Results after 12 weeks treatment of multiple doses of GSK3389404 in chronic hepatitis B (CHB) subjects on stable nucleos(t)ide therapy in a phase 2a double-blind, placebo-controlled study

Abstract

Background: GSK3389404 (GSK404) is a 2nd generation, liver targeted antisense oligonucleotide. A Phase 2a study was conducted in CHB patients on stable nucleos(t)ide therapy to assess the safety, tolerability, and pharmacokinetic (PK) profile of GSK404, and to identify one or more efficacious dose(s) and dosing regimen(s). Methods: 66 subjects (demographics in table) were randomized to either placebo, GSK404.30 mg weekly (wk), 60 mg wk, 120 mg bi‐weekly (BW), 120 mg wk subcutaneous injections for 12 weeks. The primary objectives were to assess the safety, tolerability, and PK profile of GSK404 and to identify efficacious dose(s) and dosing regimen(s). GSK financially sponsored the study [NCT03020745]. Results: Efficacy: Dose‐dependent HBsAg declines occurred in both HBeAg positive and negative subjects with mean HBsAg declines of 0.02 log IU/mL in placebo, 0.13 log IU/mL in 30 mg wk, 0.34 log IU/mL in 60 mg wk, 0.44 log Iu/mL in 120 mg BW, and 0.75 log IU/mL in 120 mg wk treatment arms by Day 85. Three subjects, from the 60 mg wk, 120 mg BW, and 120 mg wk treatment arms, had HBsAg 1.54 log reduction (Day 85), 2.36 log (Day 92), and 2.72 log (Day 85) without ALT elevation > 2X ULN, respectively. Two subjects had ALT > 2xULN with HBsAg decline, 0.37 log IU/mL [ALT 182 U/L; baseline 19 U/L] and 1.45 log IU/mL decline [ALT 113 U/L; baseline 39 U/L]. No subjects had undetectable HBsAg levels at end of treatment. Safety: Overall, GSK404 had an acceptable safety profile. There was 1 SAE of renal colic (120 mg GSK404 BW) considered unrelated to treatment and 1 withdrawal due to pruritis, rash (Grade 1 [mild] on neck; 120 mg BW) considered treatment‐related. The most frequently reported AE was injection site reactions. Most AEs were Grade 1 or Grade 2 (moderate) with no clear relationship to dose. Platelets showed dose‐dependent declines that plateaued on treatment and started to recover after dose completion. No bleeding events were reported. Two placebo subjects had Grade 4 (potentially life‐threatening) lab abnormality of creatine kinase increase attributed to physical activity PK: GSK404 had a Tmax at 2‐4 hours post dose with mean t1/2 of 3‐5 hours across dose levels No accumulation of plasma concentrations was observed with repeat dosing. Conclusion: GSK404 had an acceptable safety profile and showed target engagement with dose‐dependent declines in mean HBsAg. The Phase 2a study is ongoing with subjects in an optional post‐treatment period.