Data from the Phase 2a IM-PROVE II clinical trial indicate that a combination of imdusiran, VTP-300, and low-dose nivolumab shows promise in treating chronic hepatitis B (cHBV). The trial, involving non-cirrhotic, virally suppressed cHBV participants on stable nucleos(t)ide analogue (NUC) therapy, demonstrated increased rates of hepatitis B surface antigen (HBsAg) loss with the addition of nivolumab.
The IM-PROVE II trial included a cohort (Group C) of 22 participants with HBsAg levels between 100 and 5,000 IU/mL. Participants received repeat doses of imdusiran, Arbutus’ RNAi therapeutic, followed by Barinthus Bio’s T-cell stimulating immunotherapeutic, VTP-300, with or without low-dose nivolumab, an anti-PD-1 monoclonal antibody. Thirteen participants were eligible for nivolumab, while nine were not, based on trial criteria.
Key Findings from Group C
Preliminary data from Group C, up to Week 48 (20/22 participants), revealed:
- Imdusiran treatment led to a mean decline from baseline in HBsAg, consistent with previous data.
- Significantly greater mean declines in HBsAg levels (p < 0.017) were observed in participants receiving imdusiran and VTP-300 with nivolumab compared to other groups.
- 23% of participants (3/13) in the group receiving imdusiran, VTP-300, and low-dose nivolumab achieved HBsAg loss by Week 48.
- Increases in soluble immune biomarkers associated with immune checkpoint proteins, inflammation, and T-cell activation were observed in participants who had HBsAg loss at any point through Week 48.
- The treatment regimen with nivolumab was generally well-tolerated, with no immune-related adverse events reported.
Expert Commentary
Dr. Leon Hooftman, Chief Medical Officer of Barinthus Bio, stated, "These data demonstrated the impact of the combination of an immune stimulant such as VTP-300 and a low dose of the checkpoint inhibitor nivolumab in helping participants reach HBsAg loss." He added that the regimen is promising and consistent with data from their HBV003 trial of VTP-300 plus low-dose nivolumab.
Dr. Karen Sims, Chief Medical Officer of Arbutus Biopharma, commented, "These data continue to support our belief that lowering surface antigen is key to promoting HBV-specific immune reawakening. In this trial, imdusiran provided meaningful reductions in HBsAg prior to treatment with the immunomodulatory agents, VTP-300 and low dose nivolumab, leading to improved response rates with this combination."
Trial Design
The IM-PROVE II trial initially enrolled 40 non-cirrhotic, virally suppressed cHBV participants in Groups A and B. These participants received imdusiran (60mg every 8 weeks) for 24 weeks with ongoing NUC therapy and were then randomized to receive either VTP-300 (Group A) or placebo (Group B) at Weeks 26 and 30.
The trial was amended to include Group C, enrolling 22 participants, 13 of whom received imdusiran (60mg every 8 weeks) for 24 weeks with ongoing NUC therapy followed by VTP-300 at Weeks 26 and 30 plus up to two low doses of nivolumab (0.3 mg/kg) at Week 30. The remaining 9 participants received the imdusiran/NUC/VTP-300 regimen without nivolumab.
Upon completion of the treatment period at Week 48, participants meeting certain criteria could discontinue NUC therapy and be followed for an additional 48 weeks.
