Clinical Outcomes in Adults/Adolescents with Hemophilia B Treated Long Term with Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis: Interim Results of the B-Yond Extension Study
Authors: Matsushita Tadashi , Mahlangu Johnny , Shapiro Amy D , Pasi K John , Ragni Margaret V. , Ozelo Margareth C , Oldenburg Johannes , Baker Ross I , Yuan Huixing , Ramirez-Santiago Alejandra , Ferrante Francesca , Lethagen Stefan 
Published: November 2019

Abstract
Introduction: The phase 3 B-LONG study (NCT01027364) demonstrated the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) for the prevention and treatment of bleeding episodes in adults and adolescents with severe hemophilia B. The ongoing rFIXFc extension study B-YOND (NCT01425723) is evaluating long-term safety and efficacy of rFIXFc in children and adults with hemophilia B. Safety and efficacy data for adult and adolescent subjects from the second B-YOND interim data cut are reported here.
Methods: The B-LONG study enrolled males aged ≥12 years with severe hemophilia B (≤2 IU/dL endogenous factor IX [FIX] activity) who had received prior treatment with FIX. Subjects completing B-LONG could enroll in 1 of 4 treatment groups in B-YOND: weekly prophylaxis (WP; 20-100 IU/kg every 7 d), individualized prophylaxis (IP: 100 IU/kg every 8-16 d), modified prophylaxis (MP; for subjects not achieving optimal prophylactic dosing with IP or WP), or episodic treatment (ET). Subjects could change treatment groups at any point in B-YOND. The primary endpoint was development of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay). Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs). The incidence of adverse events (AEs), treatment of bleeding episodes, and weekly dosing and dosing intervals are also reported. Here, data are reported from the second interim data cut of B-YOND (11 September 2015) for subjects treated with ≥1 dose of rFIXFc.
Results: 93/115 subjects (81%) who completed B-LONG enrolled in B-YOND. As of the second interim data cut, 21 subjects had completed B-YOND, 61 subjects were ongoing in B-YOND, and 11 subjects had discontinued (1 due to lack of efficacy, 2 lost to follow up, 4 withdrawal by subject, and 4 other reasons). From the start of B-LONG to the second B-YOND interim data cut, subjects had a median 4.1 y of treatment with rFIXFc, and a median 181.0 cumulative rFIXFc EDs. In B-YOND, 68.8% of subjects had ≥100 EDs.No inhibitors were observed. The AE profile was typical of the hemophilia B population in a clinical trial and was generally similar to what is expected in the overall population of adults/adolescents with hemophilia B. There were no reports of serious allergic reactions or anaphylaxis associated with rFIXFc, and no thromboembolic events. 16/93 subjects (17.2%) enrolled in B-YOND changed treatment groups during the course of B-YOND, including 5 subjects who changed treatment groups from the start of B-YOND and then switched back to their original treatment group before the second interim data cut. 4/15 subjects changed from ET to prophylactic treatment. Among subjects treated prophylactically during B-LONG (n=71), 5.6% of subjects lengthened, 11.3% of subjects shortened, and 83.1% of subjects had no change to their dosing interval during B-YOND compared with their dosing interval in B-LONG. Overall, the median (interquartile range [IQR]) average dosing interval in the IP and MP groups was 13.8 (10.1-14.0) days and 6.9 (4.9-7.0) days, respectively. Compared with the end of B-LONG, the median (IQR) total weekly prophylactic dose was similar at the second B-YOND interim data cut (50.0 [30.0-58.3] vs 50.0 [40.0-60.0]). Median (IQR) overall ABRs were low with rFIXFc prophylaxis (Figure). Median (IQR) spontaneous ABRs were also low in each prophylaxis group: WP, 1.2 (0.0-2.7); IP, 0.6 (0.3-1.9); MP, 0.3 (0.0-1.8); and ET, 3.8 (1.2-14.6). The majority of bleeding episodes were controlled with 1-2 intravenous infusions (WP: 96.9%; IP: 96.8%; MP: 96.5%; ET: 98.8%).
Conclusion: Interim data from adults and adolescents with severe hemophilia B treated with rFIXFc in B-YOND confirm the long-term safety of rFIXFc and maintenance of low ABRs with prophylactic dosing every 1-2 weeks.
This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content.

Disclosures
Matsushita: CSL Behring: Honoraria, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; KaketsuKen: Honoraria, Research Funding; JB: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahlangu:Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy. Shapiro:Kedrion Biopharma: Consultancy, Research Funding; Selexys: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; ProMetic Life Sciences: Consultancy, Research Funding; PTC Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pasi:Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Biogen: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ragni:Baxalta: Research Funding; Genentech: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Alnylam Pharmaceuticals: Consultancy, Research Funding; SPARK: Research Funding; Tacere Benitec: Consultancy; OPKO: Research Funding; Vascular Medicine Institute: Research Funding. Ozelo:Novo Nordisk: Research Funding, Speakers Bureau; Bayer: Research Funding; Baxter: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Biogen: Research Funding. Baker:Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: 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; Novo Nordisk: Other: Conference travel support ; Baxter: Other: Conference travel support , Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Astellas: Research Funding; CSL Behring: Research Funding; Biogen: Membership on an entity's Board of Directors or advisory committees. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Ferrante:Sobi: Employment. Lethagen:Sobi: Employment.