AAV gene therapy in hemophilia B shows robust bleeding reduction and variable factor IX expression: A bayesian meta-analysis of randomized controlled trials

Abstract

Abstract Introduction Hemophilia B, a congenital X-linked bleeding disorder caused by factor IX (FIX) deficiency, poses significant challenges despite advances in prophylactic factor replacement therapy. Gene therapy, leveraging adeno-associated virus (AAV) vectors to restore FIX expression, has emerged as a transformative approach, with pivotal trials like HOPE-B, BENEGENE-2, and 101HEMB01/02 demonstrating potential to reduce bleeding rates and improve quality of life. However, variability in efficacy, safety, and long-term outcomes across these studies underscores the need for a robust synthesis. This Bayesian meta-analysis integrates data from these trials to provide a clinically actionable assessment of gene therapy's impact on annualized bleeding rate (ABR), FIX activity levels, and zero-bleed achievement, addressing heterogeneity and informing therapeutic decision-making in hemophilia B management. Methods We performed a Bayesian meta-analysis of three trials—HOPE-B, BENEGENE-2, and 101HEMB01/02—comparing gene therapy with AAV vectors (AAV5, AAV-Spark100, and AAVrh10, respectively) to baseline or prophylactic treatment in hemophilia B patients. Outcomes included ABR reduction (expressed as -log(rate ratio), where positive values favor gene therapy), mean FIX activity levels (%), and log relative risk of achieving zero bleeds (positive values indicating higher zero-bleed proportions). A random-effects model within a hierarchical Bayesian framework was utilized, employing shrinkage estimation to adjust individual study effects toward a pooled mean. Non-informative priors were applied for the pooled effect and between-study variance (tau), with 95% credible intervals (CrI) and prediction intervals derived from posterior distributions. Heterogeneity was quantified using tau, and subgroup analyses explored influences of vector serotype, dose, and trial phase (phase 1/2 vs. phase 3). Analyses were conducted using R 4.5.1 with data sourced from published trial reports as of August 06, 2025. Outcomes The meta-analysis encompassed 142 patients across the trials. For ABR reduction, the pooled -log(rate ratio) was 0.97 [95% CrI: 0.21, 1.71], with shrinkage-adjusted estimates of 0.83 [95% CrI: 0.43, 1.23] for HOPE-B, 1.30 [95% CrI: 0.72, 1.88] for BENEGENE-2, and 0.88 [95% CrI: -0.25, 2.01] for 101HEMB01/02, indicating a significant reduction in bleeding events with gene therapy, as the pooled CrI excludes zero. The prediction interval was 0.97 [-0.47, 2.38], suggesting potential variability in future studies. Heterogeneity was low (tau = 0.33 [0.00, 1.17]). For FIX activity levels, the pooled mean was 5.35 [95% CrI: 1.66, 9.01], with estimates of 39.00 [95% CrI: 36.33, 41.67] for HOPE-B, 27.00 [95% CrI: 24.66, 29.34] for BENEGENE-2, and 2.00 [95% CrI: 1.35, 2.65] for 101HEMB01/02, reflecting substantial variation likely due to vector and dosing differences. The prediction interval was 5.40 [-7.37, 17.95], with high heterogeneity (tau = 6.1 [5.1, 7.2]). For zero-bleed achievement, the pooled log relative risk was 0.61 [95% CrI: -0.19, 1.33], with estimates of 0.78 [95% CrI: 0.20, 1.35] for HOPE-B, 0.59 [95% CrI: -0.02, 1.21] for BENEGENE-2, and 0.22 [95% CrI: -1.09, 1.54] for 101HEMB01/02, suggesting a potential benefit, though the CrI crosses zero. The prediction interval was 0.62 [-0.85, 1.95], with low heterogeneity (tau = 0.30 [0.00, 1.16]). Conclusion This Bayesian meta-analysis robustly affirms that gene therapy significantly reduces ABR in hemophilia B, offering a paradigm shift from traditional prophylaxis, with consistent evidence across trials. Elevated FIX activity levels, particularly in phase 3 trials, support durable expression, though variability highlights the need for optimized vector and dosing strategies. The uncertain benefit in zero-bleed achievement calls for larger studies to confirm clinical relevance. These findings advocate for integrating gene therapy into clinical guidelines, with a focus on personalized approaches to maximize efficacy and safety, potentially revolutionizing hemophilia B management.