Inhibitor development, safety and efficacy of Advate® among previously treated patients with hemophilia A in a postmarketing surveillance in Japan
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Rurioctocog alfa (recombinant factor VIII: Advate®) is available for the control of bleeding in patients with hemophilia A in Japan. To evaluate the inhibitor development, safety, and efficacy of rurioctocog alfa, a non-interventional and observational postmarketing surveillance was conducted on 352 previously treated Japanese patients aged 1–76 years with ≥ 4 exposure days under the conditions of routine clinical practice. A post-hoc comparison of the mean annualized bleeding rates which required treatment with rurioctocog alfa detected a statistically significant difference (P < 0.0001) between patients treated on regular prophylaxis (8.5 bleeds/year) and patients treated on an on-demand basis (36.6 bleeds/year). Favorable prophylactic and on-demand hemostatic efficacy (“excellent” or “good”) were shown in 88.5–100% of patients across all treatment regimens. A total of 22 events of adverse drug reactions were reported in 13 male patients. Of the 352 patients, 3 (0.9%) patients, all of whom had ≤ 50 exposure days before enrollment, developed de novo FVIII inhibitor. No deaths or allergic reactions were reported. Rurioctocog alfa was found to be well-tolerated and effective among patients with hemophilia A in a postmarketing routine clinical practice.
KeywordsRecombinant factor VIII Hemophilia A Previously treated patients Postmarketing surveillance Advate
This manuscript is dedicated to the memory of our esteemed colleague Dr. Hideji Hanabusa, MD, whose untimely passing in October 2016 left a permanent void. He touched the lives of many as a mentor, scholar, collaborator, and friend. Dr. Hanabusa was instrumental in gaining approval for this product in Japan, and the creation and interpretation of the data included herein, and would have been a co-author of this manuscript. We thank Shire PMS and PV teams for the support of data clarification. We recognize with gratitude the patients and institutions that participated in the studies: Aichi Sannomaru Hospital, Aihara Internal Medicine and Pediatric Clinic, Asahikawa Medical University Hospital, Chiba Children’s Hospital, Dokkyo Medical University Hospital, Ehime University Hospital, Fukui-ken Saiseikai Hospital, Gunma University Hospital, Hasegawa Pediatric Clinic, Hayashi Pediatric Clinic, Higashiosaka City Medical Center, Hirano Internal Medicine, Hiroshima University Hospital, Hitachi General Hospital, Hokkaido Cancer Center, Hospital of the University of Occupational and Environmental Health Japan, Hyogo College of Medicine Hospital, Ibaraki Children’s Hospital, Iizuka Family Clinic, Iou Hospital, Ishinkai Yao General Hospital, Ishiyama Internal Medicine Clinic, Itoigawa Sogo Hospital, Iwaki Kyouritsu Hospital, Iwate Prefectural Miyako Hospital, Izumiotsu Municipal Hospital, Japanese Red Cross Morioka Hospital, Jichi Medical University Hospital, Jichi Medical University Saitama Medical Center, Jusendo General Hospital, Kagawa National Children’s Hospital, Kagawa University Hospital, Kanagawa Children’s Medical Center, Kariya Toyota General Hospital, Kitasato University Hospital, Kochi Health Sciences Center, Komatsu Municipal Hospital, Kumamoto University Hospital, Kurume University Hospital, Kyoto Okamoto Memorial Hospital, Kyushu Medical Center, Kyushu University Hospital, Matsudo City General Hospital, Mie Chuo Medical Center, Mie University Hospital, Miyoshi Central Hospital, Nagasaki University Hospital, Nagoya City University Hospital, Nagoya University Hospital, Nanbu Medical Center / Nanbu Child Medical Center, Nara Medical University Hospital, Nihonkai General Hospital, Niigata Saiseikai Sanjo Hospital, Nippon Medical School Tama Nagayama Hospital, Odate Municipal General Hospital, Ogaki Municipal Hospital, Ogikubo Hospital, Oita Memorial Hospital, Osaka City General Hospital, Osaka National Hospital, Rakusai Newtown Hospital, Saga University Hospital, Saitama Children’s Medical Center, Sakou Internal Medicine, Saku Central Hospital, Sanaikai Genaral Hospital, Sapporo Tokushukai Hospital, Sendai Medical Center, Sendai Nishitaga Hospital, Shibuya Children’s Clinic, Shizuoka Children’s Hospital, Shizuoka Medical Center, Soka Municipal Hospital, St. Marianna University School of Medicine Hospital, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Tatebayashi Kosei Hospital, The Jikei University Hospital, Tokuyama Central Hospital, Tokyo Dental College Ichikawa General Hospital, Tokyo Medical University Hospital, Tokyo Metropolitan Children’s Medical Center, Tokyo Women’s Medical University Medical Center East, Toyokawa City Hospital, University Hospital Kyoto Prefectural University of Medicine, Watari Hospital, Yakumo General Hospital, Yokohama City University Medical Center, and Yuri Kumiai General Hospital.
KF, MT, TM, KN, MS, AY, JT, and AS collected and interpreted data, and revised the manuscript. WE analyzed the statistics, interpreted data, and revised the manuscript. HU, HT, and MA interpreted data and drafted and revised the manuscript. All authors had full editorial control of the manuscript and provided their approvals for the content of the manuscript prior to submission.
This research was funded by Baxalta (part of Shire, Lexington, MA, USA).
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Conflict of interest
Katsuyuki Fukutake has received grants and personal fees from Shire outside the submitted work and holds concurrent posts as a professor for the Department of Molecular Genetics of Coagulation Disorders supported by CSL Behring without additional salary; is an advisory committee member of Chugai Pharmaceutical and consultant of Chugai Pharmaceutical; has received research funding from Bayer, Biogen/Bioverativ, Kaketsuken, Novo Nordisk, and Pfizer; has received honoraria for consulting, speaking or advising from Bayer, Biogen/Bioverativ, Chugai Pharm./Roche, CSL Behring, Japan Blood Products, Kaketsuken, MSD, Novo Nordisk, Octapharma, and Pfizer. Masashi Taki has received grants and personal fees from CSL Behring outside the submitted work, personal fees from Shire, Bayer, Bioverativ, Chugai, Kaketsuken, Pfizer, and Novo Nordisk outside the submitted work. Tadashi Matsushita has received personal fees from Shire for the submitted work; grants and personal fees from Bayer, Shire, Novo Nordisk, Kaketsuken, and Biogen-idec outside the submitted work. Keiji Nogami has received grants from Shire and funding for research from Shire, Bayer, Novo Nordisk, Bioverativ, Chugai, and honoraria from Shire, Bayer, Novo Nordisk, Bioverativ, CSL-Behring, Chugai outside the submitted work. Midori Shima has received personal fees and grants from Shire, Bayer, Novo Nordisk, CSL-Behring, Chugai, and Pfizer; personal fees from Bioverativ and Roche; grants from Kaketsuken outside the submitted work. Akira Yoshioka has received honoraria from Shire, Japan Red Cross, Daiichi Sankyo, and Bayer outside the submitted work. Junki Takamatsu and Akira Shirahata have declared no conflict of interest. Werner Engl, Haruhiko Uchikawa, Hiroshi Takagi, and Morio Arai are full-time employees of Shire; Werner Engl and Morio Arai own Shire stock.
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