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.

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

“…HBV RNA decline is stronger with CpAM (ABI-H0731) compared to NA therapy (118)(119)(120)(121)(122)(123)(124) (77,78) Inhibition of gene expression/gene silencing Antisense oligonucleotides and locked nucleic acids GSK3389404 (GlaxoSmith Kline) Phase II Methoxyethyl antisense oligonucleotide conjugated to N-acetylgalactosamine moieties. Acceptable safety and pharmacokinetic profile in phase I (68) Locked nucleic acid platform-based singlestranded oligonucleotides (Roche) Preclinical Liver-targeted single-stranded oligonucleotide therapeutics based on the locked nucleic acid platform. Rapid and long-lasting reduction of HBsAg in a mouse model (67) RNA interference ARC-520 (Arrowhead) Development discontinued Decrease in HBsAg level in HBeAg-positive but not in HBeAg-negative patients (25) JNJ-3989 (Janssen) formerly ARO-HBV-1001 (Arrowhead)…”

“…Different single-stranded oligonucleotides are under development. (67,68) Small interfering RNA (siRNA) can be designed to target any viral transcript and induce its degradation by the RISC/Ago2 complex resulting in gene silencing. In a phase II study, a single dose of ARC-520 in combination with entecavir resulted in a profound and durable decrease in serum HBV DNA in both HBeAg-positive and HBeAg-negative patients and a decrease in HBsAg level in HBeAg-positive but not in HBeAg-negative patients.…”

“…Delivery can be achieved, for example, by conjugating the single‐stranded oligonucleotides to N‐acetylgalactosamine (GalNAc) moieties. Different single‐stranded oligonucleotides are under development …”

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

“…Different single-stranded oligonucleotides are under development. 71,72 Small interfering RNA (siRNA) can be designed to target any viral transcript and induce its degradation by the RISC/Ago2 complex resulting in gene silencing. In a phase II study, a single dose of ARC-520 in combination with entecavir resulted in a profound and durable decrease in serum HBV DNA in both HBeAg-positive and HBeAg-negative patients and a decrease in HBsAg level in HBeAgpositive but not in HBeAg-negative patients.…”

The Role of RNA Interference in Functional Cure Strategies for Chronic Hepatitis B

“…VIR-2218 (Alnylam Pharmaceuticals, Vir Biotechnology) uses an Enhanced Stabilization Chemistry-Plus (ESC+)-GalNAc delivery platform and is in phase 1 and 2 trials (NCT03672188), which are due to complete in March 2021. IONIS-HBVRx (Ionis Pharmaceuticals, GlaxoSmithKline) uses antisense oligonucleotide technology, which identified no safety concerns from their phase 1 data [35]. They are currently in phase 2 trials in CHB (NCT02981602), and it is a platform which incidentally has recently reported encouraging phase 2 data in nonalcoholic liver disease [36••].…”