Preliminary safety and antiviral activity of VIR-2218, an X-targeting HBV RNAi therapeutic, in chronic hepatitis B patients

Abstract

Background and Aims: VIR-2218 is an investigational GalNAcconjugated ribonucleic acid interference (RNAi) therapeutic in development for functional cure of chronic hepatitis B virus infection (CHB). VIR-2218 was created using Enhanced Stabilization Chemistry Plus (ESC+), which retains enhanced metabolic stability needed for in vivo potency while reducing sequence matched off-target effects. VIR-2218 is designed to silence all HBV transcripts, from both cccDNA and integrated DNA, across all 10 HBV genotypes. We present interim safety and antiviral activity data from a Phase 2 trial of VIR-2218 in patients with CHB. Method: HBeAg- or HBeAg+, virally suppressed patients on nucleos (t)ide reverse transcriptase inhibitor therapy and without significant fibrosis/cirrhosis received 2 subcutaneous doses of VIR-2218 or placebo on Day 1 (Week 0) and Day 29 (Week 4). Four cohorts of HBeAg- subjects received 20, 50, 100 or 200 mg; two cohorts were added at the 50 and 100 mg dose levels. Two cohorts of HBeAg+ subjects received 50 or 200 mg. Each cohort includes 4 subjects randomized 3:1 to receive VIR-2218 or placebo. Assessments included safety and HBsAg levels with 12 week follow-up after the second dose for all patients and an additional 32 weeks follow-up for patients achieving a pre-specified HBsAg decline target. Results: In this ongoing trial, 24 patients with CHB have received VIR2218 and are at varying stages of follow-up. No patients discontinued due to an adverse event (AE) and the majority of treatment emergent AEs were mild in severity. No clinically significant ALTelevations were observed. A subset of patients in the 50 mg dose level have achieved maximal decline in HBsAg levels at Week 12, with a mean decline of 1.5 log10 from baseline in VIR-2218 treated patients (see Figure). Notably, a mean decline of 1.0 log10 in HBsAg has been maintained through Week 28 in this cohort. Declines in HBsAg continue in other cohorts with at least two patterns observed: an early response and a delayed response. Data through at least Week 16 will be presented for all dose levels. Conclusion: Two monthly doses of VIR-2218 at 20–200 mg were well tolerated in CHB patients. Substantial reductions in HBsAg were observed in both HBeAg- and HBeAg+ patients and across all dose levels. Differential patterns of decline suggest that early responses (<8 weeks) in HBsAg may not predict the final magnitude of decline. Evaluation of VIR-2218 in CHB patients is ongoing.