JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2

Background & Aims: Achieving a functional cure for chronic hepatitis B (CHB) requires finite-duration treatment. Two investigational agents aimed at achieving this goal are the small-interfering RNA JNJ-73763989 (JNJ-3989) and the capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir).
Methods: The REEF-2 study, a phase IIb, double-blind, placebo-controlled, randomized trial, enrolled 130 patients with CHB who were hepatitis B e-antigen (HBeAg)-negative and suppressed on nucleos(t)ide analogues (NAs). Participants received either JNJ-3989 (200 mg subcutaneously every 4 weeks) + JNJ-6379 (250 mg orally daily) + NA (active arm) or placebo for JNJ-3989 and JNJ-6379 + active NA (control arm) for 48 weeks, followed by a 48-week off-treatment follow-up.
Results: At Week 24 of follow-up, no patients achieved the primary endpoint of functional cure, defined as off-treatment hepatitis B surface antigen (HBsAg) seroclearance. Similarly, no functional cure was observed by Week 48 of follow-up. However, at Week 48 of treatment, the active arm demonstrated a significant reduction in mean HBsAg levels compared to baseline (1.89 vs. 0.06 log₁₀ IU/ml; p = 0.001). By Week 48 of follow-up, 81.5% of patients in the active arm had HBsAg reductions >1 log₁₀ IU/ml, compared to 12.5% in the control arm. Additionally, 38/81 (46.9%) patients in the active arm achieved HBsAg levels <100 IU/ml, versus 6/40 (15.0%) in the control arm. Off-treatment HBV DNA relapses and alanine aminotransferase (ALT) flares were less frequent in the active arm, with only 7/77 (9.1%) and 11/41 (26.8%) patients restarting NAs in the active and control arms, respectively, during follow-up.
Conclusions: Finite 48-week treatment with JNJ-3989 + JNJ-6379 + NA was associated with fewer and less severe post-treatment HBV DNA relapses and ALT flares, as well as higher rates of off-treatment HBV DNA suppression and reductions in HBsAg levels. However, functional cure was not achieved.
Impact and Implications: Functional cure for CHB remains an unmet medical need. This study evaluated the efficacy of JNJ-3989 and JNJ-6379 combined with NAs in achieving functional cure and improving clinical outcomes after treatment discontinuation. While no patients achieved functional cure, the regimen demonstrated substantial reductions in HBsAg levels, maintained up to 48 weeks post-treatment, alongside fewer HBV DNA relapses and ALT flares. These findings provide important insights for future research on finite treatment strategies and offer clinically relevant data for healthcare providers managing patients with NA-suppressed HBeAg-negative CHB.