Publication Number: 4847

 

Abstract Title : Assessment of coagulation potential of concomitant factor VIII administration in patients with haemophilia a receiving emicizumab prophylaxis (CAGUYAMA Study): A multicenter, open-label, non-randomized clinical trial

 

Category: 300s - Hemostasis, Thrombosis and Vascular Wall Biology

 

Review Category: 322. Hemophilia A and B: Clinical and Epidemiological

 

Authors

 

Masahiro Takeyama^{1, 2}, Kenichi Ogiwara¹, Naoki Ozu³, Kana Sasai¹, Masato Kasahara³, Yasuko Furuichi⁴, Toshio Takase⁵, Iyou Nakagawa⁶, Katsuyuki Fukutake⁷, Akira Ishiguro⁸, Kagehiro Amano⁹, Eisuke Adachi¹⁰, Kumiko Ono¹¹, Chiai Nagae¹², Atsuki Yamashita¹³, Satoshi Higasa¹⁴, Teruhisa Fujii¹⁵, Masanori Matsumoto¹⁶, Midori Shima¹⁷, Keiji Nogami¹

 

¹ Nara Medical University, Department of Pediatrics, Kashihara, Japan, ² National Hospital Organization, Osaka National Hospital, Division of Hemophilia, Osaka, Japan, ³ Nara Medical University Hospital, Institute for Clinical and Translational Science, Kashihara, Japan, ⁴ Higashiosaka City Medical Center, Department of Pediatrics, Higashiosaka, Japan, ⁵ Osaka Gyoumeikan Hospital, Department of Pediatrics, Osaka, Japan, ⁶ Japan Community Health Care Organization Hoshigaoka Medical Center, Department of Pediatrics, Hirakata, Japan, ⁷ Ogikubo Hospital, Department of Blood Coagulation, Tokyo, Japan, ⁸ National Center for Child Health and Development, Center for Postgraduate Education and Training, Tokyo, Japan, ⁹ Tokyo Medical University, Department of Laboratory Medicine, Tokyo, Japan, ¹⁰ The University of Tokyo, Department of Infectious Diseases and Applied Immunology, IMSUT Hospital, The Institute of Medical Science, Tokyo, Japan, ¹¹ The University of Tokyo, Department of Joint Surgery, IMSUT Hospital, The Institute of Medical Science, Tokyo, Japan, ¹² St. Marianna University School of Medicine, Department of Pediatrics, Kawasaki, Japan, ¹³ Yokohama City Seibu Hospital, St. Marianna University School of Medicine, Department of Pediatrics, Yokohama, Japan, ¹⁴ Hyogo College of Medicine, Department of Hematology, Nishinomiya, Japan, ¹⁵ Hiroshima University Hospital, Division of Transfusion Medicine and Hemophilia Treatment Center, Hiroshima, Japan, ¹⁶ Nara Medical University, Department of Blood Transfusion Medicine, Kashihara, Japan, ¹⁷ Nara Medical University, The Center of Thrombosis and Hemostasis, Kashihara, Japan

 

Abstract Body

 

Introduction

Emicizumab prophylaxis reduces bleeding in people with hemophilia A (PwHA), offering hemostatic activity equivalent to ~15% of normal factor VIII activity (FVIII:C) level. Thus, additional FVIII supplementation would be required at breakthrough bleeding or surgery. A standard dosage of FVIII product does not account for baseline coagulant potential of emicizumab, however.

 

Aim

The CAGUYAMA study (jRCTs051210137) aimed to assess global coagulation function in PwHA without inhibitors receiving emicizumab and FVIII concomitantly, and to determine an appropriate FVIII dose for clinical management.

 

Methods and Analyses

The multicenter, open-label, non-randomized trial (CAGUYAMA study) enrolled 100 PwHA without inhibitors. Total 32 events involving FVIII administration (30±5 U/kg) for breakthrough bleeding or surgery were analyzed. Each event included blood sampling at pre and post FVIII administration.

 

The primary endpoint was change in adjusted maximum coagulation rate (Ad|min1|) by clot waveform analysis (CWA). CWA was initiated by a diluted mixture of PT and APTT reagents (Nogami K. JTH 2018). The degree of improvement in maximum coagulation rate (IMCR%) was defined relative to healthy controls (100%) and untreated PwHA (0%).

 

Secondary endpoints included clinical hemostatic assessment, thrombin generation assay (TGA), and rotational thromboelastometry (ROTEM; non-activated mode), performed with or without anti-emicizumab antibodies (anti-Emi-Ab) to isolate FVIII effects alone. TGA was evaluated using peak thrombin; ROTEM was evaluated using clotting time (CT) as primary outcome. Exploratory endpoints included correlation between emicizumab concentration and coagulation parameters.

 

Results

A total of 100 PwHA (mean age 31 years) from 13 institutions were enrolled (mean follow-up: 26.5 months). Among 32 events, 47% were bleeding episodes (e.g., joint, muscle, gastro-intestine) and 53% were surgeries (e.g., tooth extraction, synovectomy).

 

Mean administered FVIII dose was 30.8±3.3 U/kg, yielding the FVIII:C of 77.1±20.4% and in vivo recovery of 2.5±0.7 %/U/kg. The IMCR% calculated by CWA increased from 39.4% (pre-FVIII) to 92.1% (post-FVIII). With the addition of anti-Emi-Abs, the IMCR% was 3.2% (pre-FVIII) and 78.6% (post-FVIII), indicating that calculated FVIII effect was 52.7% in the presence of emicizumab and 75.4% in its absence. All events achieved effective clinical hemostasis.

 

In TGA triggered by ellagic acid and tissue factor, peak thrombin (IMCR%) by FVIII administration increased from 249 nM (55.4%; pre) to 348 nM (88.0%; post). With the addition of anti-Emi-Abs, the IMCR% was 6.4% (pre) and 74.6% (post), indicating that calculated FVIII effect was 32.6% in the presence of emicizumab and 68.2% in its absence.

 

In addition, ROTEM analysis (11 events) revealed that the CT decreased from 1,190±169 s (pre) to 1,158±301 s (post) (control: 938±128 s). With the addition of anti-Emi-Abs, the CT was changed from 5,213±2,915 s to 1,459±447 s.

 

At enrollment of this study, CWA and TGA confirmed emicizumab’s contribution to baseline hemostasis as follows; Ad|min1| decreased from 5.4 (37.2%) to 4.0 (0.9%) and peak thrombin from 238 nM (51.9%) to 92.7 nM (4.3%) by the addition of anti-Emi-Abs. Plasma emicizumab concentration was 51.2±17.8 µg/mL, and a moderate positive correlation was observed with baseline Ad|min1| in CWA (r=0.42), but not with peak thrombin in TGA (r=0.05), suggesting CWA seemed to better reflect emicizumab-driven hemostatic function. No abnormalities in platelets counts, coagulation or fibrinolysis laboratory markers were observed during the follow-up.

 

Conclusion

In PwHA receiving emicizumab prophylaxis, FVIII supplementation at 30±5 U/kg was safe and effective for breakthrough bleeding and surgical hemostasis. These findings could support clinical use of FVIII with consideration of emicizumab’s baseline effect.

 

 

 

Keywords: Human, Biological Therapies, Bleeding and Clotting, Practice Models, Clinical Practice (Health Services And Quality), Treatment Considerations, Study Population, Bispecific Antibody Therapy, Diseases

 

Disclosure : Masahiro Takeyama: Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk Pharma Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Company Limited, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Pfizer Japan Inc., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Fujimoto Pharmaceutical Corporation, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Bayer Yakuhin, Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, KM Biologics Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Kenichi Ogiwara: Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Naoki Ozu: None declared, Kana Sasai: None declared, Masato Kasahara: Kissei Co.,Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novartis Pharma KK., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Otsuka Pharmaceutical Co.,Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Asteki holdings Co.,Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Yasuko Furuichi: None declared, Toshio Takase: None declared, Iyou Nakagawa: None declared, Katsuyuki Fukutake: Chugai Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Pfizer Japan Inc., Sanofi K.K, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Chugai Pharmaceutical Co., Ltd, CellGen Tech Inc., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Akira Ishiguro: Novo Nordisk, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Co, LTD, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co, LTD, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Pfizer, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Japan Blood Products Organization, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Kagehiro Amano: Pfizer, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Bayer, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sekisui Medical Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Fujimoto Pharmaceutical, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, KM biologics, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk Pharma, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Eisuke Adachi: ViiV Healthcare, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Gilead Sciences, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, GlaxoSmithKline, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Merck & Co., Inc., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, AbbVie GK, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Kumiko Ono: Bayer Yakuhin, Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk Pharma Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Company Limited, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Fujimoto Pharmaceutical Corporation, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chiai Nagae: Chugai Pharmaceutical Co., Ltd, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Co. Ltd, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Atsuki Yamashita: Fujimoto Pharmaceutical Corporation, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk Pharma Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Bayer Yakuhin, Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Satoshi Higasa: CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk Pharma Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Bayer Yakuhin, Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Company Limited, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Teruhisa Fujii: Bayer Yakuhin, Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Japan Blood Products Organization, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Pfizer Japan Inc., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk Pharma Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, KM Biologics Co., Ltd., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Fujimoto Pharmaceutical Corporation, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Company Limited, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Masanori Matsumoto: Takeda, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Alexion, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Alfessa Pharma Corporation, Consultancy (Includes expert testimony): No, Patents & Royalties: Yes, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Midori Shima: Sanofi S.A., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring Co., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk A/S, Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Chugai Pharmaceutical Co., Ltd., Consultancy (Includes expert testimony): Yes, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: No, Pfizer Inc., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Keiji Nogami: Bayer, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Takeda Pharmaceutical Co., Ltd, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Pfizer, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: No, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sekisui Medical Co. Ltd, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Sanofi, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Fujimoto Pharmaceutical Co., Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Novo Nordisk, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, Chugai Pharmaceutical Co., Ltd, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, CSL Behring, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes, KM Biologics, Consultancy (Includes expert testimony): No, Patents & Royalties: No, Ended employment in the past 24 months: No, Research Funding: Yes, Divested equity in a private or publicly-traded company in the past 24 months: No, Current equity holder in publicly-traded company: No, Current Employment: No, Current holder of stock options in a privately-held company: No, Current equity holder in private company: No, Honoraria: Yes