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

Abstract

Background & aims: RNA interference therapy has been shown to reduce hepatitis B surface antigen (HBsAg) levels in preclinical models, which could confer functional cure in patients with chronic hepatitis B. This phase IIa trial (ClinicalTrials.gov Identifier: NCT03365947) assessed the safety and efficacy of the small-interfering RNA JNJ-73763989 (JNJ-3989) plus a nucleos(t)ide analogue (NA), with/without the capsid assembly modulator JNJ-56136379 (JNJ-6379) in patients with chronic hepatitis B.

Methods: Treatment-naïve and NA-suppressed patients received 3 subcutaneous JNJ-3989 doses every week (QW; 100, 200, or 300 mg), 2 weeks (Q2W; 100 mg) or 4 weeks (Q4W; 25, 50, 100, 200, 300, or 400 mg), or JNJ-3989 Q4W (200 mg) plus oral JNJ-6379 250 mg daily for 12 weeks. Patients received NAs throughout.

Results: Eighty-four patients were recruited. All treatments were well tolerated, with all 5 serious adverse events considered unrelated to study drugs. JNJ-3989 100 to 400 mg Q4W resulted in HBsAg reductions ≥1 log10 IU/ml from baseline in 39/40 (97.5%) patients at the nadir. All patients receiving the triple combination (n = 12) had HBsAg reductions ≥1 log10 IU/ml from baseline at the nadir. HBsAg reductions were similar for HBeAg-positive (n = 21) and HBeAg-negative (n = 47) patients in all JNJ-3989 Q4W treatment arms, including the triple combination (n = 68). Smaller HBsAg reductions were seen with 25 mg (n = 8) and 50 mg (n = 8) than with 100 to 400 mg (n = 40). Shorter dosing intervals (QW [n = 12] and Q2W [n = 4]) did not improve response vs. Q4W dosing. HBsAg reductions ≥1 log10 IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose.

Conclusions: JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose.

Clinical trial number: NCT03365947.

Lay summary: Hepatitis B virus affects people's livers and produces particles called hepatitis B surface antigen (HBsAg) that damage a person's liver and can help the virus infect a person for a long time, known as chronic hepatitis B (CHB). In this study, a new treatment called JNJ-3989 was assessed (in combination with normal treatment known as nucleos(t)ide analogues), for its safety and effectiveness in reducing the number of HBsAg particles in people with CHB. The results of this study showed that treatment with JNJ-3989 could be safe for people with CHB, lowered their HBsAg levels, and kept HBsAg levels lowered for 336 days in 38% of patients after receiving their last dose of JNJ-3989.

Keywords: Hepatitis B virus; JNJ-3989; RNA interference; antiviral therapy; chronic hepatitis B; hepatitis B surface antigen.

Conflict of interest statement

Conflicts of interest MFY serves as advisor/consultant for AbbVie, Arbutus Biopharma, Allovir International, Aligos Therapeutics, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, and Roche and received grant/research support from Assembly Biosciences, Arrowhead Pharmaceuticals, Dicerna Pharmaceuticals, Gilead Sciences, Merck Sharp and Dohme, Roche, and Vir Biotechnology. SS received honoraria for advisory boards or speaker fees from AbbVie, AstraZeneca, Bayer, BMS, Chiesi, CSL Behring, Dr Falk, Eisai, Gilead, Ipsen, MSD, Pfizer, and Roche Products. WS received payments from Janssen for providing a clinical site for the current study. AJT served on advisory boards for Janssen, Gilead, AbbVie, Merck, BMS, Roche, Bayer, Eisai, Roche Diagnostics, and Assembly Biosciences; received speaker fees from Gilead, AbbVie, Merck, Roche, and BMS; received institutional research grants from NHMRC/MRFF, Gilead Sciences, and Roche Diagnostics; and serves as a board member and director of the Gastroenterological Society of Australia. BG, TS, and JH are current or former employees of Arrowhead and may be Arrowhead shareholders. MB, RK, MB, OL, and FDR are current or former employees of Janssen Pharmaceuticals and may be Johnson & Johnson stockholders. GC is an Abbott employee and shareholder. KJ receives funding from SpringBank Pharmaceuticals. CLL discloses sponsored lectures for Gilead Sciences. RGG is/has been a consultant and/or advisor to Abbot, AbbVie, Access Biologicals, Alexion, Antios, Arrowhead, Bayer AG, Bristol Myers Squibb, Eiger, Eisai, Enyo, eStudySite, Forty-Seven Inc, Gilead Sciences, HepaTX, HepQuant, Intercept, Ionis Pharmaceuticals, Janssen, Laboratory for Advanced Medicine, Lilly, Merck, Salix, Shionogi, and Trimaran and Viking Therapeutics; provides consulting for ADMA Biologics, AEC Partners, Arena Pharmaceuticals Inc, Arterys Inc, Cirina, Consumer Health Products Assoc, DRG Abacus, Intellia, Iqvia, KannaLife, Labyrinth Holdings, Organovo, Patient Connect and Spring Bank; is on scientific or clinical advisory boards for Abbott, AbbVie, Merck, Arrowhead, Bayer, Dova Pharmaceuticals, Eiger, Enyo, Hatch Biofund, HepQuant, Intercept, Janssen, and Medimmune; is an advisory consultant for Biocollections, Fujifilm/Wako, and Quest; is chair of the clinical advisory board for Prodigy, is on the data safety monitoring board for Altimmune, Arrowhead, CymaBay Therapeutics, and Durect; has speaker contracts with AbbVie, Bayer, Bristol Myers Squibb, Dova Pharmaceuticals, Eisai, Genentech, Gilead, Intercept, Salix, and Shionogi; is a minor stock shareholder in Athenex, Cocrystal, RiboSciences, and Triact; and holds stock options in Athenex, Eiger, HepaTx, and HepQuant; over 80% of income from Pharma received by RGG is directed to research, education, public policy, and/or donated to charities. EG has been an advisor and/or speaker for AbbVie, Arrowhead, Assembly, Gilead, GSK, Janssen, Merck, Novartis, Roche, and Vir Biotechnology. SL, THL, WC, CS, and DKHW have no disclosures to report. Please refer to the accompanying ICMJE disclosure forms for further details.

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