Dose response with the 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

Background: JNJ‐3989 (ARO‐HBV) is designed to silence HBV RNA transcripts from episomal cccDNA and integrated HBV DNA. In the phase 2 study AROHBV1001, serum HBsAg levels decreased by ≥1 log10 in all 24 pts who received 3 monthly (Q4w) JNJ‐3989 doses (100–400 mg) with a NA (tenofovir or entecavir), regardless of baseline HBeAg status or prior NA therapy (EASL 2019). JNJ‐3989 reduced all measurable viral products (HBV DNA, RNA, HBeAg, HBcrAg) and was well tolerated. Q4w cohorts were expanded (from 4 to 8 pts), and two lower dose cohorts (25 and 50 mg) (n = 8/cohort) were added. Methods: HBeAg positive or negative, NA experienced or naïve CHB pts were enrolled, and received 3 subcutaneous JNJ‐3989 doses of 25, 50, 100, 200, 300 or 400 mg Q4w on days 1, 27 and 57. Pts started/continued with a NA on day 1 and continued beyond the end of JNJ‐3989 dosing. Assessments included safety and levels of HBsAg, HBeAg, HBV DNA, RNA and HBcrAg. Planned follow‐up is 11 months. Results: All pts received planned JNJ‐3989 doses with no treatment discontinuations or drug‐ related serious adverse events. Duration of post‐treatment follow‐up was 14–56 days (25 and 50 mg, n = 16) and 56–285 days for 100–400 mg cohorts (n = 32). At day 113 (typical mean nadir after 3 doses, 56 days after last dose), mean HBsAg (SE) log10 reduction from day 1 (n = 8 unless stated) was 1.00 (0.18) with 25 mg, 1.54 (0.18) with 100 mg, 1.77 (0.18, n = 7) with 200 mg, 1.48 (0.11) with 300 mg and 1.75 (0.16) with 400 mg JNJ‐3989 (Figure); 6/8 pts in the 50 mg cohort have not reached day 113. Proportion of pts with ≥113 day data who achieved ≥1.0 log10 reduction in HBsAg from day 1 at nadir was 4/8 (25 mg), 7/8 (100 mg), 8/8 (200 mg), 8/8 (300 mg) and 8/8 (400 mg). For pts with HBsAg > 100 IU/mL (day 1) and with ≥113 day data, 2/7 (25 mg), 5/7 (100 mg), 6/6 (200 mg), 6/8 (300 mg) and 5/7 (400 mg) achieved HBsAg < 100 IU/mL with JNJ‐3989 treatment. HBV DNA, RNA, HBeAg and HBcrAg also declined under treatment Conclusion: Monthly doses of JNJ‐3989 at 25–400 mg with a NA were well tolerated in CHB pts. With 100–400 mg JNJ‐3989, 97% of pts (31/32) achieved a ≥1.0 log10 reduction in HBsAg; the 25 mg dose was active but seemed less effective Evaluation of 50 mg JNJ‐3989 is ongoing.