RO7062931 antisense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy

Abstract

Background and Aims: RO7062931 is a N-acetylgalactosamine (GalNAc) conjugated single-stranded oligonucleotide (SSO) with locked nucleic acid (LNA) that results in RNAse H mediated degradation of HBV transcripts. We previously reported (AASLD 2019) results from Part 1 of the Phase 1 study (NCT03505190) where single doses of RO7062931 up to 4 mg/kg were safe and well tolerated in healthy volunteers (HVs). Herein we present the results from Study Part 2 of multiple dose RO7062931 treatment regimens in patients with chronic hepatitis B (CHB). Method: 59 CHB patients on established nucleos(t)ide therapy were randomized 3:1 to RO7062931 (0.5, 1.5, 3, or 4 mg/kg) or placebo across six 4-week treatment regimens. Eligible subjects were BeAgpositive or negative at screening with serum levels of HBsAg ≥1,000 IU/mL, HBV DNA ≤90 IU/mL and ALT ≤1.5× upper limit of normal (ULN). Depending on the dosing frequency (monthly [QM], bi-weekly [Q2W] or weekly [QW]), subjects received between 2–5 subcutaneous RO7062931 doses in total. Subsequently, all subjects entered a 12-week post-treatment follow-up. Results: Majority of subjects were male (88%), Asian (90%), with a mean (range) age of 45 (25 to 65) years. At baseline, 58% were HBeAgnegative, 86% had ALT ≤ULN, and the mean HBsAg level was 5,172 (952 to 27,620) IU/mL. No serious AEs, severe AEs, or withdrawals due to AEs were reported. Injection site reactions were reported for 7 (12%) subjects, of which 5 and 2 were of mild and moderate intensity, respectively. Laboratory safety parameters were unremarkable except for 2 subjects (3 mg/kg QW group) with transient ALT >3× ULN elevations that were associated with declining HBsAg levels. RO7062931 treatment was associated with dose-dependent reductions in HBsAg. At Day 29, mean (SD) change in HBsAg IU/mL levels were −0.03 (0.05) in the placebo group; −0.03 (0.04), −0.15 (0.21) and −0.17 (0.07) in the 0.5, 1.5 and 3 mg/kg QM groups; −0.23 (0.17) and −0.38 (0.25) in the 3 mg/kg Q2W and QW groups; and −0.14 (0.28) in the 4 mg/kg QW group. Nadir HBsAg change from baseline data with mean ± 95CI are shown in below Figure, which were similar regardless of baseline HBeAg status. A rebound in HBsAg levels was typically evident by 2–3 weeks post-treatment, which returned to baseline levels by 12-weeks post-treatment. Pharmacokinetic data in CHB patients was consistent to that previously reported for HVs. Conclusion: RO7062931 administered over 4-weeks, at doses of up to 4 mg/kg, in CHB patients is safe, well tolerated, and demonstrates target engagement by antiviral activity.