Extended Half-Life Factor Concentrates in Haemophilia Treatment

For prevention of musculoskeletal bleeds in patients with severe and moderate haemophilia A (HA) or B (HB), prophylaxis is recommended. Clotting factor concentrates with standard half-life (SHL) necessitate frequent infusions associated with high treatment burden, leading to the development of extended half-life (EHL) factor concentrates and non-factor therapies (NFT).

This review aimed to summarize knowledge on EHL for HA and HB. Those employ fragment crystallizable fusion, albumin fusion or PEGylation to extend half-life and reduce clearance. Half-life extension for factor VIII (FVIII) has been limited due to binding to and elimination with endogenous von Willebrand factor (VWF). With linking the FVIII molecule to a D'D3 domain of the VWF, binding to endogenous VWF is inhibited, enabling the development of a FVIII concentrate with an ultra-long half-life. EHL allows less frequent prophylaxis, and clinical trials and real-world data show reduced ABR, better joint outcomes, improved adherence and better patient-reported health-related quality of life. Inhibitor rates in previously treated patients are very low and seem to be similar or lower compared to SHL recombinant FVIII (rFVIII) in previously untreated patients, but robust head-to-head comparative data are limited. Close monitoring remains essential. For PEG-containing products, extensive non-clinical and clinical experience has not identified clear PEG-related organ toxicity in humans, but theoretical concerns about life-long exposure, rare anti-PEG antibody-mediated loss of efficacy, and potential tissue accumulation mean that careful pharmacovigilance and monitoring of recovery and clinical response are still recommended, especially in young children.

EHL enables efficacious and safe prophylaxis as well as bleed treatment with the possibility of individualization. With improved ABRs, joint health and low treatment burden, they prove clinical benefit compared to SHL and coexist with NFT.