Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

Johnny Mahlangu, Jerry S Powell, Margaret V. Ragni, Pratima Chowdary, Neil C. Josephson, Ingrid Pabinger, Hideji Hanabusa, Naresh Gupta, Roshni Kulkarni, Patrick Fogarty, David Perry, Amy Shapiro, K. John Pasi, Shashikant Apte, Ivan Nestorov, Haiyan Jiang, Shuanglian Li, Srividya Neelakantan, Lynda M. Cristiano, Jaya GoyalJurg M. Sommer, Jennifer A. Dumont, Nigel Dodd, Karen Nugent, Gloria Vigliani, Alvin Luk, Aoife Brennan, Glenn F. Pierce

Research output: Contribution to journalArticle

214 Citations (Scopus)

Abstract

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). a subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-foldvsrFVIII (12.4 hours; P <.001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.

Original languageEnglish (US)
Pages (from-to)317-325
Number of pages9
JournalBlood
Volume123
Issue number3
DOIs
StatePublished - Jan 16 2014

Fingerprint

Hemophilia A
Fusion reactions
Pharmacokinetics
Hemorrhage
Half-Life
Proteins
Hemostatics
Therapeutics
Safety
Injections
factor VIII-Fc fusion protein
Population

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Mahlangu, J., Powell, J. S., Ragni, M. V., Chowdary, P., Josephson, N. C., Pabinger, I., ... Pierce, G. F. (2014). Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood, 123(3), 317-325. https://doi.org/10.1182/blood-2013-10-529974

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. / Mahlangu, Johnny; Powell, Jerry S; Ragni, Margaret V.; Chowdary, Pratima; Josephson, Neil C.; Pabinger, Ingrid; Hanabusa, Hideji; Gupta, Naresh; Kulkarni, Roshni; Fogarty, Patrick; Perry, David; Shapiro, Amy; Pasi, K. John; Apte, Shashikant; Nestorov, Ivan; Jiang, Haiyan; Li, Shuanglian; Neelakantan, Srividya; Cristiano, Lynda M.; Goyal, Jaya; Sommer, Jurg M.; Dumont, Jennifer A.; Dodd, Nigel; Nugent, Karen; Vigliani, Gloria; Luk, Alvin; Brennan, Aoife; Pierce, Glenn F.

In: Blood, Vol. 123, No. 3, 16.01.2014, p. 317-325.

Research output: Contribution to journalArticle

Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P, Josephson, NC, Pabinger, I, Hanabusa, H, Gupta, N, Kulkarni, R, Fogarty, P, Perry, D, Shapiro, A, Pasi, KJ, Apte, S, Nestorov, I, Jiang, H, Li, S, Neelakantan, S, Cristiano, LM, Goyal, J, Sommer, JM, Dumont, JA, Dodd, N, Nugent, K, Vigliani, G, Luk, A, Brennan, A & Pierce, GF 2014, 'Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A', Blood, vol. 123, no. 3, pp. 317-325. https://doi.org/10.1182/blood-2013-10-529974
Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 Jan 16;123(3):317-325. https://doi.org/10.1182/blood-2013-10-529974
Mahlangu, Johnny ; Powell, Jerry S ; Ragni, Margaret V. ; Chowdary, Pratima ; Josephson, Neil C. ; Pabinger, Ingrid ; Hanabusa, Hideji ; Gupta, Naresh ; Kulkarni, Roshni ; Fogarty, Patrick ; Perry, David ; Shapiro, Amy ; Pasi, K. John ; Apte, Shashikant ; Nestorov, Ivan ; Jiang, Haiyan ; Li, Shuanglian ; Neelakantan, Srividya ; Cristiano, Lynda M. ; Goyal, Jaya ; Sommer, Jurg M. ; Dumont, Jennifer A. ; Dodd, Nigel ; Nugent, Karen ; Vigliani, Gloria ; Luk, Alvin ; Brennan, Aoife ; Pierce, Glenn F. / Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. In: Blood. 2014 ; Vol. 123, No. 3. pp. 317-325.
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abstract = "This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). a subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-foldvsrFVIII (12.4 hours; P <.001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30{\%} of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3{\%} of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.",
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AU - Mahlangu, Johnny

AU - Powell, Jerry S

AU - Ragni, Margaret V.

AU - Chowdary, Pratima

AU - Josephson, Neil C.

AU - Pabinger, Ingrid

AU - Hanabusa, Hideji

AU - Gupta, Naresh

AU - Kulkarni, Roshni

AU - Fogarty, Patrick

AU - Perry, David

AU - Shapiro, Amy

AU - Pasi, K. John

AU - Apte, Shashikant

AU - Nestorov, Ivan

AU - Jiang, Haiyan

AU - Li, Shuanglian

AU - Neelakantan, Srividya

AU - Cristiano, Lynda M.

AU - Goyal, Jaya

AU - Sommer, Jurg M.

AU - Dumont, Jennifer A.

AU - Dodd, Nigel

AU - Nugent, Karen

AU - Vigliani, Gloria

AU - Luk, Alvin

AU - Brennan, Aoife

AU - Pierce, Glenn F.

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N2 - This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). a subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-foldvsrFVIII (12.4 hours; P <.001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.

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