Liver concentrations of JNJ-73763989 siRNA triggers in patients with chronic hepatitis B (CHB): The INSIGHT study panel 3 results

Background JNJ-73763989 is a 2:1 combination of 2 N-acetylgalactosamine (GalNAc)–conjugated short interfering RNAs (siRNA) targeting the S (daplusiran) and X (tomligisiran) regions of the hepatitis B virus genome. In phase 2b studies, 48 weeks of JNJ-73763989-based combination treatments led to dose-dependent reductions in viral markers, including hepatitis B surface antigen. The objective of the INSIGHT study Panel 3 was to quantify intrahepatic concentrations of the siRNAs in human livers during and after treatment. Methods In the open-label, single-arm, single-center study, participants with chronic hepatitis B received 48 weeks of treatment with JNJ-73763989 200 mg every 4 weeks and nucleos(t)ide analog, with optional pegylated interferon α2a 180 µg weekly added after Treatment Week (TW) 40. Core liver biopsies were collected at TW12, TW40, and at Follow-up Week (FUW) 24. Results Liver biopsies were available from all 4 participants at TW12 and from 3 at TW40 and FUW24. Between TW12 and TW40, liver concentrations of daplusiran and tomligisiran increased 1.5- to 2.6-fold, consistent with intrahepatic accumulation. Twenty-eight weeks after the last injection of JNJ-73763989, the triggers were still measurable in 2 of 3 participants with 4.5- to 15-fold reduced concentrations from peak levels; the estimated liver half-life ranged from approximately 2.9 to 16.1 weeks. Conclusions In this first study to assess liver concentrations of GalNAc-siRNA in humans with sequential biopsies, long persistence of JNJ-73763989 triggers in human livers may partially explain the prolonged suppressive effect on viral parameters observed in phase 2 studies.