Abstract

Background: Prophylactic replacement of coagulation factor IX (FIX) in patients with hemophilia B improves clinical outcomes; however, the short half-life of conventional FIX products often necessitates frequent intravenous infusions (2-3 times/week). 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.

Introduction: The phase 3 B-LONG study (NCT01027364) demonstrated the safety, efficacy and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) in adults and adolescents (aged ≥12 years) with hemophilia B. Here, we report interim safety and efficacy data for adults and adolescents enrolled in the ongoing rFIXFc extension study, B-YOND (NCT01425723).

Methods: Upon completing B-LONG, eligible subjects could participate in one of 4 treatment groups in B-YOND: weekly prophylaxis (WP; 20 to 100 IU/kg every 7 days), individualized prophylaxis (IP: 100 IU/kg every 8 to 16 days), modified prophylaxis (MP; for subjects in whom optimal prophylactic dosing could not be achieved with either individualized or weekly prophylaxis), or episodic treatment. 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 (a positive result was defined as a neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay at a central laboratory, confirmed upon retesting within 2 to 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 longitudinal changes in prophylactic regimens.

Results: Of the 115 subjects who completed B-LONG, 93 (81%) enrolled in B-YOND. As of the interim data cut (17 October 2014), 18 subjects had completed, 7 had discontinued, and 68 remained on study (median time on study: 27.6 [range: 3.2-32.7] months). From the start of B-LONG to the B-YOND interim data cut, subjects had a median of 39.5 (range: 8.1-52.6) months treatment with rFIXFc; 68 subjects (73%) had ≥100 cumulative rFIXFc EDs. As of the B-YOND interim data cut, no inhibitors were reported (n=93 subjects with at least 1 evaluable inhibitor test result). During B-YOND, AEs were generally typical of the hemophilia B population; 76% of subjects reported at least 1 AE and 23% reported at least 1 serious AE (SAE) on study. No subject discontinued due to an AE. 4 subjects each experienced an AE assessed by the investigator as related to rFIXFc treatment, 1 serious and 3 nonserious; all 4 AEs resolved, and none led to study discontinuation. There were no reports of serious hypersensitivity reactions and no vascular thrombotic events associated with rFIXFc. During B-YOND, most subjects remained in the same treatment group in which they had participated during B-LONG; 29/90 subjects (32%) from the B-LONG prophylactic and episodic treatment arms changed treatment groups, including 9/19 subjects who changed from episodic to prophylactic treatment (1 subject changed back to episodic treatment before the interim data cut). Among subjects treated prophylactically in B-LONG (n=71), 78% had either no change to or decreased their total weekly prophylactic dose during B-YOND; 89% maintained or lengthened their prophylactic infusion interval during B-YOND. The median (IQR) average weekly prophylactic dose was 49.5 (39.9, 62.8) IU/kg, 50.2 (48.2, 61.5) IU/kg, and 61.7 (41.5, 81.8) IU/kg in the WP, IP, and MP groups, respectively. The median (IQR) average dosing intervals in the IP and MP groups were 13.7 (10.1, 14.0) days and 6.9 (4.9, 7.0) days, respectively. Median ABRs were low with rFIXFc prophylaxis (Fig. 1). In all prophylaxis groups, the median ABR was <1 for spontaneous bleeds and spontaneous joint bleeds. 87% of bleeding episodes were controlled with 1 infusion; 97% with 1 or 2 infusions.

Conclusion: Interim data from B-YOND in adults and adolescents confirm the long-term safety of rFIXFc and the maintenance of a low ABR with prophylactic dosing every 1 to 2 weeks.

Disclosures

Mahlangu:Amgen: Speakers Bureau; Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Roche: Research Funding. Shapiro:Biogen: Speakers Bureau; 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; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding. Pasi:Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Ragni:Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Biomarin: Research Funding; SPARK: Research Funding; Pfizer: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Biogen: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Vascular Medicine Institute: Research Funding; Dimension: Research Funding; Genentech Roche: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ozelo:Biogen: Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau. Oldenburg:SOBI: Consultancy. Matsushita:Biogen, Novo Nordisk, Baxalta, Bayer, and Octapharma: Membership on an entity's Board of Directors or advisory committees; Biogen, Novo Nordisk, Baxalta, CSL Behring, Bayer, Chugai, KaketsuKen, JB, and Octapharma: Honoraria; Biogen, Novo Nordisk, Baxalta, CSL Behring, Bayer, Chugai, KaketsuKen, and JB: Research Funding. Baker: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; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Other: conference travel support; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; 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. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Allen:Biogen: Employment, Equity Ownership. Mei:Biogen: Employment, Equity Ownership.

Author notes

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Asterisk with author names denotes non-ASH members.