ARB-001467

Nowadays, hepatitis B virus (HBV) is the world's most common serious liver infection. Immigration patterns are increasing the incidence of HBV worldwide and the prevalence of chronic HBV. Current standard therapy for HBV using nucleoside antivirals (NA) like tenofovir disoproxil fumarate, tenofovir alafenamide and entecavir can suppress HBV replication over the long term but usually does not lead to a cure, as indicated by hepatitis B surface antigen (HBsAg) clearance and development of anti-HBs antibodies. The optimal strategy proposed for developing a cure for chronic HBV would be to target multiple aspects of the HBV lifecycle. It is anticipated that a long-term HBV cure will require combinations of therapy designed to address multiple targets simultaneously. ARB-001467 (ARB-1467) is a drug being developed to address these targets.

ARB-001467

ARB-001467, a lipid nanoparticle (LNP) formulation containing three double-stranded small interfering RNAs (siRNAs), targets three distinct and highly conserved sites in the viral genome to achieve post-transcriptional gene suppression of HBV proteins generated from both covalently closed circular DNA (cccDNA) and integrated DNA, including HBsAg. ARB-001467 is designed to inhibit viral replication, reduce all HBV transcripts, and lower all viral antigens. Reducing viral proteins, in particular, HBsAg, has the potential to migrate viral suppression and reawaken the immune system.

• Key Characteristics of ARB-001467:
  • Primary viral target is HBsAg
  • Novel RNA interference (RNAi) product
  • Target sites are highly-conserved regions in HBV viral genome
  • Unique 3-trigger design
  • Inhibits HBV replication
  • Reduces all HBV transcripts
  • Lowers all HBV antigens
  • Delivered via proprietary LNP technology
  • Generally safe and well-tolerated to date

ARB-001467 Phase II Trial

This is a single-blind, placebo-controlled, multi-dose study in non-cirrhotic, virally suppressed subjects to evaluate the safety and efficacy of ARB-001467 over 12 weeks. 24 subjects on stable nucleoside therapy were enrolled in 3 cohorts: Cohort 1, HBeAg (−) at 0.2 mg/kg; Cohort 2, HBeAg (−) at 0.4 mg/kg; Cohort 3, HBeAg (+) at 0.4 mg/kg. Subjects were randomized 3:1 (active vs placebo) to 3 monthly doses and monitored for safety, pharmacokinetics and HBV markers. The results indicated that baseline characteristics were similar for the 3 cohorts. Of 24 subjects, 19 (79%) were male, mean age was 45.5 years and mean baseline HBsAg (log₁₀ IU/mL) levels were: 3.46; 3.38; 3.62 and 3.43 in Cohorts 1, 2, 3 and placebo, respectively.

• Conclusions:
  1. Treatment with ARB-001467 was generally well tolerated.
  2. All subjects receiving ARB-001467 experienced a reduction in HBsAg from baseline.
  3. Greater HBsAg reductions were observed with more frequent dosing (bi-weekly) and at the higher dose (0.4 mg/kg).
  4. Reductions in hepatitis B core-related antigen (HBcrAg) and HBV-RNA were observed in some individual patients.
  5. Overall no apparent correlation was observed between declines in HBV-RNA or HBcrAg and declines in HBsAg.
  6. Evaluation of the utility of these markers across different populations and treatment duration is required.

In conclusion, treatment was generally safe and well-tolerated, with no drug-related serious adverse events and two discontinuations due to adverse events (one with hepatitis E super-infection and one with a mild infusion reaction, joint pain and hair loss). Please refer to the following sections for more information.

• Delivery Systems Development for Gene Therapy
• RNAi Therapy Development Service
• Gene Therapy Development for Disease