Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen supression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment.

Abstract

Background and Aims: RNA interference (RNAi) therapy with JNJ-3989 silences HBV RNA transcripts from episomal cccDNA and integrated HBV DNA. In AROHBV1001 (phase 2a), JNJ-3989 (3 monthly doses 25-400 mg) + a nucleos(t)ide analogue (NA) demonstrated antiviral activity in patients (pts) with chronic hepatitis B (CHB) by reducing serum viral parameters (AASLD 2019). 9-month follow-up data for pts on >=100 mg are presented. Method(s): 8 CHB pts/cohort (NA experienced or naive; HBeAg +ve or -ve) received 3 subcutaneous JNJ-3989 doses (days 1, 27, 57) of 100, 200, 300 (n = 16) or 400 mg. Pts started/continued with an NA on day 1 and continued throughout the study. Safety and viral parameters (HBsAg, HBeAg, HBV DNA, HBV RNA, HBcrAg) were assessed. For all parameters, sustained suppression was defined as a >=1.0 log10 reduction from day 1 or a value >lower limit of quantification at day 336. Result(s): 40 pts were enrolled: 73% males; 85% Asian; median age 45 (26-66) yrs; HBeAg: 14 +ve, 26 -ve; 80% NA experienced. No deaths, treatment discontinuations or drug-related serious adverse events (AEs) were seen; 1 pt was lost to follow up. The most common drug-related AEs were mild injection site AEs (7 pts). One AE of elevated ALT (peak 136 U/L) was reported. HBsAg levels rapidly declined during treatment. At the HBsAg nadir, 39/40 pts had a >=1.0 log10 HBsAg reduction from day 1; range 1.11-3.77; for 1 pt the maximum decline was 0.77 log10. Mean nadir for HBsAg (SE) log10 reduction from day 1 was 1.72 (0.18; 100 mg), 1.79 (0.14; 200 mg), 2.04 (0.20; 300 mg; 11/16 HBeAg +ve) and 1.90 (0.18; 400 mg). 22/39 (56%) pts had sustained HBsAg reductions (>=1.0 log10 reduction at day 336, ~9 months after last JNJ-3989 dose, Fig); mean (SE; range) HBsAg reductions in pts with sustained suppression were: 1.74 (0.77; 1.00-3.38) vs 0.61 (0.06; 0.15-0.96) for non-sustained suppression. For pts with quantifiable parameters on day 1 and available data at day 336, a sustained suppression was observed for HBV RNA in 15/26, HBeAg in 9/14 and HBcrAg in 10/24 pts. [Figure presented] Conclusion(s): JNJ-3989 (100-400 mg) with an NA was well tolerated in CHB pts. A >=1.0 log10 reduction in HBsAg at nadir was achieved in 98% of pts. A subset of pts had sustained suppression of HBsAg ~9 months after the last RNAi dose (mean 1.74); sustained suppression of other viral parameters was also seen. Studies with longer term dual therapy (48 weeks) and triple therapy including a capsid assembly modulator are underway.Copyright © 2020 European Association for the Study of the Liver