at nadir. For pts with HBsAg >100 IU/mL (day 1), 2/7 (25 mg), 3/8 (50 mg), 5/7 (100 mg), 6/6 (200 mg), 6/8 (300 mg) and 5/7 (400 mg) achieved HBsAg<100 IU/mL at day 113. HBV DNA, RNA, HBeAg and HBcrAg declined under treatment. Conclusion(s): JNJ-3989 monthly doses, 25-400 mg, with an NA were well tolerated in CHB patients. With 100-400 mg JNJ-3989, 97% of patients (31/32) achieved a >=1.0 log10 HBsAg reduction; the 25 mg and 50 mg doses were active but seemed less effective. (Figure Presented) .