Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB

Yuen, Man‐Fung; Locarnini, Stephen; Lim, Tien Huey; Strasser, Stephan; Sievert, William; Cheng, Wendy; Thompson, Alex; Given, Bruce D.; Schluep, Thomas; Hamilton, James; Biermer, Michael; Kalmeijer, Ronald; Beumont, Maria; Lenz, Oliver; Ridder, Filip De; Cloherty, Gavin; Wong, Danny Ka‐Ho; Schwabe, Christian; Jackson, Kathy Merlock; Lai, Ching Lung; Gish, Robert G.; Gane, Edward

doi:10.1016/j.jhep.2022.07.010

Cited by 62 publications

(55 citation statements)

References 24 publications

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“…All TEAEs were of mild severity and resolved by study end, and no SAEs or AEs resulted in early study discontinuation or death. This is consistent with results from other studies of JNJ‐73763989, wherein reported AEs were also mostly mild to moderate, and few participants ended treatment early 6–9,11 …”

Section: Discussionsupporting

confidence: 91%

Pharmacokinetics, Safety, and Tolerability of the siRNA JNJ‐73763989 in Healthy Chinese Adult Participants

Niu

Zhang

et al. 2022

Clinical Pharm in Drug Dev

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JNJ‐73763989, composed of the 2 short‐interfering RNA triggers JNJ‐73763976 and JNJ‐73763924, targets all hepatitis B virus messenger RNAs, thereby reducing all viral proteins. In this phase 1, single‐site, open‐label, parallel‐group, randomized study, participants were given 1 subcutaneous injection of JNJ‐73763989 (100 or 200 mg) to investigate the pharmacokinetics, safety, and tolerability of JNJ‐73763989 in healthy Chinese adult participants. Plasma and urine pharmacokinetic parameters were determined for each trigger up to 48 hours after dosing. Eighteen participants, 9 per dose group, were enrolled. The median age and weight were 33.0 years and 73.65 kg; 83.3% were male. Exposure of both triggers increased dose proportionally. Median time to maximum concentration ranged from 6.0 to 10.0 hours, and mean elimination half‐life ranged from 4.5 to 4.8 hours across both triggers and doses. Mean urinary excretion for JNJ‐73763976 and JNJ‐73763924 ranged from 17.7% to 19.4% and 13.1% to 13.2% for the 100‐ and 200‐mg dose groups, respectively. All treatment‐emergent adverse events (AEs) were mild and resolved by study end, and no AEs or serious AEs resulted in premature study discontinuation or death. Overall, the pharmacokinetics of JNJ‐73763989 in healthy Chinese participants were consistent with previous studies, and JNJ‐73763989 was generally safe and well tolerated after a single dose.

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Section: Discussionsupporting

confidence: 91%

Pharmacokinetics, Safety, and Tolerability of the siRNA JNJ‐73763989 in Healthy Chinese Adult Participants

Niu

Zhang

et al. 2022

Clinical Pharm in Drug Dev

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“…In the CHB patient cohort (12 patients who all received JNJ-73763989 200 mg, JNJ-56136379 and an NA) from the non-Japanese study, 2/12 (16.7%) patients experienced at least one TEAE through Day 112, both were of mild severity and considered not related to treatment. One patient experienced an upper respiratory tract infection and one patient hypertension [24].…”

Section: Resultsmentioning

confidence: 99%

“…Grade 1 transient isolated ALT elevations (57–112 U/L) were reported in 5/12 patients with CHB. All elevations were resolved during continued dosing [24].…”

Section: Resultsmentioning

confidence: 99%

“…Evaluation of the antiviral activity of JNJ-73763989 is ongoing; significant antiviral activity of the predecessor siRNA, ARC-520, was shown in two clinical trials in patients with CHB [28], as well as in a long-term follow-up study [29]. The phase 2a part of the non-Japanese study described herein is evaluating the antiviral activity of JNJ-73763989, in combination with an NA (with or without JNJ-56136379), in patients with CHB [24]. Separately, large phase 2b studies in patients with CHB, the REEF-1 (NCT03982186) and REEF-2 (NCT04129554) studies, are underway evaluating the safety and efficacy of 48 weeks of combination therapy with JNJ-73763989 and an NA, with and without JNJ-56136379, alongside therapy with JNJ-56136379 and an NA.…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2022

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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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“…Notably, the benchmark of ≥30% patients achieving this endpoint 4 has not been met by any of the currently developing novel compounds, despite initial promising results in qHBsAg knockdown by RNA interference-based therapy. 5,6 This has engendered discussions about the practicability of such stringent treatment endpoint. 7 Taking a step back, a 'looser' endpoint of achieving serum qHBsAg <10 IU/mL or <100 IU/mL (HBsAg cut-off levels still subjected to debate) by novel compounds might be more feasible, as such endpoint implies that a patient with CHB had a lower risk of off-therapy virological relapse and can potentially employ the 'stop-to-cure' approach to induce functional cure.…”

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confidence: 99%

Correspondence on Editorial regarding “HBV pgRNA and HBcrAg reductions at week 4 predict favourable HBsAg response upon long-term nucleos(t)ide analogue in CHB”

2023

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We sincerely appreciate the editorial piece from Liang, Wong, Wong and Yip 1 reviewing our recent paper on the role of early on-treatment decline in viral biomarkers in predicting favourable HBsAg response in chronic hepatitis B infection, published in Clinical and Molecular Hepatology. 2 We agree with Liang and co-authors on the potential use of hepatitis B core-related antigen (HBcrAg) and hepatitis B virus (HBV) pre-genomic RNA (pgRNA) in multiple facets of management in the clinical context of chronic hepatitis B (CHB) infection. Our study provided serum-liver correlations in the magnitude of decline in viral biomarkers upon nucleos(t)die analogue (NA) treatment

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Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB

Cited by 62 publications

References 24 publications

Pharmacokinetics, Safety, and Tolerability of the siRNA JNJ‐73763989 in Healthy Chinese Adult Participants

Pharmacokinetics, Safety, and Tolerability of the siRNA JNJ‐73763989 in Healthy Chinese Adult Participants

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

Correspondence on Editorial regarding “HBV pgRNA and HBcrAg reductions at week 4 predict favourable HBsAg response upon long-term nucleos(t)ide analogue in CHB”

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