siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares

Wedemeyer H., Gane E., Agarwal K., TABAK Ö. F., Forns X., Akarca U. S., ...More

Journal of Hepatology, 2026 (SCI-Expanded, Scopus)

  • Publication Type: Article / Article
  • Publication Date: 2026
  • Doi Number: 10.1016/j.jhep.2026.05.007
  • Journal Name: Journal of Hepatology
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE
  • Keywords: chronic hepatitis B, chronic hepatitis D, DAP/TOM, daplusiran, HBV, hepatitis D virus, HDV replication, JNJ-3989, tomligisiran
  • Karadeniz Technical University Affiliated: Yes

Abstract

Background & Aims HDV requires HBsAg for viral assembly. The siRNA JNJ-73763989 (JNJ-3989) targets all HBV transcripts and reduces HBsAg in patients with chronic hepatitis B. We evaluated whether HBsAg reduction with JNJ-3989 leads to a decline in HDV RNA and ALT in patients with chronic hepatitis D (CHD). Methods REEF-D, a two-part, phase II, randomized, double-blind, placebo-controlled study, enrolled 22 adults with CHD in Part 1. Participants were randomized 4:1 to receive JNJ-3989 (100 mg subcutaneously every 4 weeks) + nucleos(t)ide analogue (NA) for 144 weeks (active arm, n = 17) or for 96 weeks after 52 weeks of placebo + NA (deferred treatment arm, n = 5). During the 48-week follow-up period, NA therapy was continued. The primary endpoint was achievement of a ≥2 log10 IU/ml reduction of HDV RNA from baseline (or 10,000 IU/ml) at screening experienced unexpected ALT elevations, sometimes severe, with a return to baseline levels after discontinuation of JNJ-3989. Both HDV RNA reduction and ALT elevation are critical observations for a better understanding of HDV biology and the interplay between viral antigens and the infected hepatocyte. Despite the low sample size and majority of participants not completing the planned treatment course, these findings are important for caregivers and researchers developing novel treatment strategies for patients with chronic hepatitis D.