Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients
Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharm...
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| Published in | Blood Vol. 119; no. 3; pp. 666 - 672 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Washington, DC
Elsevier Inc
19.01.2012
Americain Society of Hematology American Society of Hematology |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0006-4971 1528-0020 1528-0020 |
| DOI | 10.1182/blood-2011-07-367003 |
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| Abstract | Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716. |
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| AbstractList | Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716. Current factor IX (FIX) products display a half-life (t(1/2)) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG(1), to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t(1/2) and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.Current factor IX (FIX) products display a half-life (t(1/2)) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG(1), to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t(1/2) and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716. Current factor IX (FIX) products display a half-life (t(1/2)) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG(1), to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t(1/2) and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716. Current factor IX (FIX) products display a half-life (t 1/2 ) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG 1 , to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t 1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716. |
| Author | Goyal, Jaya Cheng, Gregory Bitonti, Alan J. Josephson, Neil C. Euwart, Donald Peters, Robert T. Valentino, Leonard A. Tubridy, Karen L. Hallén, Bengt Powell, Jerry S. Ragni, Margaret V. Pierce, Glenn F. Thompson, Arthur R. Shapiro, Amy D. Key, Nigel S. Li, Lian Jiang, Haiyan Dumont, Jennifer A. Luk, Alvin Gozzi, Peter |
| Author_xml | – sequence: 1 givenname: Amy D. surname: Shapiro fullname: Shapiro, Amy D. email: ashapiro@ihtc.org organization: Indiana Hemophilia and Thrombosis Center, Indianapolis, IN – sequence: 2 givenname: Margaret V. surname: Ragni fullname: Ragni, Margaret V. organization: University of Pittsburgh, Pittsburgh, PA – sequence: 3 givenname: Leonard A. surname: Valentino fullname: Valentino, Leonard A. organization: Rush University Medical Center, Chicago, IL – sequence: 4 givenname: Nigel S. surname: Key fullname: Key, Nigel S. organization: University of North Carolina, Chapel Hill, NC – sequence: 5 givenname: Neil C. surname: Josephson fullname: Josephson, Neil C. organization: Puget Sound Blood Center, Seattle, WA – sequence: 6 givenname: Jerry S. surname: Powell fullname: Powell, Jerry S. organization: University of California–Davis, Davis, CA – sequence: 7 givenname: Gregory surname: Cheng fullname: Cheng, Gregory organization: Chinese University of Hong Kong, Hong Kong, Peoples Republic of China – sequence: 8 givenname: Arthur R. surname: Thompson fullname: Thompson, Arthur R. organization: Puget Sound Blood Center, Seattle, WA – sequence: 9 givenname: Jaya surname: Goyal fullname: Goyal, Jaya organization: Biogen Idec, Cambridge, MA – sequence: 10 givenname: Karen L. surname: Tubridy fullname: Tubridy, Karen L. organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 11 givenname: Robert T. surname: Peters fullname: Peters, Robert T. organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 12 givenname: Jennifer A. surname: Dumont fullname: Dumont, Jennifer A. organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 13 givenname: Donald surname: Euwart fullname: Euwart, Donald organization: Biogen Idec, Cambridge, MA – sequence: 14 givenname: Lian surname: Li fullname: Li, Lian organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 15 givenname: Bengt surname: Hallén fullname: Hallén, Bengt organization: Swedish Orphan Biovitrum AB, Stockholm, Sweden – sequence: 16 givenname: Peter surname: Gozzi fullname: Gozzi, Peter organization: Swedish Orphan Biovitrum AB, Stockholm, Sweden – sequence: 17 givenname: Alan J. surname: Bitonti fullname: Bitonti, Alan J. organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 18 givenname: Haiyan surname: Jiang fullname: Jiang, Haiyan organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 19 givenname: Alvin surname: Luk fullname: Luk, Alvin organization: Biogen Idec Hemophilia, Waltham, MA; and – sequence: 20 givenname: Glenn F. surname: Pierce fullname: Pierce, Glenn F. email: glenn.pierce@biogenidec.com organization: Biogen Idec Hemophilia, Waltham, MA; and |
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| Keywords | Human Factor IX Hematology Phase I trial Hemophilia B Hemopathy Recombinant protein Fusion protein Coagulopathy Biological activity Genetic disease Prolonged |
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| Snippet | Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients... Current factor IX (FIX) products display a half-life (t(1/2)) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients... Current factor IX (FIX) products display a half-life (t 1/2 ) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients... |
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| SubjectTerms | Adolescent Adult Aged Biological and medical sciences Clinical Trials and Observations Factor IX - metabolism Female Half-Life Hematologic and hematopoietic diseases Hemophilia B - metabolism Hemophilia B - therapy Humans Male Medical sciences Middle Aged Platelet diseases and coagulopathies Recombinant Fusion Proteins - pharmacokinetics Recombinant Fusion Proteins - therapeutic use Safety Thrombosis and Hemostasis Young Adult |
| Title | Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients |
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