HHE Haematology supplement 2018 - Page 14

haemophilia A). rFVIIIFc has a lower clearance, compared with conventional rFVIII therapies, of approximately 33%, as well as 1.5-fold longer half-life and a greater mean elimination half-life (19.0 versus 12.4 hours) in adults and adolescents with haemophilia A. 3 There is also potential to individualise dosing with rFVIIIFc according to according to clinical and patient objectives, either by reducing the number of injections per week and/or weekly consumption while at least maintaining the desired trough level, based on modelling of pharmacokinetic profiles of patients receiving FVIII replacement in the Phase I/IIa and Phase III studies. 2,4,5 Recombinant factor IX Fc fusion protein (rFIXFc; Alprolix ® , approved in 2016 for the treatment of haemophilia B) also demonstrates a reduced clearance and prolonged half life when compared with conventional rFIX. 6 Clinical experience with recombinant Factors VIIIFc and FIXFc rFVIIIFc and rFIXFc were evaluated in the pivotal Phase III A-LONG (NCT01181128) and B-LONG (NCT01027364) studies 3,6 and paediatric studies 7,8 (NCT01458106 and NCT01440946). Extension studies (NCT0145473 and NCT01425723) have also been conducted 9,10 in haemophilia A and B. Overall, rFVIIIFc and rFIXFc count with >3.5 and ~4.0 years of real-world evidence, respectively (Figure 2). 11–14 Data from the Phase III A-LONG trial showed a median ABR for rFVIIIFc of 1.6 for patients on individualised prophylactic treatment and 3.6 for those receiving a weekly prophylactic regimen vs. 33.6 for patients receiving on-demand treatment. The median rates for annualised spontaneous bleeding and joint bleeding were zero, and 45.3% of patients experienced no bleeding episodes. Moreover, the majority of the bleeding episodes was controlled with 1–2 injections of clotting factor. 3 A post hoc analysis of A-LONG data showed reduced ABRs with individualised rFVIIIFc prophylaxis in the last three months of the study, compared to before the study, with a median dosing interval of 3.5 days and 98.8% of the patients decreasing injection frequency. 3,15 A post-hoc analysis of data showed prophylaxis with rFVIIIFc also resulted in continuous improvements in the Modified Haemophilia Joint Health scores (mHJHs) during the extension study (ASPIRE), which was approximately 4 years in adults and adolescents, and 3 years in children. The components of the mHJHs showing the greatest improvements were swelling, range of motion, and strength, with a mean change in total score from the A-LONG baseline of –4.1 after 2 years. 16,17 In addition, health-related QoL scores in the sports and leisure, physical health, and feeling subdomains in the Haem-A-QoL questionnaire also improved over time. 18 Compared with conventional rFIX therapies, rFIXFc presented a 4.8 longer half-life, with reduced ABRs in adults and adolescents in the Phase III B-LONG study (reduction by 83% and 87% for weekly and interval-adjusted prophylaxis compared with episodic treatment); the median prophylactic dosing interval in this study was 14 days, achieved by 53.8% of the patients in the last three months of treatment. 6,19 Subsequent analysis showed that more than three-quarters of patients receiving prophylaxis continued or increased their physical activity, and physical health and sports and leisure scores also improved in the B-LONG study. 20,21 Additionally, rFIXFc shows efficacy when used for perioperative management, with haemostasis rated as ‘excellent’ by investigators in the majority of major and minor surgeries from the pre- operative dose until the end of the procedure with a single infusion, and no serious adverse events deemed to be related to the blood coagulation factor or the development of neutralising inhibitor antibodies. 10,22,23 rFVIIIFc also showed efficacy in the perioperative management of major and minor surgeries. 3,7,9,24 Finally, interim data from the ASPIRE and B-YOND extension studies confirmed the long- term safety of both products, with no inhibitor development during the parent studies, 9,10 and real-world surveillance data confirms the unchanged benefit–risk profiles. 11–14 rFVIIIFc and rFIXFc are currently being tested in previously untreated patients in the PUPs A-LONG (NCT02234323) and PUPs B-LONG (NCT02234310) studies. rFVIIIFC is not approved for immune tolerance induction (ITI) in haemophilia patients with inhibitors; however, two prospective studies are ongoing to assess rFVIIIFc for ITI in patients with severe haemophilia A who are undergoing the first treatment for ITI (NCT03093480) or who have failed prior ITI therapy (NCT03103542). figure 2 Clinical experience with rFVIIIFc in haemophilia A and rFIXFc in haemophilia B Previously treated patients Phase I/IIa study Complete Phase III pivotal study Complete Phase III paediatric study Complete Phase extension study Complete – interim results available, clinical observation period of >4 years Real-world experience >3.5 and ~4 years of real-world use with Elocta and Alprolix respectively with unchanged risk-benefit profile (as of February 2018) 14 HHE 2018 | hospitalhealthcare.com