Masashi Taki - Academia.edu (original) (raw)

Papers by Masashi Taki

Research paper thumbnail of Two Possible Pathways for Acquisition of Mutations Related to Nelfinavir Resistance

Japanese Journal of Infectious Diseases, 1999

Research paper thumbnail of Status of Anti HIV-1 Chemotherapy in Japan

Japanese Journal of Infectious Diseases, 1999

Research paper thumbnail of Safety and Prophylactic Efficacy Profiles of ACE910, a Humanized Bispecific Antibody Mimicking the FVIII Cofactor Function, in Japanese Hemophilia A Patients Both without and with FVIII Inhibitors: First-in-Patient Phase 1 Study

Blood, 2014

Background: Although routine supplementation of exogenous factor VIII (FVIII) effectively prevent... more Background: Although routine supplementation of exogenous factor VIII (FVIII) effectively prevents bleeding complications in hemophilia A patients, the development of FVIII inhibitors and the need for frequent venous access are still problematic. To overcome these medical problems, a humanized bispecific antibody to factors IXa and X (ACE910) mimicking the FVIII cofactor function has been created. Objectives: To investigate the safety, pharmacokinetic and pharmacodynamic profiles of ACE910 as well as its prophylactic efficacy on bleeding, a first-in-patient open-label phase I study was conducted with once-weekly subcutaneous (SC) administration of ACE910 in Japanese hemophilia A patients both without and with FVIII inhibitors. Methods: In the present study, Japanese patients with severe hemophilia A (FVIII:C <1%, ages 12 to 59 years) were treated with once-weekly SC ACE910 at one of the following dose levels for 12 successive weeks: 0.3 (C-1), 1 (C-2) and 3 mg/kg (C-3). Loading d...

Research paper thumbnail of Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI

Blood, 2015

[Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can e... more [Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can eradicate factor (F)VIII and FIX inhibitors in patients with hemophilia A (HA) and B (HB), respectively. Although results of several retrospective cohort studies have been published, predictors of successful outcome are still debated. Nonetheless, little information is so far available in terms of large ITI cohort in non-Caucasian countries. [Aim] In this study, we performed a retrospective cohort study on ITI therapy carried out for Japanese hemophilia patients with inhibitors to understand the status of practice on this therapy in Japan and to study the predictors of successful outcome. [Methods] As of March 31, 2015, the registry of ITI therapy in Japanese hemophilia patients had received reports on 155 HA patients (140 severe type, high responder 69.1%) and 7 HB patients (7 severe type, high responder 42.5%) who have undergone this therapy from 45 hospitals including Hemophilia Treatment Centers since 2000. The ITI outcome was centrally reviewed. The success of ITI was defined as an undetectable inhibitor for 2 successive measurements, and the salvage ITI was defined as any rescue ITI regimen by using von Willebrand factor-containing FVIII concentrates. [Results] Among the completed ITI courses, the overall success rate of ITI therapy was 71.2% (94/132) and 83.3% (5/6) for HA and HB patients, respectively. Cumulated ITI success rates of 50% and 80% for HA patients were achieved at 1.6 and 4.3 years after the inhibitor diagnosis, and 0.6 and 2.3 years after the initiation of ITI, respectively. Significant predictors for success of ITI in HA were (i) low responding inhibitors (success 35/37 (94.5%)) compared to high responding inhibitors (59/93 (63.4%); p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001), (ii) shorter intervals from inhibitor diagnosis to the initiation of ITI (success (S): 1.85±3.52 vs failure (F): 3.38±3.77 years; p =0.02), (iii) lower historical peak titers on pre-ITI (S: 24.9±55.2 vs F: 132±295 BU/ml; p =0.04), and (iv) lower peak inhibitor titers on-ITI (S: 72.4±231 vs F: 916±1,307 BU/ml; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). However, outcome was not significantly different (p =0.77) between high dose regimens (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90 IU/kg, 7 days/wk) and low dose regimens (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 IU/kg, 3 days/wk). Also, either FVIII products (plasma-derived or recombinant) at the initiation or the insertion of central venous access devise (CVAD) did not affect the outcome (p =0.32 and 0.85). Although the outcome prediction was difficult for HB because of low number of the cases registered, success rate was much higher than those of previous reports. The success rate of salvage ITI was 50% (6/12) for HA. The significant predictive parameter for outcome was only the age at the initiation of salvage ITI (p =0.03). The inhibitor relapsed in 6 cases, and all cases were HA patients (4.5% 6/140). In 86 cases with insertion of CVAD, the catheter-related infection was complicated in 21 cases (12.9%). [Conclusion] This study underscores the importance of initiating the ITI as early as possible after the diagnosis of inhibitor and the low response of inhibitor titer before and during the…

Research paper thumbnail of Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors

Blood advances, Jan 10, 2017

Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII... more Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remain...

Research paper thumbnail of Sub analysis of Japanese patients with hemophilia B in rIX-FP clinical trial

Japanese Journal of Thrombosis and Hemostasis, 2017

A recombinant coagulation factor IX albumin fusion protein (rIX-FP, CSL654) was developed with an... more A recombinant coagulation factor IX albumin fusion protein (rIX-FP, CSL654) was developed with an improved PK profile to support a longer dosing interval for routine prophylaxis treatment. Japanese subjects have participated in a Study CSL654_3001, phase 3 open label, multinational, pivotal study of rIX-FP. Male hemophilia B patients with no inhibitor, 12-65 years of age, at least 150 exposure days with previous FIX products were eligible for enrollment. 10 of the 63 Study 3001 subjects were recruited in Japan. The mean t 1/2 of rIX-FP in Japanese and all subjects were 95 h and 102 h respectively. The mean annualized spontaneous bleeding rate in Japanese and all subjects were 12.8 and 14.6 respectively for on-demand treatment, 1.8 and 0.6 respectively for weekly prophylaxis regimen, 0.4 and 1.1 respectively for every 2 weeks prophylaxis regimen. No patient developed an inhibitor and no safety concerns were identified in Study 3001. The results of Japanese subjects were consistent with those observed for the global population. rIX-FP is safe and effective for preventing bleeding episodes at weekly and every 2 weeks dosing regimens in Japanese patients with hemophilia B.

Research paper thumbnail of 川崎病の心筋障害とミオシン軽鎖 抗ヒト心筋ミオシン軽鎖モノクローナル抗体を用いた検討

Research paper thumbnail of Japanese subject subpopulation analysis of B-LONG: a Phase 3 study of long-acting recombinant factor IX Fc fusion protein

Japanese Journal of Thrombosis and Hemostasis, 2015

The multinational Phase 3 B-LONG study demonstrated the prolonged half-life of recombinant factor... more The multinational Phase 3 B-LONG study demonstrated the prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) versus native recombinant factor IX (rFIX), and the safety and efficacy of rFIXFc for treatment of bleeding and routine prophylaxis in subjects with hemophilia B. This post hoc subgroup analysis of B-LONG evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in Japanese subjects. Previously treated males with moderately severe to severe hemophilia B (endogenous FIX ≤2 IU/dL) received weekly prophylaxis (starting at 50 IU/kg/week, with dose adjustment), individualized interval prophylaxis (starting at 100 IU/kg every 10 days, with interval adjustment), episodic treatment, or perioperative management with rFIXFc. Primary endpoints were annualized bleeding rates (ABRs) and safety. rFIXFc pharmacokinetics were comparable between Japanese subjects (n=6) and non-Japanese subjects. Median ABRs for Japanese subjects in the weekly prophylaxis (n=4) and individualized interval prophylaxis (n=2) groups were 3.27 and 4.28, respectively, which were within the range for non-Japanese subjects. For Japanese subjects, most (95.8%) bleeding episodes were resolved with 1 or 2 rFIXFc infusions, and no treatment-related adverse events or inhibitors were observed. rFIXFc was safe and efficacious for prophylaxis and treatment of bleeding in Japanese subjects with outcomes and pharmacokinetics comparable to non-Japanese subjects.

Research paper thumbnail of Clinical Study of Recombinant Factor VIIa (NN-007) in Hemophilia Patients with Inhibitors

Japanese Journal of Thrombosis and Hemostasis, 1994

Phase I study was conducted to evaluate the pharmacokinetics and safety of two dose levels of rec... more Phase I study was conducted to evaluate the pharmacokinetics and safety of two dose levels of recombinant factor Vila (rF VIIa, NN-007) in two hemophilia A patients with inhibitor. The mean half-life of rF Vila was 2.5±0.5 hours. rF VIIa shortened the activated partial thromboplastin time (APTT) and the prothrombin time (PT). No adverse events were observed.Phase III study was conducted to evaluate the safety, efficacy and also pharmacokinetics of rF VIIa in 17 hemophilia A or B patients with inhibitor. The mean half-life of rF VIIa was 2.6±0.5 hours. Both the APTT and the PT were significantly shortened by rF VIIa. In 407 bleeding episodes treated with rF VIIa the efficacy rate of hemostatic effect was 72.7%. No adverse events including laboratory or clinical DIC were observed during the study. There was no indication of new antibody formation against rF VIIa, BHK protein, murine IgG and bovine serum protein.These results indicate that rF VIIa is safe and effective for the hemostatic management in hemophiliacs with inhibitor.

Research paper thumbnail of Successful treatment with vincristine of an infant with intractable Kasabach-Merritt syndrome

Pediatrics international : official journal of the Japan Pediatric Society, 2006

Correspondence : Masashi Taki MD, Department of Pediatrics, St. Marianna University School of Med... more Correspondence : Masashi Taki MD, Department of Pediatrics, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. Email: m2taki@ marianna-u.ac.jp Received 9 September 2004; revised 12 January 2005; accepted 14 January 2005. Kasabach – Merritt syndrome (KMS) is a congenital disorder in which severe signifi cant thrombocytopenia and consumption coagulopathy are accompanied by rapidly expanding hemangiomas of the trunk, extremities and/or abdominal viscera, sometimes associated with bleeding and anemia. 1 Although this disorder is found in only about 1% of the children with hemangioma, its mortality rate reaches around 50% because of complications such as disseminated intravascular coagulation (DIC), respiratory failure due to a pressured airway, and highoutput heart failure due to the presence of huge hemangiomas. 2

Research paper thumbnail of 血友病在宅自己注射療法の基本ガイドライン（２００３年版）

Japanese Journal of Thrombosis and Hemostasis, 2003

Research paper thumbnail of The International Immune Tolerance Induction Study and its follow-up study on Japanese hemophilia A patients with inhibitors

International Journal of Hematology, 2015

14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of the... more 14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study Abstract The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I-ITI off-study, three cases of I-ITI onstudy, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low-dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in

Research paper thumbnail of Current use of bypassing agents in Japan in patients with congenital hemophilia and inhibitors

Japanese Journal of Thrombosis and Hemostasis, 2007

Research paper thumbnail of A 3-year consecutive survey on current status of acquired inhibitors against coagulation factors in Japan

Japanese Journal of Thrombosis and Hemostasis, 2008

Research paper thumbnail of Support for patients with hemophilia affected by the Great East Japan Earthquake

Japanese Journal of Thrombosis and Hemostasis, 2011

Research paper thumbnail of Japanese clinical study of single/high dose treatment by recombinant activated factor VII for haemophilia patients with inhibitors

Japanese Journal of Thrombosis and Hemostasis, 2008

遺伝子組換え活性型凝固第 VII 因子製剤(rFVIIa：注射用ノボセブン ®)は，インヒビターを保有 する血友病 A および B 患者の止血を目的に開発されたバイパス止血製剤である．海外では ... more 遺伝子組換え活性型凝固第 VII 因子製剤(rFVIIa：注射用ノボセブン ®)は，インヒビターを保有 する血友病 A および B 患者の止血を目的に開発されたバイパス止血製剤である．海外では rFVIIa 高 用量単回投与の臨床研究が複数行われ，2007 年 EU において高用量単回投与法が正式に承認された． 今回，国内で行われた，高用量(270 μg / kg)単回投与に関する医師主導型臨床研究の結果を報告す る． 第 I 相試験では rFVIIa 270 μg / kg 単回投与に対する安全性と凝血学的薬理作用を検証した． さらに， 第 II 相試験では 270 μg / kg の高用量単回投与と 90 μg / kg の標準用量 3 回投与における有効性と安全 性の差異を，無作為割り付けクロスオーバー方式で検討した．その結果，第 I 相試験では 270 μg / kg 単回投与の安全性と薬理作用が裏付けられた．さらに第Ⅱ相試験において 270 μg / kg 単回投与法は， 標準投与法に比べ，同等以上の有効性を示した．また，安全性においても，高用量単回投与法で新 たに問題となる事象は認められなかった．以上の結果から，患者・家族の負担を軽減し，QOL の改 善につながる高用量単回投与法を我が国においても普及させるべきである．

Research paper thumbnail of HLA-B Polymorphism in Japanese HIV-1–Infected Long-Term Surviving Hemophiliacs

Viral Immunology, 2005

Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency ... more Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency virus (HIV) in early 1980s through contaminated blood products. In 1995, a cohort of HIVinfected, asymptomatic patients with hemophilia was set up for follow-up study. Although the patients met the criteria for long-term non-progressor (LTNP) at the entry to the cohort, some of them later developed lymphopenia during five more years of observation. We collected blood samples from 80 long-term survivors; 42 of them did not require antiviral therapy, but the rest were under treatment. Analysis of HLA-B genotype revealed that carriers of known HIV-resistant alleles such as HLA-B*5701, B*5801, and alleles of B27 antigenic group were not increased in frequency, but that HLA-B*1507 was increased in the cohort (6.25% vs. 1.03%, OR ‫؍‬ 6.40, p ‫؍‬ 0.039). We also observed the decrease in carriers of HLA-B*5401 (3.75% vs. 14.95%, OR ‫؍‬ 0.22, p ‫؍‬ 0.016). HLA-B*5401 is a relatively common allele in East Asian populations and belongs to the same B22 antigenic group as B55 and B56 which were reported to associate with rapid progression. Our data indicated that HLA class I is one of the host factors involved in the retardation of HIV disease progression as also reported in the previous studies; however, the alleles associated with this resistance were not the same because of divergent host genetic background.

Research paper thumbnail of Current status of Japanese HIV-infected patients with coagulation disorders: coinfection with both HIV and HCV

International Journal of Hematology, 2008

We herein report on the current status of Japanese HIV-positive patients with coagulation disorde... more We herein report on the current status of Japanese HIV-positive patients with coagulation disorders, primarily hemophilia, based on the national survey of 31 May 2006. The total number of registered patients was 1,431 (Hemophilia A 1,086; Hemophilia B 325; von Willebrand disease 8; others 12), and 604 of these patients were deceased by 31 May 2006. The survival rate after the beginning of 1983 was evaluated by the Kaplan-Meier method. The total number of surviving patients was 827, and the survival rate on 31 May 2006 was 55.7 ± 1.4%. Among the 827 surviving patients, HCV antibody was observed in 740, was negative in 16, and was not reported in 71 patients. Thus, the prevalence of HCV infection was 98% in the surviving patients based on the presence of HCV antibody. Among the 604 deceased patients, liver disease was reported as a cause of death in 149 cases (25%), and infection with HCV was reported as the possible cause of liver disease in 120 cases (20%). After 1997, 63 cases among the subtotal of 148 deaths had critical hepatic disease that originated from HCV infection, which accounted for 43% of the subtotal. The cumulative rate of patients who received interferon therapy was 32%. Interferon therapy should be prescribed more frequently to HIVpositive patients with coagulation disorders in order to realize the survival benefits, although clinicians should be aware of side effects and toxicities.

Research paper thumbnail of The Number of People in Japan with Coagulation Disorders: 2001 Update

International Journal of Hematology, 2003

Surveillance of people in Japan with coagulation disorders was first conducted by Yoshida et al a... more Surveillance of people in Japan with coagulation disorders was first conducted by Yoshida et al and thereafter was carried out by Fukui et al every 5 years until 1991 [1]. From 1997 to 2000, coagulation disorder surveillance was included in a national surveillance exercise to monitor acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV)-1 infection in Japan and was carried out by research units sponsored by the Health Science Research Grants on HIV/AIDS, Ministry of Health, Labour and Welfare [2,3]. A new research unit was established in April 2001, the Research Committee on National Surveillance of Coagulation Disorders in Japan, to continue surveillance beyond 2001. The committee is affiliated with the Japanese Foundation for AIDS Prevention and monitors the clinical status and therapy of patients with coagulation disorders throughout Japan. It consists of a Clinical Subcommittee and a Quality of Life Subcommittee, the members of which are physicians, medical researchers, and patients with coagulation disorders. This letter summarizes the latest information on the number of people in Japan with coagulation disorders as of the end of May 2001. The subjects of the surveillance were patients with coagulation disorders who were alive during the interval from the beginning of June 2000 to the end of May 2001, including those who died during that interval. Taxonomy of subjects

Research paper thumbnail of Prevalence of Hepatitis C Virus Infection in Coagulation Disorders in Japan

International Journal of Hematology, 2003

Research paper thumbnail of Two Possible Pathways for Acquisition of Mutations Related to Nelfinavir Resistance

Japanese Journal of Infectious Diseases, 1999

Research paper thumbnail of Status of Anti HIV-1 Chemotherapy in Japan

Japanese Journal of Infectious Diseases, 1999

Research paper thumbnail of Safety and Prophylactic Efficacy Profiles of ACE910, a Humanized Bispecific Antibody Mimicking the FVIII Cofactor Function, in Japanese Hemophilia A Patients Both without and with FVIII Inhibitors: First-in-Patient Phase 1 Study

Blood, 2014

Background: Although routine supplementation of exogenous factor VIII (FVIII) effectively prevent... more Background: Although routine supplementation of exogenous factor VIII (FVIII) effectively prevents bleeding complications in hemophilia A patients, the development of FVIII inhibitors and the need for frequent venous access are still problematic. To overcome these medical problems, a humanized bispecific antibody to factors IXa and X (ACE910) mimicking the FVIII cofactor function has been created. Objectives: To investigate the safety, pharmacokinetic and pharmacodynamic profiles of ACE910 as well as its prophylactic efficacy on bleeding, a first-in-patient open-label phase I study was conducted with once-weekly subcutaneous (SC) administration of ACE910 in Japanese hemophilia A patients both without and with FVIII inhibitors. Methods: In the present study, Japanese patients with severe hemophilia A (FVIII:C <1%, ages 12 to 59 years) were treated with once-weekly SC ACE910 at one of the following dose levels for 12 successive weeks: 0.3 (C-1), 1 (C-2) and 3 mg/kg (C-3). Loading d...

Research paper thumbnail of Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI

Blood, 2015

[Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can e... more [Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can eradicate factor (F)VIII and FIX inhibitors in patients with hemophilia A (HA) and B (HB), respectively. Although results of several retrospective cohort studies have been published, predictors of successful outcome are still debated. Nonetheless, little information is so far available in terms of large ITI cohort in non-Caucasian countries. [Aim] In this study, we performed a retrospective cohort study on ITI therapy carried out for Japanese hemophilia patients with inhibitors to understand the status of practice on this therapy in Japan and to study the predictors of successful outcome. [Methods] As of March 31, 2015, the registry of ITI therapy in Japanese hemophilia patients had received reports on 155 HA patients (140 severe type, high responder 69.1%) and 7 HB patients (7 severe type, high responder 42.5%) who have undergone this therapy from 45 hospitals including Hemophilia Treatment Centers since 2000. The ITI outcome was centrally reviewed. The success of ITI was defined as an undetectable inhibitor for 2 successive measurements, and the salvage ITI was defined as any rescue ITI regimen by using von Willebrand factor-containing FVIII concentrates. [Results] Among the completed ITI courses, the overall success rate of ITI therapy was 71.2% (94/132) and 83.3% (5/6) for HA and HB patients, respectively. Cumulated ITI success rates of 50% and 80% for HA patients were achieved at 1.6 and 4.3 years after the inhibitor diagnosis, and 0.6 and 2.3 years after the initiation of ITI, respectively. Significant predictors for success of ITI in HA were (i) low responding inhibitors (success 35/37 (94.5%)) compared to high responding inhibitors (59/93 (63.4%); p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001), (ii) shorter intervals from inhibitor diagnosis to the initiation of ITI (success (S): 1.85±3.52 vs failure (F): 3.38±3.77 years; p =0.02), (iii) lower historical peak titers on pre-ITI (S: 24.9±55.2 vs F: 132±295 BU/ml; p =0.04), and (iv) lower peak inhibitor titers on-ITI (S: 72.4±231 vs F: 916±1,307 BU/ml; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). However, outcome was not significantly different (p =0.77) between high dose regimens (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90 IU/kg, 7 days/wk) and low dose regimens (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75 IU/kg, 3 days/wk). Also, either FVIII products (plasma-derived or recombinant) at the initiation or the insertion of central venous access devise (CVAD) did not affect the outcome (p =0.32 and 0.85). Although the outcome prediction was difficult for HB because of low number of the cases registered, success rate was much higher than those of previous reports. The success rate of salvage ITI was 50% (6/12) for HA. The significant predictive parameter for outcome was only the age at the initiation of salvage ITI (p =0.03). The inhibitor relapsed in 6 cases, and all cases were HA patients (4.5% 6/140). In 86 cases with insertion of CVAD, the catheter-related infection was complicated in 21 cases (12.9%). [Conclusion] This study underscores the importance of initiating the ITI as early as possible after the diagnosis of inhibitor and the low response of inhibitor titer before and during the…

Research paper thumbnail of Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors

Blood advances, Jan 10, 2017

Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII... more Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remain...

Research paper thumbnail of Sub analysis of Japanese patients with hemophilia B in rIX-FP clinical trial

Japanese Journal of Thrombosis and Hemostasis, 2017

A recombinant coagulation factor IX albumin fusion protein (rIX-FP, CSL654) was developed with an... more A recombinant coagulation factor IX albumin fusion protein (rIX-FP, CSL654) was developed with an improved PK profile to support a longer dosing interval for routine prophylaxis treatment. Japanese subjects have participated in a Study CSL654_3001, phase 3 open label, multinational, pivotal study of rIX-FP. Male hemophilia B patients with no inhibitor, 12-65 years of age, at least 150 exposure days with previous FIX products were eligible for enrollment. 10 of the 63 Study 3001 subjects were recruited in Japan. The mean t 1/2 of rIX-FP in Japanese and all subjects were 95 h and 102 h respectively. The mean annualized spontaneous bleeding rate in Japanese and all subjects were 12.8 and 14.6 respectively for on-demand treatment, 1.8 and 0.6 respectively for weekly prophylaxis regimen, 0.4 and 1.1 respectively for every 2 weeks prophylaxis regimen. No patient developed an inhibitor and no safety concerns were identified in Study 3001. The results of Japanese subjects were consistent with those observed for the global population. rIX-FP is safe and effective for preventing bleeding episodes at weekly and every 2 weeks dosing regimens in Japanese patients with hemophilia B.

Research paper thumbnail of 川崎病の心筋障害とミオシン軽鎖 抗ヒト心筋ミオシン軽鎖モノクローナル抗体を用いた検討

Research paper thumbnail of Japanese subject subpopulation analysis of B-LONG: a Phase 3 study of long-acting recombinant factor IX Fc fusion protein

Japanese Journal of Thrombosis and Hemostasis, 2015

The multinational Phase 3 B-LONG study demonstrated the prolonged half-life of recombinant factor... more The multinational Phase 3 B-LONG study demonstrated the prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) versus native recombinant factor IX (rFIX), and the safety and efficacy of rFIXFc for treatment of bleeding and routine prophylaxis in subjects with hemophilia B. This post hoc subgroup analysis of B-LONG evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in Japanese subjects. Previously treated males with moderately severe to severe hemophilia B (endogenous FIX ≤2 IU/dL) received weekly prophylaxis (starting at 50 IU/kg/week, with dose adjustment), individualized interval prophylaxis (starting at 100 IU/kg every 10 days, with interval adjustment), episodic treatment, or perioperative management with rFIXFc. Primary endpoints were annualized bleeding rates (ABRs) and safety. rFIXFc pharmacokinetics were comparable between Japanese subjects (n=6) and non-Japanese subjects. Median ABRs for Japanese subjects in the weekly prophylaxis (n=4) and individualized interval prophylaxis (n=2) groups were 3.27 and 4.28, respectively, which were within the range for non-Japanese subjects. For Japanese subjects, most (95.8%) bleeding episodes were resolved with 1 or 2 rFIXFc infusions, and no treatment-related adverse events or inhibitors were observed. rFIXFc was safe and efficacious for prophylaxis and treatment of bleeding in Japanese subjects with outcomes and pharmacokinetics comparable to non-Japanese subjects.

Research paper thumbnail of Clinical Study of Recombinant Factor VIIa (NN-007) in Hemophilia Patients with Inhibitors

Japanese Journal of Thrombosis and Hemostasis, 1994

Phase I study was conducted to evaluate the pharmacokinetics and safety of two dose levels of rec... more Phase I study was conducted to evaluate the pharmacokinetics and safety of two dose levels of recombinant factor Vila (rF VIIa, NN-007) in two hemophilia A patients with inhibitor. The mean half-life of rF Vila was 2.5±0.5 hours. rF VIIa shortened the activated partial thromboplastin time (APTT) and the prothrombin time (PT). No adverse events were observed.Phase III study was conducted to evaluate the safety, efficacy and also pharmacokinetics of rF VIIa in 17 hemophilia A or B patients with inhibitor. The mean half-life of rF VIIa was 2.6±0.5 hours. Both the APTT and the PT were significantly shortened by rF VIIa. In 407 bleeding episodes treated with rF VIIa the efficacy rate of hemostatic effect was 72.7%. No adverse events including laboratory or clinical DIC were observed during the study. There was no indication of new antibody formation against rF VIIa, BHK protein, murine IgG and bovine serum protein.These results indicate that rF VIIa is safe and effective for the hemostatic management in hemophiliacs with inhibitor.

Research paper thumbnail of Successful treatment with vincristine of an infant with intractable Kasabach-Merritt syndrome

Pediatrics international : official journal of the Japan Pediatric Society, 2006

Correspondence : Masashi Taki MD, Department of Pediatrics, St. Marianna University School of Med... more Correspondence : Masashi Taki MD, Department of Pediatrics, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. Email: m2taki@ marianna-u.ac.jp Received 9 September 2004; revised 12 January 2005; accepted 14 January 2005. Kasabach – Merritt syndrome (KMS) is a congenital disorder in which severe signifi cant thrombocytopenia and consumption coagulopathy are accompanied by rapidly expanding hemangiomas of the trunk, extremities and/or abdominal viscera, sometimes associated with bleeding and anemia. 1 Although this disorder is found in only about 1% of the children with hemangioma, its mortality rate reaches around 50% because of complications such as disseminated intravascular coagulation (DIC), respiratory failure due to a pressured airway, and highoutput heart failure due to the presence of huge hemangiomas. 2

Research paper thumbnail of 血友病在宅自己注射療法の基本ガイドライン（２００３年版）

Japanese Journal of Thrombosis and Hemostasis, 2003

Research paper thumbnail of The International Immune Tolerance Induction Study and its follow-up study on Japanese hemophilia A patients with inhibitors

International Journal of Hematology, 2015

14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of the... more 14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study Abstract The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I-ITI off-study, three cases of I-ITI onstudy, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low-dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in

Research paper thumbnail of Current use of bypassing agents in Japan in patients with congenital hemophilia and inhibitors

Japanese Journal of Thrombosis and Hemostasis, 2007

Research paper thumbnail of A 3-year consecutive survey on current status of acquired inhibitors against coagulation factors in Japan

Japanese Journal of Thrombosis and Hemostasis, 2008

Research paper thumbnail of Support for patients with hemophilia affected by the Great East Japan Earthquake

Japanese Journal of Thrombosis and Hemostasis, 2011

Research paper thumbnail of Japanese clinical study of single/high dose treatment by recombinant activated factor VII for haemophilia patients with inhibitors

Japanese Journal of Thrombosis and Hemostasis, 2008

遺伝子組換え活性型凝固第 VII 因子製剤(rFVIIa：注射用ノボセブン ®)は，インヒビターを保有 する血友病 A および B 患者の止血を目的に開発されたバイパス止血製剤である．海外では ... more 遺伝子組換え活性型凝固第 VII 因子製剤(rFVIIa：注射用ノボセブン ®)は，インヒビターを保有 する血友病 A および B 患者の止血を目的に開発されたバイパス止血製剤である．海外では rFVIIa 高 用量単回投与の臨床研究が複数行われ，2007 年 EU において高用量単回投与法が正式に承認された． 今回，国内で行われた，高用量(270 μg / kg)単回投与に関する医師主導型臨床研究の結果を報告す る． 第 I 相試験では rFVIIa 270 μg / kg 単回投与に対する安全性と凝血学的薬理作用を検証した． さらに， 第 II 相試験では 270 μg / kg の高用量単回投与と 90 μg / kg の標準用量 3 回投与における有効性と安全 性の差異を，無作為割り付けクロスオーバー方式で検討した．その結果，第 I 相試験では 270 μg / kg 単回投与の安全性と薬理作用が裏付けられた．さらに第Ⅱ相試験において 270 μg / kg 単回投与法は， 標準投与法に比べ，同等以上の有効性を示した．また，安全性においても，高用量単回投与法で新 たに問題となる事象は認められなかった．以上の結果から，患者・家族の負担を軽減し，QOL の改 善につながる高用量単回投与法を我が国においても普及させるべきである．

Research paper thumbnail of HLA-B Polymorphism in Japanese HIV-1–Infected Long-Term Surviving Hemophiliacs

Viral Immunology, 2005

Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency ... more Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency virus (HIV) in early 1980s through contaminated blood products. In 1995, a cohort of HIVinfected, asymptomatic patients with hemophilia was set up for follow-up study. Although the patients met the criteria for long-term non-progressor (LTNP) at the entry to the cohort, some of them later developed lymphopenia during five more years of observation. We collected blood samples from 80 long-term survivors; 42 of them did not require antiviral therapy, but the rest were under treatment. Analysis of HLA-B genotype revealed that carriers of known HIV-resistant alleles such as HLA-B*5701, B*5801, and alleles of B27 antigenic group were not increased in frequency, but that HLA-B*1507 was increased in the cohort (6.25% vs. 1.03%, OR ‫؍‬ 6.40, p ‫؍‬ 0.039). We also observed the decrease in carriers of HLA-B*5401 (3.75% vs. 14.95%, OR ‫؍‬ 0.22, p ‫؍‬ 0.016). HLA-B*5401 is a relatively common allele in East Asian populations and belongs to the same B22 antigenic group as B55 and B56 which were reported to associate with rapid progression. Our data indicated that HLA class I is one of the host factors involved in the retardation of HIV disease progression as also reported in the previous studies; however, the alleles associated with this resistance were not the same because of divergent host genetic background.

Research paper thumbnail of Current status of Japanese HIV-infected patients with coagulation disorders: coinfection with both HIV and HCV

International Journal of Hematology, 2008

We herein report on the current status of Japanese HIV-positive patients with coagulation disorde... more We herein report on the current status of Japanese HIV-positive patients with coagulation disorders, primarily hemophilia, based on the national survey of 31 May 2006. The total number of registered patients was 1,431 (Hemophilia A 1,086; Hemophilia B 325; von Willebrand disease 8; others 12), and 604 of these patients were deceased by 31 May 2006. The survival rate after the beginning of 1983 was evaluated by the Kaplan-Meier method. The total number of surviving patients was 827, and the survival rate on 31 May 2006 was 55.7 ± 1.4%. Among the 827 surviving patients, HCV antibody was observed in 740, was negative in 16, and was not reported in 71 patients. Thus, the prevalence of HCV infection was 98% in the surviving patients based on the presence of HCV antibody. Among the 604 deceased patients, liver disease was reported as a cause of death in 149 cases (25%), and infection with HCV was reported as the possible cause of liver disease in 120 cases (20%). After 1997, 63 cases among the subtotal of 148 deaths had critical hepatic disease that originated from HCV infection, which accounted for 43% of the subtotal. The cumulative rate of patients who received interferon therapy was 32%. Interferon therapy should be prescribed more frequently to HIVpositive patients with coagulation disorders in order to realize the survival benefits, although clinicians should be aware of side effects and toxicities.

Research paper thumbnail of The Number of People in Japan with Coagulation Disorders: 2001 Update

International Journal of Hematology, 2003

Surveillance of people in Japan with coagulation disorders was first conducted by Yoshida et al a... more Surveillance of people in Japan with coagulation disorders was first conducted by Yoshida et al and thereafter was carried out by Fukui et al every 5 years until 1991 [1]. From 1997 to 2000, coagulation disorder surveillance was included in a national surveillance exercise to monitor acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV)-1 infection in Japan and was carried out by research units sponsored by the Health Science Research Grants on HIV/AIDS, Ministry of Health, Labour and Welfare [2,3]. A new research unit was established in April 2001, the Research Committee on National Surveillance of Coagulation Disorders in Japan, to continue surveillance beyond 2001. The committee is affiliated with the Japanese Foundation for AIDS Prevention and monitors the clinical status and therapy of patients with coagulation disorders throughout Japan. It consists of a Clinical Subcommittee and a Quality of Life Subcommittee, the members of which are physicians, medical researchers, and patients with coagulation disorders. This letter summarizes the latest information on the number of people in Japan with coagulation disorders as of the end of May 2001. The subjects of the surveillance were patients with coagulation disorders who were alive during the interval from the beginning of June 2000 to the end of May 2001, including those who died during that interval. Taxonomy of subjects

Research paper thumbnail of Prevalence of Hepatitis C Virus Infection in Coagulation Disorders in Japan

International Journal of Hematology, 2003