Clinical Outcomes in Children with Hemophilia B Treated Long Term with rFIXFc: Interim Results of the B-YOND Extension Study
Authors: Kulkarni Roshni , Nolan Beatrice , Bennett Carolyn M. , Fischer Kathelijn , Perry David J , Barnes Christopher , Yuan Huixing , Ramirez-Santiago Alejandra , Pierce Glenn F , Mei Baisong 
Published: October 2019

Abstract
Background: Early prophylactic replacement of coagulation factor IX (FIX) improves clinical outcomes in children with hemophilia B; however, frequent intravenous infusions (2-3 times/week) are often required due to the short half-life of conventional FIX products. Recombinant FIX Fc fusion protein (rFIXFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FIX.The phase 3 Kids B-LONG study (NCT01425723) demonstrated the safety, efficacy and prolonged half-life of once weekly recombinant factor IX Fc fusion protein (rFIXFc) in children aged <12 years with hemophilia B (endogenous FIX ≤2 IU/dL). Here, we report interim safety and efficacy data for children enrolled in the ongoing rFIXFc extension study, B-YOND (NCT01425723).
Methods: Upon completing Kids B-LONG, eligible subjects could participate in one of 3 treatment groups in B-YOND: weekly prophylaxis (WP; 20-100 IU/kg every 7 days), individualized prophylaxis (IP; 100 IU/kg every 8-16 days), or modified prophylaxis (MP; for subjects not achieving optimal prophylactic dosing with individualized or weekly prophylaxis). Subjects could change treatment groups at the start of or at any time during the study; for efficacy analyses, data were summarized according to the treatment group in which they participated, for the time period they were in that treatment group. The primary endpoint was development of inhibitors (neutralizing antibodies; confirmed at a central laboratory per Nijmegen-modified Bethesda assay result ≥0.6 BU/mL observed twice within 2-4 weeks). Secondary outcomes included incidence of adverse events (AEs), annualized bleeding rate (ABR), and rFIXFc exposure days (EDs). Post hoc analyses of subjects' prophylactic dose and dosing interval were performed to evaluate the stability of prophylactic dosing regimens over time.
Results: At the time of the B-YOND interim data cut (17 October 2014), 23 subjects had completed Kids B-LONG; all enrolled in B-YOND (<6 years of age cohort, n=9; 6 to <12 years of age cohort, n=14). As of the interim data cut, 2/23 subjects had completed and 21/23 subjects continued B-YOND (median time on study: 11.0 [range: 2.7-13.9] months). From the start of Kids B-LONG to the B-YOND interim data cut, subjects had a median 21.9 (range: 14.4-25.4) months of treatment with rFIXFc, and a median 94 (interquartile range: 87-106) cumulative rFIXFc EDs. No inhibitors were reported during B-YOND with rFIXFc treatment (n=23 subjects with at least 1 evaluable inhibitor test result). AEs were generally typical of the pediatric hemophilia B population; 17 subjects (74%) reported at least 1 AE and 2 subjects (9%) reported at least 1 serious AE (SAE) on study. None of the AEs that emerged during B-YOND were assessed by the investigator as related to rFIXFc treatment, and no subject discontinued the study due to an AE. There were no reports of serious allergic reactions or anaphylaxis associated with rFIXFc, no vascular thrombotic events, and no deaths. Compared with their prophylactic regimen at the end of Kids B-LONG, 70% of subjects had either no change to or decreased their total weekly prophylactic dose during B-YOND; the median (IQR) total weekly prophylactic dose at the B-YOND data cut was 60.0 (50.0, 70.0) IU/kg. During B-YOND, 22/23 subjects (96%) either did not change or lengthened their prophylactic dosing interval, including 4 subjects who extended their dosing interval to every 10 days (3 subjects) or every 14 days (1 subject). Median ABRs were low in both age cohorts (Table); the overall median ABRs for spontaneous bleeds and spontaneous joint bleeds were 0.00 in all treatment groups. Overall, 95% of bleeding episodes were controlled with 1 or 2 infusions.
Conclusions: These data confirm the long-term safety of rFIXFc and the maintenance of a low ABR in children treated with extended-interval prophylaxis.
Table 1. Median (IQR) ABR during B-YOND Prophylactic treatment group: Weekly Individualized Modified Age cohort: <6 yrs (n=9) 6 to <12 yrs (n=10) 6 to <12 yrs (n=5) 6 to <12 yrs (n=1) Overall ABR 0.0 (0.0, 1.3) 2.7 (1.1, 3.2) 2.4 (2.0, 6.3) 3.1 Spontaneous ABR 0.0 (0.0, 0.0) 0.0 (0.0, 3.2) 0.0 (0.0, 0.9) 0.0 Spontaneous joint ABR 0.0 (0.0, 0.0) 0.0 (0.0, 1.6) 0.0 (0.0, 0.0) 0.0 No subjects from the <6 years of age cohort participated in the individualized or modified prophylaxis group. ABR=annualized bleeding rate; IQR=interquartile range

Disclosures
Kulkarni: 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; BPL: Membership on an entity's Board of Directors or advisory committees. Nolan:Biogen and Sobi: Research Funding. Fischer:Baxalta/Baxter, Bayer, Pfizer, Novo Nordisk, and Biogen: Consultancy; Baxalta/Baxter, Bayer, Pfizer, and Novo Nordisk: Research Funding; Baxalta/Baxter, Bayer, Pfizer, Novo Nordisk, CSL Behring, and Octopharma: Speakers Bureau. Perry:Biogen: Consultancy, Honoraria; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barnes:Bayer, Novo Nordisk, and Pfizer: Research Funding; Bayer, Baxter, and Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Mei:Biogen: Employment, Equity Ownership.