Safety and antiviral activity of VIR-2218, an X-targeting RNAi therapeutic, in participants with chronic hepatitis B infection: week 48 follow-up results

Abstract

ackground and aims: VIR-2218 is an investigational GalNAcconjugated small interfering ribonucleic acid (siRNA) therapeutic in development for functional cure of chronic hepatitis B virus infection (CHB). VIR-2218 was created using Enhanced Stabilization Chemistry Plus, which retains in vivo potency while reducing off-target effects. VIR-2218 targets a conserved region of the X gene and is designed to silence all major HBV transcripts, from both cccDNA and integrated DNA, across all 10 HBV genotypes as a single siRNA. We present final safety and antiviral activity data from a Phase 2 trial of VIR-2218 in participants with CHB. Method: Non-cirrhotic, virologically suppressed participants received 2 subcutaneous doses of VIR-2218 or placebo on Day 1 and Day 29 (Week 4). HBeAg- participants received 20, 50, 100 or 200 mg, and HBeAg+ participants received 50 or 200 mg. Cohorts included 4 or 8 participants randomized 3:1 to VIR-2218 or placebo. Assessments included safety, HBsAg levels and other viral markers, with 12 weeks of follow-up after the 2nd dose for all participants and an additional 32-weeks follow-up for participants achieving prespecified HBsAg declines. Results: Twenty-four CHB participants received VIR-2218 (18 HBeAg-; 6 HBeAg+). Maximum mean HBsAg log10 IU/ml declines in HBeAg- participants receiving 20, 50, 100, and 200 mg of VIR-2218 were 1.03, 1.23, 1.50, and 1.65, respectively. For the HBeAg+ participants receiving 50 and 200 mg of VIR-2218, the maximum mean HBsAg log10 IU/ml declines were 1.16 and 1.57, respectively. Most participants achieved maximum HBsAg decline by week 16. Most participants had levels of HBV DNA and HBV RNA <LOQ at baseline, and significant changes were not detected. Declines in qHBeAg and HBcrAg were observed in HBeAg+ subjects receiving 200 mg VIR-2218. No participants discontinued due to an adverse event (AE), and the majority of treatment emergent AEs were mild in severity. No clinically significant ALT elevations were observed. Conclusion: Two doses of VIR-2218 at 20–200 mg given 4 weeks apart were well tolerated in CHB participants. Substantial reductions in HBsAg were observed in both HBeAg- and HBeAg+ participants across all dose levels, suggesting that VIR-2218 may silence transcripts from both cccDNA and integrated DNA. The antiviral activity of VIR-2218 demonstrated in this study support continued development as part of combination regimens targeting functional cure.