Molecular pathogenesis and therapeutic advances in haemophilia, an update of the current evidence

Table 4 Comparison of approved gene therapies for haemophilia A and B

Feature	Valoctocogene roxaparvovec (roctavian)[46,50,52,53]	Etranacogene dezaparvovec (hemgenix)[47-50]
Indication	HA	HB
Vector capsid	AAV5	AAV5
Transgene	B-domain-deleted FVIII, codon-optimized FVIII-SQ	FIX-Padua variant (R338 L), approximately 5-10 × higher specific activity
Mechanism of action	Hepatic expression of FVIII-SQ leads to endogenous FVIII production sufficient to convert severe HA to mild/normal range	Hepatic expression of FIX-Padua generates supraphysiologic FIX activity at low vector doses
Peak factor levels	Median FVIII 11.9%-62.3% at weeks 49-52 in phase 3	Approximately 30 IU/mL at 12 months across trials
Long-term factor expression	Decline over time typical: Approximately 50%-60% reduction from peak by 24 months	FIX expression more stable than FVIII; long-term persistence observed
Reduction in ABR	Meta-analysis: -7.58 treated bleeds/year; > 90% reduction in factor use	Meta-analysis: 5.64-fold ABR reduction; near-universal cessation of prophylaxis
Proportion of patients stopping prophylaxis	Majority (> 90%) discontinue FVIII prophylaxis	Majority discontinue FIX prophylaxis; FIX activity sufficient for stable haemostasis
Durability and challenges	Expression decline over several years; FVIII synthesis is hepatocyte-stressful (UPR/ER stress)	Durable expression; lower dose requirement improves safety margin
Key safety issues	Transaminase elevations common; very high vector dose raises hepatotoxicity concerns potential genomic integration events	ALT elevations possible but generally manageable lower vector dose reduces risk of hepatotoxicity
Advantages	First approved gene therapy for HA; major reductions in bleeding and factor use; high initial FVIII expression	High efficiency due to Padua transgene; stable FIX expression; very low dosing requirements

HA: Haemophilia A; HB: Haemophilia B; ALT: Alanine aminotransferase; ABR: Annualized bleeding rate.