Safety and efficacy of REP 2139-Mg in patients with HDV-related advanced liver disease in an international compassionate access program

Background & Aims REP 2139-Mg (REP), a nucleic acid polymer, blocks HBV subviral particle assembly and HDV replication. We report the outcomes of REP treatment in patients with HDV enrolled in a compassionate access program (NCT05683548). Methods Thirty-three patients with HDV and advanced chronic liver disease received weekly subcutaneous REP 250 mg plus a nucleotide analogue for a planned 48-week treatment course. Pegylated interferon-α (PegIFN) 45–180 μg weekly was added in 20 patients without contraindications. Safety and efficacy were assessed regularly, and intrahepatic markers were evaluated in one liver explant. Results Among the 33 patients (age 21–69 years; 21 males), 85% (28/33) had prior treatment failure, and six had decompensated cirrhosis (ascites in five). Suboptimal responses to REP were managed with dose modifications (250 mg intravenously or 500 mg subcutaneously or intravenously) and/or treatment extension in 21 patients. At end of therapy, HDV RNA declined by >2 log₁₀ in 70% (23/33) and became undetectable in 58% (19/33). HBsAg loss occurred in 27% (9/33). Among the 28 patients with available follow-up, HDV RNA and HBsAg remained undetectable in 46% (13/28) and 18% (5/28), respectively. ALT normalized in 50% (14/28). Responses were similar with or without PegIFN. Ascites improved in two of five affected patients. Three patients underwent liver transplantation while receiving REP without complications. In one liver explant, HDV RNA and HDAg were undetectable, and intrahepatic covalently closed circular DNA activity and HBsAg levels were very low. No REP-related serious adverse events were observed. Conclusions REP treatment was safe and effective in patients with HDV and advanced chronic liver disease. REP may induce sustained virological response of HDV and functional cure of HBV, independent of PegIFN co-administration. Clinical improvement may also occur in patients with decompensated cirrhosis. Impact and implications No approved antiviral therapy exists for patients with chronic hepatitis D (CHD) and decompensated cirrhosis, or for those who have failed bulevirtide and/or pegylated interferon. In the Replicor Compassionate Access Program, 33 patients with CHD and advanced chronic liver disease received REP 2139-Mg (REP) plus a nucleotide analogue, with or without pegylated interferon. HBsAg loss occurred in 27% at end of treatment and remained undetectable in 18% after 1 year, indicating sustained HDV virological response and HBV functional cure. Among six patients with decompensated cirrhosis, five achieved a virological response and two showed clinical improvement with reduced ascites. No REP-related serious adverse events were observed. Overall, REP demonstrated promising efficacy and acceptable tolerability in this difficult-to-treat population and warrants evaluation in a response-guided clinical trial.