| dc.description.abstract | Haemophilia B is a rare X-linked bleeding disorder resulting from a deficiency of clotting factor IX (FIX), with severe haemophilia B defined as FIX levels < 0.01 IU/mL. Severe haemophilia is characterised by haemarthrosis, spontaneous and potentially life-threatening bleeds and in the longer term, progressive joint arthropathy. This results in chronic and acute pain, mobility problems and difficulties with activities of daily living (ADLs) and impacts on health-related quality of life (HRQOL).
The current standard of care for people with severe haemophilia B (PWSHB) is regular prophylaxis with recombinant factor IX (rFIX) administered intravenously to prevent bleeding, maintain joint health, and optimise outcomes. Prophylaxis with standard half-life (SHL) rFIX requires frequent intravenous infusion, usually self-administered twice or three times weekly, resulting in a considerable treatment burden. The development of extended half-life (EHL) products with longer terminal half-life and reduced clearance has permitted reduced frequency of administration. These EHL rFIX replacement therapies are becoming more widely used, but real-world experience remains limited, and questions remain, particularly around perioperative use.
In 2017, Ireland became the first country in the world whereby all PWSHB switched from SHL rFIX to recombinant factor IX Fc fusion protein concentrate (rFIXFc) prophylaxis. rFIXFc also became the primary treatment for all people with haemophilia B (PWHB) undergoing surgery requiring factor replacement. rFIXFc is a recombinant monomeric fusion protein composed of a single molecule of FIX covalently fused to the human IgG1 Fc domain, which binds to the neonatal Fc receptor delaying lysosomal degradation and extending the terminal half-life of FIX. Clinical trials have demonstrated safety and efficacy of rFIXFc, but there is a need to evaluate if these outcomes can be replicated in the real-world setting.
This thesis evaluates real-world outcomes in an unselected, national cohort of PWSHB (≥ 18 years) who switched from conventional SHL rFIX treatment to rFIXFc prophylaxis. We hypothesised that the switch to rFIXFc would result in higher rates of prophylaxis, improved adherence, less bleeding events with reduced infusions and factor usage, and this in turn, would result in overall improved HRQOL for PWSHB. Furthermore, we postulated that rFIXFc would provide equivalent haemostatic efficacy compared to SHL rFIX in the perioperative setting, but with the advantage of reduced infusion frequency.
The Long-Acting Factor 9 (LAF 9) study enrolled 28 PWSHB, representing 90% of the Irish adult population with severe haemophilia B. At two years following switchover, all participants continued rFIXFc prophylaxis, representing a 21% increase in rates of prophylaxis compared to those achieved with SHL rFIX. Annualised bleeding rates improved significantly on rFIXFc prophylaxis but importantly, with reduced infusion frequency and factor usage. This demonstrated that prophylaxis with an EHL rFIX is a viable long-term treatment option for all PWSHB, particularly those unable to receive regular prophylaxis with SHL rFIX due to venous access issues.
Patient reported outcomes (PROs), assessed using the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire, demonstrated a reduction in chronic pain and improvement in ADLs in PWSHB after switching to rFIXFc prophylaxis. Semi-structured qualitative interviews illustrated that switching to rFIXFc prophylaxis resulted in an improved sense of wellbeing.
Outcomes of PWHB who underwent surgical procedures with rFIXFc treatment for perioperative haemostasis management are also included in this thesis. Our data provides real-world evidence that rFIXFc is safe and effective in achieving haemostasis in PWHB undergoing surgery.
The LAF 9 study provides unique insights into real-world experience of switching to rFIXFc prophylaxis in an unselected cohort of PWSHB, demonstrating high rates of prophylaxis, reduced infusion frequency, reduced bleeding, and lower FIX consumption. It also demonstrates improvements in HRQOL and safe and efficacious management of PWHB perioperatively. | en |
