Hepatitis B virus (HBV) surface antigen (HBsAg) inhibition with isis 505358 in chronic hepatitis B (CHB) patients on stable nucleos(t)ide analogue (NA)-naïve CHB patients: phase 2a, randomized, double-blind, placebo-controlled study.

Abstract

Background and Aims: HBsAg plays a major role in enabling and maintaining persistent HBV infection by repressing host immune responses against the virus. ISIS 505358 (now known as GSK3228836) is a 2´-MOE modified antisense oligonucleotide (ASO) targeting all HBV RNAs. The aim of the current study was to evaluate antiviral activity and safety in CHB patients. Method: All patients were HBsAg positive ≥ 6 month and were >50 IU/mL at screening. Patients on NA were on stable regimen ≥ 12 months with plasma HBV DNA below lower limit of quantitation (LLoQ, 20 IU/mL). NA-naïve patients had HBV DNA ≥ 2 × 103 IU/mL. Exclusion criteria included: liver cirrhosis; HCV, HIV, or HDV coinfection; ALT or AST >5xULN, or bilirubin >1.1xULN. Both HBeAg positive and negative patients were eligible. ASO (300 mg) or placebo was administered subcutaneously on Days 1, 4, 8, 11, 15, and 22. The primary assessment for effect on HBV was on Day 29. Results: For patients on NA, mean HBsAg log10 IU/mL ±SE change from baseline was −2.514 ± 0.783 for ASO (n = 4) and −0.008 for placebo (Pbo, n = 2). In ASO group, 3 patients had reductions >3.0 log10 IU/mL where one was <LLoQ (0.05 IU/mL). Another reached <LLoQ on Day 36. For NA-naïve patients, HBsAg mean changes for ASO (n = 12) were −1.556 ± 0.398 (p = 0.001 vs Pbo, n = 6) and was −1.655 ± 0.427 (p < 0 001) for HBV DNA. Three and 4 ASO patients had HBsAg and HBV DNA reductions >3.0 log10 IU/mL, respectively, where 2 and 1 also had levels reduced to <LLoQ. 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. Post-ASO ALT flares with peaks ranging from 1.7 to 15xULN occurred in the other HBsAg<LLoQ patients. ALT flares were asymptomatic and selfresolved. The most common adverse events for the 300 mg ASO patients (5 of 17) were at injection sites [erythema, pain, pruritus, swelling, and/or bruising]. Conclusion: Significant reductions of HBsAg levels were observed with 4-week ISIS 505358/GSK3228836 treatment in both patients on stable NA regimens and NA-naïve patients. Significant reductions in HBV DNA were also observed in naïve patients. The tolerability and safety were acceptable for proceeding to longer treatment durations. This study was financially supported by GlaxoSmithKline.