The Critical Need to Consolidate All Gene Therapy Data in Haemophilia

Authors: Konkle, B; Coffin, D; Hermans, C; Naccache, M; O’Mahony, B; Pierce, GF.

Affiliations: World Federation of Hemophilia, Montreal, Quebec, Canada.

Publication: Haemophilia. 2025

ABSTRACT: Gene therapy for haemophilia has been in development for several decades, with the first clinical attempts initiated in the 1990s [1]. These early studies, including six initial trials, laid the foundation for subsequent systemic liver-directed adeno-associated virus (AAV) trials that ultimately led to regulatory approvals. A pivotal milestone came in 2011 with the publication by Nathwani et al. [2], which demonstrated the first successful systemic AAV8-FIX gene therapy for haemophilia B, achieving sustained therapeutic factor IX levels with immune modulation using prednisolone. Since then, 16 gene therapy products (seven for haemophilia A (PWH-A) and nine for haemophilia B (PWH-B)) have been assessed in 20 distinct trials (8 HEM-A, 12 HEM-B) [3], with more clinical trials expected in the future. Of these, three advanced to Phase III clinical trials (valoctocogene roxaparvovec, fidanacogene elaparvovec, and etranacogene dezaparvovec) while the remaining products did not progress beyond Phase I or II. One of the products among those that advanced to Phase III clinical trial was subsequently discontinued by the manufacturer after receiving regulatory approval but before any commercial dosing took place [4]. As a result, only two gene therapy products, from two manufacturers, are currently approved and available in some jurisdictions, primarily within FDA- and EMA-regulated markets.