Adeno-associated virus gene therapy for hemophilia B: a comparative appraisal of the licensed products

Among the inherited bleeding disorders, hemophilia B has become the leading target for adeno-associated virus (AAV) gene therapy. The compact factor IX (FIX) coding sequence, the abundance and durability of hepatocyte-derived FIX expression and the hyperactive FIX-Padua variant together made single-infusion phenotypic correction achievable earlier and more convincingly for FIX deficiency than for factor VIII (FVIII) deficiency. Three FIX-Padua AAV products have reached regulatory approval: etranacogene dezaparvovec, licensed in the United States, Canada and Europe; fidanacogene elaparvovec, initially licensed in the same regions but discontinued worldwide by its manufacturer; and dalnacogene ponparvovec (BBM-H901), licensed in China. This review outlines the biological differences between FVIII and FIX, the immunological and analytical challenges common to all AAV FIX products, and the pivotal trial data for each licensed therapy. Because FIX-Padua activity is reagent dependent, activity is standardized throughout to a single one-stage scale (HemosIL SynthASil), permitting a like-for-like comparison: mean activity 27-55 IU/dL, annualized bleeding rates 0.6-1.5 and reductions in FIX consumption exceeding 90% for all three products, sustained to five years for etranacogene dezaparvovec and six for the fidanacogene elaparvovec phase 1/2a cohort. Only dalnacogene ponparvovec has published data in adolescents. The review compares the three products' capsids, genome configurations, doses, impact of pre-existing anti-AAV immunity and immunomodulation, and weighs their reassuring but surveillance-dependent long-term safety, including the theoretical risk of insertional oncogenesis. Finally, it considers why the clearest efficacy successes have coincided with limited real-world uptake, and what the divergent commercial and regulatory trajectories imply for equitable global access.

Abstract from PubMed (PMID 42984386). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.