Phase 2a, randomized, double-blind, placebo-controlled study of an antisense inhibitor (ISIS 505358) in treatment-naïve chronic hepatitis B (CHB) patients: safety and antiviral efficacy

Abstract

Background: Hepatitis B virus (HBV) surface antigen (HBsAg) is suspected to play a major role in enabling and maintaining persistent HBV infection. Ionis‐HBVRx (ISIS 505358) is a 2′‐MOE modified antisense oligonucleotide (ASO) targeting all HBV RNAs. It was selected for clinical study based on its activity against HBsAg in non‐clinical studies. The safety of the ASO was previously evaluated in healthy volunteers. The aim of the current study was to extend the safety and tolerability evaluation to CHB patients and to assess the antiviral activity of treatment given for 4 weeks. Methods: This study was conducted in treatment‐naïve patients with HBV DNA ≥2 x 103 IU/mL and HBsAg > 50 IU/mL. Exclusion criteria included: history or evidence of liver cirrhosis; coinfection with HCV, HIV, or HDV; ALT or AST > 5xULN, bilirubin > 1.1xULN, or serum creatinine > 1.1xULN. Both HBeAg positive and negative patients were eligible. Treatment was administered by subcutaneous injections on Days 1, 4, 8, 11, 15, and 22. The primary assessment for effect on HBV was on Day 29. Thereafter, all patients received a 6‐month course of tenofovir. Results: Treatments with placebo (n = 6) and 150 mg (n = 6) and 300 mg (n = 12) ASO were studied. Dose related reductions of HBsAg and HBV DNA were observed. At 300 mg, HBsAg and HBV DNA mean ± SD log10 IU/mL changes from baseline were ‐1.556 ± 1.379 (p = 0.001 vs placebo) and ‐1.655 ± 1.479 (p < 0.001), respectively. Three of these patients had HBsAg and HBV DNA reductions > 3.0 log10 IU/mL where 2 also had HBsAg and HBV DNA levels reduced to below the lower limit of quantitation (LLoQ, 0.05 and 20 IU/mL, respectively). HBsAg remained below LLoQ for at least 28 and 102 days post‐ASO treatment All 3 patients were HBeAg negative throughout. One SAE occurred in the study: post‐ ASO treatment ALT flare to 781 U/L (24xULN) in a patient with HBsAg and HBV DNA reductions to <LLoQ. A post‐ASO ALT flare to 479 U/L (15xULN) occurred in the other <LLoQ patient. Otherwise, the AEs in > 1 ASO patient and with higher incidence than placebo patients were pyrexia (22%), injection site (IS) pruritis (17%), and anemia, myalgia and IS pain (11% each). Conclusion: Dose‐related reductions of HBsAg levels were observed with only 4‐week ISIS 505358 treatment indicating the ASO has significant inhibitory activity against HBsAg and HBV DNA. The tolerability and safety were acceptable for proceeding to longer treatment durations. This study was financially supported by GlaxoSmithKline.