A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects

Abstract

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment-related AEs were injection site reactions (19.0% [n = 8/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (Tmax) of 1–4 hours and an elimination half-life of 3–6 hours in plasma. Plasma area under the concentration-time curve (AUC) and maximum observed concentration (Cmax) were dose-proportional. Dose-normalized plasma AUC from time 0 to infinity averaged 69.9 ng·h/(mL·mg dose) across cohorts, and Cmax 9.5 ng/(mL·mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once-weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.