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 Goyal, Jurg M Sommer, Jennifer A Dumont, Nigel Dodd, Karen Nugent, Gloria Vigliani, Alvin Luk, Aoife Brennan, Glenn F Pierce, A-LONG Investigators, Simon J McRae, Ingrid Pabinger, Cedric Hermans, Margareth C Ozelo, Victor Blanchette, Man-Chiu Poon, Claude Negrier, Johannes Oldenburg, Robert Klamroth, Raymond S Wong, Godfrey Chi-Fung Chan, Alok Srivastava, Shashikant J Apte, Cecil R Ross, Joseph M John, Naresh Gupta, Jacob Luboshitz, Elena Santagostino, Massimo Morfini, Giancarlo Castaman, Katsuyuki Fukutake, Hideji Hanabusa, Masashi Taki, Michio Sakai, Tadashi Matsushita, Keiji Nogami, Paul Harper, Paul Ockelford, Mark Smith, Johnny Mahlangu, Nicolas Novitzky, Rafael Parra Lopez, Maria Teresa Alvarez Roman, Fariba Baghaei, Brigitte Brand, K John Pasi, David J Perry, Pratima Chowdary, Graeme Thomson, Catherine Bagot, Savita Rangarajan, Jerry Powell, Amy Shapiro, Neil C Josephson, Jonathan Bernstein, Judith Lin, Donald Macfarlane, Doris Quon, Margaret Ragni, George Rodgers, Kimo Stine, Vivek Sharma, Miguel Escobar, Alice Ma, Rebecca Kruse-Jarres, Roshni Kulkarni, Amit Soni, Patrick Fogarty, Douglass Drelich, Christopher Walsh, Annette von Drygalski, Michael Guerrera, 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 Goyal, Jurg M Sommer, Jennifer A Dumont, Nigel Dodd, Karen Nugent, Gloria Vigliani, Alvin Luk, Aoife Brennan, Glenn F Pierce, A-LONG Investigators, Simon J McRae, Ingrid Pabinger, Cedric Hermans, Margareth C Ozelo, Victor Blanchette, Man-Chiu Poon, Claude Negrier, Johannes Oldenburg, Robert Klamroth, Raymond S Wong, Godfrey Chi-Fung Chan, Alok Srivastava, Shashikant J Apte, Cecil R Ross, Joseph M John, Naresh Gupta, Jacob Luboshitz, Elena Santagostino, Massimo Morfini, Giancarlo Castaman, Katsuyuki Fukutake, Hideji Hanabusa, Masashi Taki, Michio Sakai, Tadashi Matsushita, Keiji Nogami, Paul Harper, Paul Ockelford, Mark Smith, Johnny Mahlangu, Nicolas Novitzky, Rafael Parra Lopez, Maria Teresa Alvarez Roman, Fariba Baghaei, Brigitte Brand, K John Pasi, David J Perry, Pratima Chowdary, Graeme Thomson, Catherine Bagot, Savita Rangarajan, Jerry Powell, Amy Shapiro, Neil C Josephson, Jonathan Bernstein, Judith Lin, Donald Macfarlane, Doris Quon, Margaret Ragni, George Rodgers, Kimo Stine, Vivek Sharma, Miguel Escobar, Alice Ma, Rebecca Kruse-Jarres, Roshni Kulkarni, Amit Soni, Patrick Fogarty, Douglass Drelich, Christopher Walsh, Annette von Drygalski, Michael Guerrera
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-fold vs rFVIII (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.
Trial registration: ClinicalTrials.gov NCT01181128.
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Source: PubMed