JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B

Abstract

Background JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). Methods Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). Results Thirty non-Japanese ( n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants ( n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4–9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. Conclusion JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.

Pharmacokinetics of JNJ‐73763989 and JNJ‐56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment

“…In both studies, the area under the plasma concentration–time curve (AUC) for JNJ‐73763976 and JNJ‐73763924 generally increased in a dose‐proportional manner between doses of 25 to 400 mg when administered subcutaneously in the abdomen. The t 1/2 for JNJ‐73763976 and JNJ‐73763924 in plasma was 4 to 9 hours, the median time to maximum plasma concentration (C max ) was 1.5 to 6.0 hours, and renal elimination was dose dependent 10 . Liver concentrations and t 1/2 are expected to be higher than in plasma, allowing for infrequent dosing 11 .…”

“…Liver concentrations and t 1/2 are expected to be higher than in plasma, allowing for infrequent dosing 11 . No differences in pharmacokinetics were found between the 2 study populations 10 . In participants with chronic hepatitis B, JNJ‐73763989 (given as 3 monthly subcutaneous injections of 25 to 400 mg) with nucleos(t)ide analogs (NAs), and without or with JNJ‐56136379, led to dose‐dependent decreases in HBsAg.…”

“…Sustained decreases in HBsAg, hepatitis B e antigen (HBeAg), hepatitis B core‐related antigen (HBcrAg), and HBV DNA and RNA were observed with higher doses (100 to 400 mg) 8 . These studies of single dose and multiple doses both reported JNJ‐73763989 to be generally well tolerated, with observed adverse events (AEs) that were mostly mild to moderate, and none of which were considered to be related to JNJ‐73763989 8,10 …”

“…The t 1/2 for JNJ-73763976 and JNJ-73763924 in plasma was 4 to 9 hours, the median time to maximum plasma concentration (C max ) was 1.5 to 6.0 hours, and renal elimination was dose dependent. 10 Liver concentrations and t 1/2 are expected to be higher than in plasma, allowing for infrequent dosing. 11 No differences in pharmacokinetics were found between the 2 study populations.…”

“…11 No differences in pharmacokinetics were found between the 2 study populations. 10 In participants with chronic hepatitis B, JNJ-73763989 (given as 3 monthly subcutaneous injections of 25 to 400 mg) with nucleos(t)ide analogs (NAs), and without or with JNJ-56136379, led to dosedependent decreases in HBsAg. Sustained decreases in HBsAg, hepatitis B e antigen (HBeAg), hepatitis B core-related antigen (HBcrAg), and HBV DNA and RNA were observed with higher doses (100 to 400 mg).…”