Preliminary results of a Phase 2 study of VIR-2218, an X-targeting RNAi therapeutic, in patients with chronic hepatitis B: sub-analyses of HBeAg-negative and HBeAg-positive patients

Abstract

Objectives: VIR-2218 is a GalNAc-conjugated short interfering ribonucleic acid in development for chronic hepatitis B virus infection (CHB). VIR-2218 is designed to silence HBV transcripts from cccDNA and integrated DNA across all 10 HBV genotypes. We present safety and antiviral data from a Phase 2 study in CHB patients, focusing on baseline virologic characteristics and post-treatment HBsAg reductions in HBeAg-negative and HBeAg-positive subgroups. Materials and methods: Noncirrhotic, virologically suppressed CHB patients received 2 subcutaneous doses of VIR-2218 or placebo (Day 1 and day 29). HBeAg-negative patients received 20, 50, 100 or 200 mg and HBeAg-positive patients received 50 or 200 mg. Cohorts included 4 or 8 subjects randomized 3:1 (VIR-2218:placebo). Assessments included safety for 12 weeks post-treatment and HBsAg follow-up for 48 weeks. Preliminary 24-week data are presented. Results: 24 CHB patients received VIR-2218 (n = 18 HBeAg-negative; n = 6 HBeAg-positive). Most adverse events were mild in severity with no events leading to treatment discontinuation. No clinically significant changes in safety laboratory parameters were observed. At baseline, HBeAg-positive patients had higher burdens of HBsAg, HBV RNA and HBcrAg. Similar maximum post-treatment HBsAg declines were observed for both subgroups, with magnitude of reduction related to dose. For the 200 mg dose, the mean HBsAg reduction was ≥ 1 log by week 12 and sustained through week 24 in both subgroups. Conclusion: VIR-2218 was tolerated across all dose levels with no safety signals observed. Similar magnitude of HBsAg reduction in HBeAg-positive and HBeAg-negative CHB patients suggests that it could silence transcripts from both cccDNA and integrated DNA.