Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B

Jerry S Powell, K. John Pasi, Margaret V. Ragni, Margareth C. Ozelo, Leonard A. Valentino, Johnny N. Mahlangu, Neil C. Josephson, David Perry, Marilyn J. Manco-Johnson, Shashikant Apte, Ross I. Baker, Godfrey C. Chan, Nicolas Novitzky, Raymond S. Wong, Snejana Krassova, Geoffrey Allen, Haiyan Jiang, Alison Innes, Shuanglian Li, Lynda M. CristianoJaya Goyal, Jurg M. Sommer, Jennifer A. Dumont, Karen Nugent, Gloria Vigliani, Aoife Brennan, Alvin Luk, Glenn F. Pierce

Research output: Contribution to journalArticle

196 Scopus citations

Abstract

BACKGROUND: Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS: We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS: As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B.

Original languageEnglish (US)
Pages (from-to)2313-2323
Number of pages11
JournalNew England Journal of Medicine
Volume369
Issue number24
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Powell, J. S., Pasi, K. J., Ragni, M. V., Ozelo, M. C., Valentino, L. A., Mahlangu, J. N., Josephson, N. C., Perry, D., Manco-Johnson, M. J., Apte, S., Baker, R. I., Chan, G. C., Novitzky, N., Wong, R. S., Krassova, S., Allen, G., Jiang, H., Innes, A., Li, S., ... Pierce, G. F. (2013). Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. New England Journal of Medicine, 369(24), 2313-2323. https://doi.org/10.1056/NEJMoa1305074