Low Bleeding Rates with Increase or Maintenance of Physical Activity in Patients Treated with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the A-LONG and Kids A-LONG Studies
Authors: Quon Doris V. , Klamroth Robert , Kulkarni Roshni , Shapiro Amy D , Baker Ross I , Castaman Giancarlo , Kerlin Bryce A. , Tsao Elisa , Allen Geoffrey 
Published: October 2019

Abstract
Background: The phase 3 A-LONG and Kids A-LONG studies demonstrated low annualized bleeding rates (ABRs) with reduced infusion frequency rFVIIIFc prophylaxis 1-2 times/week in adults, adolescents, and children with severe hemophilia A. Median prestudy and on-study total weekly prophylactic factor consumption was comparable for subjects previously receiving FVIII prophylaxis.
Aims: To evaluate the effect of rFVIIIFc on subjects' physical activity across age groups using a subject-reported assessment and examine ABRs according to change in physical activity and prestudy treatment regimen (prophylaxis or episodic) in A-LONG and Kids A-LONG.
Methods: Previously treated males with severe haemophilia A (<1 IU/dL endogenous FVIII activity) were eligible for A-LONG (≥ 12 years of age) and Kids A-LONG (<12 years of age). A-LONG enrolled subjects into 1 of 3 arms: Arm 1, individualized prophylaxis; Arm 2, weekly prophylaxis; or Arm 3, episodic treatment. All subjects in Kids A-LONG received rFVIIIFc prophylaxis. There were no restrictions on physical activity in either study. Physical activity assessments were conducted at Weeks 7, 14, 28, 38, and 52 (A-LONG) and Weeks 2, 7, 12, 17, 22, and 26 (Kids A-LONG). At each visit after their first rFVIIIFc dose, subjects were asked to report their activity levels relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of activity. To summarize changes in physical activity throughout the study versus baseline, subjects were classified into 1 of 4 groups: more, same, less, or undetermined. Within treatment groups, prestudy and on-study ABRs were analyzed according to change in physical activity category and prestudy regimen. Analyses included all subjects who received ≥ 1 dose of rFVIIIFc during the efficacy period and who completed ≥ 1 physical activity assessment.
Results: This analysis included 163 subjects from A-LONG and 69 subjects from Kids A-LONG. The majority of subjects in both studies reported more or the same amount of physical activity; few subjects reported less physical activity (more, same, less, undetermined): A-LONG Arm 1 (n = 117), 51%, 36%, 8%, 5%; Arm 2 (n = 23), 39%, 48%, 9%, 4%; Arm 3 (n = 23), 26%, 52%, 9%, 13%; and Kids A-LONG (n = 69), 61%, 26%, 6%, 7%, respectively. Similar physical activity results were observed in subjects with target joints at baseline. Median ABRs were lower with rFVIIIFc prophylaxis in A-LONG for all categories of change in physical activity, regardless of prestudy regimen (Table). In Kids A-LONG subjects on prestudy prophylaxis who reported more or similar physical activity, median ABRs with rFVIIIFc were similar or lower than prestudy ABRs.
Summary/Conclusion: The majority of subjects in A-LONG (86%) and Kids A-LONG (87%) reported maintained or increased physical activity levels on-study, with low ABRs. These results suggest that people with severe hemophilia A across age groups may maintain or increase physical activity levels with rFVIIIFc while maintaining low bleeding rates with reduced infusion frequency.
Table 1. Prestudy and On-study Median (IQR) ABR by Physical Activity Level in A-LONG and Kids A-LONG Parent study: A-LONG Kids A-LONG On-study rFVIIIFc prophylaxis: Arm 1 (Individualized) Arm 2 (Weekly) Twice-weekly Prestudy FVIII regimen: Prophylaxis (n = 85)a Episodic (n = 31) Episodic (n = 23)b Prophylaxis (n = 62) Episodic (n = 7) Median (IQR) ABR by physical activity category More n = 38 n = 21 n = 9 n = 35 n = 7 Prestudy 6.0 (3.0, 15.0) 24.0 (17.0, 40.0) 25.0 (20.0, 30.0) 2.0 (1.0, 7.0) 12.0 (10.0, 16.0) On-study 2.15 (0, 5.42) 0 (0, 1.81) 1.93 (0, 3.59) 2.01 (0, 4.04) 2.05 (0, 3.96) Same n = 36 n = 6 n = 11 n = 18 n = 0 Prestudy 6.0 (1.0, 16.5) 33.0 (23.0, 42.0) 33.0 (16.0, 43.0) 2.0 (1.0, 3.0) On-study 2.76 (0, 6.06) 0.86 (0, 2.03) 4.34 (1.86, 7.62) 0 (0,0) Less n = 7 n = 2 n = 2 n = 4 n = 0 Prestudy 2.0 (1.0, 9.0) 66.5 (13.0, 120.0) 37.5 (23.0, 52.0) 1.5 (0.5, 3.5) On-study 0 (0, 3.78) 0.72 (0, 1.44) 15.04 (8.36, 21.71) 4.07 (1.01, 8.31) Undetermined n = 4 n = 2 n = 1 n = 5 n = 0 Prestudy 21.5 (6.0, 40.5) 25.5 (14.0, 37.0) 29.0 3.0 (2.0, 4.0) On-study 2.80 (1.50, 7.55) 0 (0,0) 4.02 4.18 (2.01, 6.41) ABR, annualized bleeding rate; IQR, interquartile range. aOne subject did not have prestudy ABR data available and was excluded from the analysis. bAll subjects in Arm 2 received prior episodic treatment.

Disclosures
Quon: Baxter, Biogen, and Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Speakers Bureau. Klamroth:Biogen and SOBI: Honoraria, Speakers Bureau; Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau. Kulkarni:BPL: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding, Speakers Bureau. Shapiro:Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees; Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding. Baker:Novo Nordisk: Other: conference travel support; Bristol- Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: conference travel support, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support , Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Portola Pharmaceuticals: Research Funding; Astellas: Research Funding; CSL Behring: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support. Castaman:Bayer, Baxalta, CSL Behring, Kedrion, Novo Nordisk, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Kerlin:Bayer Healthcare US and Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding. Tsao:Biogen: Employment, Equity Ownership. Allen:Biogen: Employment, Equity Ownership.