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

  • Antivir Ther. 2022 Jun;27(3):13596535221093856. doi: 10.1177/13596535221093856.
Ed Gane  1 ,  Man-Fung Yuen  2 ,  Thomas N Kakuda  3 ,  Tetsuro Ogawa  4 ,  Yasushi Takahashi  4 ,  Nele Goeyvaerts  5 ,  Isabelle Lonjon-Domanec  6 ,  Tamisha Vaughan  7 ,  Thomas Schluep  7 ,  James Hamilton  7 ,  Emmanuel Njumbe Ediage  5 ,  Vera Hillewaert  5 ,  Jan Snoeys  5 ,  Oliver Lenz  5 ,  Willem Talloen  5 ,  Michael Biermer  5
Affiliations
  • 1. New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand.
  • 2. Department of Medicine, 25809The University of Hong Kong, Hong Kong, China.
  • 3. 333755Janssen BioPharma Inc, South San Francisco, CA, USA.
  • 4. 38200Janssen Pharmaceutical KK, Tokyo, Japan.
  • 5. 50148Janssen Pharmaceutica NV, Beerse, Belgium.
  • 6. Janssen-Cilag, Issy-les-Moulineaux, France.
  • 7. 17519Arrowhead Pharmaceuticals, Pasadena, CA, USA.
PMID: 35695169 DOI: 10.1177/13596535221093856
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.

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