Inhibitor development, safety, and efficacy of Advate® in previously untreated 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 immunogenicity, safety, and efficacy of prophylactic and on-demand use of rurioctocog alfa, postmarketing surveillance was conducted on 114 previously untreated Japanese patients aged 0–82 years with ≤ 3 exposure days under the conditions of routine clinical practice. A post-hoc comparison of mean annualized bleeding rates between patients in the regular prophylaxis group (7.4 bleeds/year) and in the on-demand treatment group (15.7 bleeds/year) using a negative binomial model found a statistically significant difference (P = 0.0164) in the subset of patients with severe hemophilia A. Favorable prophylactic and on-demand hemostatic efficacy (“excellent” or “good”) was shown in 71.4–88.5% across all treatment regimens. A total of 31 events of adverse drug reactions were reported. Of 114 patients, 21 (18.4%) developed de novo FVIII inhibitor; of these, 17 occurred within 50 exposures. One death was reported. A family history of positive inhibitors was significantly associated with inhibitor development (Fisher exact P value = 0.0004); no other risk factors were identified. Rurioctocog alfa was found to be well-tolerated and effective in previously untreated Japanese patients with hemophilia A in this postmarketing surveillance of routine clinical practice.
KeywordsRecombinant factor VIII Advate Hemophilia A Previously untreated patients Postmarketing surveillance
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 the development of this product, 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: Akita University Hospital, Asahikawa City Hospital, Chiba Children’s Hospital, Dokkyo Medical University Hospital, Fukuoka Higashi Medical Center, Fukuoka University Hospital, Gamagori City Hospital, Hamada Medical Center, Hamanomachi Hospital, Hasegawa Pediatric Clinic, Higashiosaka City Medical Center, Hiroshima University Hospital, Hospital of the University of Occupational and Environmental Health, Hyogo College of Medicine Hospital, Ibaraki Children’s Hospital, Iwakuni Clinical Center, Japanese Red Cross Kitami Hospital, Japanese Red Cross Kumamoto Hospital, Japanese Red Cross Kyoto Daiichi Hospital, Japanese Red Cross Kyoto Daini Hospital, Japanese Red Cross Osaka Hospital, Jichi Medical University Hospital, Juntendo University Nerima Hospital, Kakogawa Central City Hospital, Kanagawa Children’s Medical Center, Kansai Medical University Hirakata Hospital, Kansai Medical University Takii Hospital, Kindai University Sakai Hospital, Kobe City Nishi-Kobe Medical Center, Kurume University Hospital, Kyoto Okamoto Memorial Hospital, Matsudo City General Hospital, Mie University Hospital, Miyagi Children’s Hospital, Nagasaki University Hospital, Nagoya City University hospital, Nagoya University Hospital, Nara Medical University Hospital, Nihon University Itabashi Hospital, Niigata Saiseikai Sanjo Hospital, Ogikubo Hospital, Oita University Hospital, Osaka City General Hospital, Osaka Women’s and Children’s Hospital, Sagamihara Kyodo Hospital, Saitama Children’s Medical Center, Sapporo Tokushukai Hospital, Shibuya Children’s Clinic, Shikoku Medical Center for Children and Adults, Shizuoka Children’s Hospital, St. Marianna University School of Medicine Hospital, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Tokyo Medical University Hospital, Tottori University Hospital, Yamagata City Hospital SAISEIKAN, Yao Municipal Hospital, Yokkaichi Municipal Hospital, and Yokohama City University Hospital.
MT, KF, 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, now part of Shire.
Compliance with ethical standards
Conflict of interest
Masashi Taki has received personal fees from Shire during the conduct of the study; 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. 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. 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.
- 6.Jiménez-Yuste V, Auerswald G, Benson G, Lambert T, Morfini M, Remor E, et al. Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present and the future. Blood Transfus. 2014;12:314–9.Google Scholar
- 10.Pharmaceutical administration and regulations in Japan (individual chapters) Chapter 4 Post-marketing surveillance of drugs. http://www.jpma.or.jp/english/parj/pdf/2015.pdf.
- 12.White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85:560.CrossRefGoogle Scholar
- 17.Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost. 2010;8:1256–65.CrossRefGoogle Scholar
- 19.Shirahata A, Fukutake K, Higasa S, Mimaya J, Oka T, Shima M, et al. An analysis of factors affecting the incidence of inhibitor formation in patients with congenital haemophilia in Japan. Haemophilia. 2011;17:771–6.Google Scholar