Long-Term Efficacy and Quality of Life with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Prophylaxis in Pediatric, Adolescent, and Adult Subjects with Target Joints and Severe Hemophilia a
Authors: Wang Michael , Pasi K John , Pabinger Ingrid , Kerlin Bryce A. , Kulkarni Roshni , Nolan Beatrice , Liesner Raina , Brown Simon A , Hanabusa Hideji , Tsao Elisa , Winding Bent , Lethagen Stefan , Jain Nisha 
Published: October 2019

Abstract
Introduction: The completed Phase 3 A-LONG (NCT01181128) and Kids A-LONG (NCT01458106) studies established the safety and efficacy of rFVIIIFc among adults/adolescents and children with severe hemophilia A, respectively. Long-term safety and efficacy of rFVIIIFc are being evaluated in the ongoing ASPIRE extension study (NCT01454739). For people with hemophilia, frequent bleeding into the same joint (a target joint) may contribute to hemophilic arthropathy (chronic joint disease). Here we report longitudinal data from subjects with target joints at entry into A-LONG and Kids A-LONG throughout ASPIRE.
Methods: Subjects with ≥1 target joint (major joint with ≥3 bleeding episodes in a 6-mo period) at entry into the parent study (A-LONG or Kids A-LONG) with available prestudy (pre-parent study) and on-study data were evaluated. There are 4 treatment groups in ASPIRE for subjects ≥12 y: individualized prophylaxis (IP), weekly prophylaxis (WP), modified prophylaxis (MP; for subjects not achieving optimal prophylaxis, as intended by treating physician, with IP or WP), or episodic treatment. Subjects <12 y can participate in IP or MP. Outcomes evaluated included: annualized bleeding rate (ABR), number and resolution of target joint bleeding episodes, and prophylactic dose and dosing interval. Quality of life measures were assessed by Haem-A-QOL for prophylaxis subjects who were ≥17 y and had ≥1 resolved target joint during the study, with Haem-A-QOL scores both at A-LONG baseline and ASPIRE Year 2. Outcomes were analyzed over the cumulative duration of the parent study through the second ASPIRE interim data cut (8 Dec 2014).
Results: 113 subjects from A-LONG had target joints at baseline; 111 had prestudy and on-study data. These 111 subjects had 287 target joints at baseline (elbow [n=100; 34.8%], ankle [n=92; 32.1%], knee [n=63; 22.0%], shoulder [n=17; 5.9%], wrist [n=9; 3.1%], hip [n=6; 2.1%]). 13 subjects from Kids A-LONG had 15 target joints at baseline (ankle [n=10; 66.7%], elbow [n=4; 26.7%], knee [n=1; 6.7%]). Cumulative median (interquartile range [IQR]) duration of rFVIIIFc exposure was 157.2 (145.9-161.0) and 98.8 (26.3-103.9) weeks for subjects from A-LONG/ASPIRE and Kids A-LONG/ASPIRE, respectively. Median (IQR) on-study overall ABRs with rFVIIIFc prophylaxis were lower than bleeding rates with prestudy prophylaxis for adults/adolescents; on-study target joint and spontaneous target joint ABRs were low for adults/adolescents and children on prophylaxis (Figure). 46.3% of IP, 40.7% of WP, and 21.4% of MP A-LONG subjects had no target joint bleeding episodes; 53.8% of IP Kids A-LONG subjects had no target joint bleeding episodes. Among prophylaxis subjects with target joints at baseline and 12 months of follow-up, 100% (93/93) of A-LONG and 100% (7/7) of Kids A-LONG subjects had ≥1 target joint resolved (ie, ≤2 spontaneous bleeding episodes 12 consecutive mo); 98.3% (231/235) and 100% (9/9) of target joints (based on all bleeds) in A-LONG and Kids A-LONG subjects were resolved, respectively.Overall, median (IQR) prophylactic dose among prophylaxis subjects with target joints at baseline was similar to overall study populations (A-LONG: target joint, 76.0 [68.0-90.9] IU/kg; overall, 75.0 [70.0-113.8] IU/kg; Kids A-LONG: target joint, 83.5 [79.9-111.6] IU/kg; overall, 95.0 [75.0, 113.0] IU/kg). Median (IQR) dosing intervals were comparable (A-LONG: target joint, 3.8 [3.5-5.6] days and overall, 3.5 [3.0-5.0] days; Kids A-LONG: target joint, 3.5 [3.5-3.5] days and overall, 3.5 [3.5-3.5] days). Among the 48 subjects included in the Haem-A-QOL analysis, quality of life improved at ASPIRE Year 2 compared with A-LONG baseline (18% or 5.4 point reduction in total Haem-A-QOL score [P <0.05]). Domains reduced ≥6 points and ≥20% from baseline (P <0.05) included Feeling (toward hemophilia), Physical Health, Sports & Leisure, and Work & School.
Conclusion: Efficacy data from the phase 3 and extension trials show low target joint ABRs and effective target joint resolution in pediatric, adolescent, and adult subjects on long-term rFVIIIFc prophylaxis. Improvement in quality of life was seen in subjects with target joint resolution with rFVIIIFc prophylaxis.
This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and approved feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content.

Disclosures
Wang: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Pasi:Biogen: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Kerlin:Bayer Healthcare US: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring Foundation: Research Funding. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Nolan:Sobi: Research Funding; Biogen: Research Funding. Liesner:Grifols: Consultancy, Honoraria; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Cangene: Research Funding; BPL: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Brown:Baxter: Consultancy; Novo Nordisk: Consultancy; Biogen: Consultancy. Hanabusa:Bayer: Honoraria; KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Lethagen:Sobi: Employment. Jain:Biogen: Employment, Equity Ownership.