Abstract

Background: New treatment concepts focus on enhancing rates of functional cure of chronic hepatitis B (HBV) with the aims of stopping nucleos(t)ide treatment (NA) with no risk of virological relapse or liver disease progression and further decreasing the risk of hepatocellular carcinoma (HCC). Induction of a CD8+ T cell response to HBV is likely a required mechanism to achieve a functional cure. VTP-300 is an antigen-specific investigational immunotherapy consisting of a Chimpanzee Adenovirus (ChAdOx1) prime and Modified Vaccinia Ankara virus (MVA) boost delivering antigens associated with hepatitis B infection. A Phase 1b/2a study in 54 patients previously showed VTP-300 had meaningful and durable hepatitis B surface antigen (HBsAg) responses as a monotherapy and in combination with low dose nivolumab (LDN). This study will examine different dose timing and boosting regimens to further optimize HBsAg level reductions.

Methods: A Phase 2b trial is enrolling up to 120 patients (40 patients in each of 3 groups) with CHB, on antivirals for at least six months before screening with a HBV-DNA viral load of ≤1000 IU/mL and HBsAg ≥10 IU/mL and ≤4,000 IU/mL). Group 1, ChAdOx1-HBV (2 x 10*10 viral particles) followed by MVA-HBV (1 x 10*8 pfu) and LDN (0.3 mg/kg IV) at D29; Group 2, ChAdOx1-HBV (2 x 10*10 viral particles) followed by MVA-HBV (1 x 10*8 pfu) and LDN (0.3 mg/kg IV) at D29 followed by MVA-HBV (1 x 10*8 pfu) and LDN at D85; Group 3, ChAdOx1-HBV (2 x 10*10 viral particles) followed by MVA-HBV (1 x 10*8 pfu) at D29 followed by LDN at D36 followed by MVA-HBV (1 x 10*8 pfu) at D85 (only if HBsAg is ≥10IU/mL. The primary endpoint is the percentage of participants with a greater than 1 log HBsAg reduction at 6 months after initiation of therapy. HBV specific T cell responses are assessed using genotype C and D HBV peptides spanning the HBV immunogen in an IFNg ELISpot assay during the one-year follow-up period.

Results: As of 22 May 2023, 51 participants have been enrolled in HBV003 and efficacy and safety data continue to accrue. At the 2023 AASLD meeting, we expect to report on at least 50 participants who will have reached D113, showing the effects of a second MVA-HBV booster on HBsAg levels and the impact of a LDN administration at D36 rather than at the time of MVA-HBV administration. In addition, at least 40 participants are expected to have reached the D169 timepoint when they will be evaluated for NA discontinuation. We expect recruitment to be complete by December 2023 with final results available early 2025.

Conclusion: VTP-300 is a novel antigen-specific investigational immunotherapy which has shown (in a Phase 1b/2a study) meaningful and durable HBsAg reductions in patients with HBV as a monotherapy and in combination with LDN. Evaluating the addition and timing of PD-1 inhibitor administration and a second boost of MVA-HBV is critical to optimizing the regimen of VTP-300 which may be a critical component of a functional cure regimen.