Masashi Taki

Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A

BACKGROUND In patients with severe hemophilia A, standard treatment is regular prophylactic and episodic intravenous infusions of factor VIII. However, these treatments are burdensome, especially for children, and may lead to the formation of anti-factor VIII alloantibodies (factor VIII inhibitors). Emicizumab (ACE910), a humanized bispecific antibody mimicking the cofactor function of factor VIII, was developed to abate these problems. METHODS We enrolled 18 Japanese patients with severe hemophilia A (with or without factor VIII inhibitors) in an open-label, nonrandomized, interindividual dose-escalation study of emicizumab. The patients received subcutaneous emicizumab weekly for 12 weeks at a dose of 0.3, 1.0, or 3.0 mg per kilogram of body weight (cohorts 1, 2, and 3, respectively). The end points were safety and pharmacokinetic and pharmacodynamic profiles. An additional, exploratory end point was the annualized bleeding rate, calculated as 365.25 times the number of bleeding episodes, divided by the number of days in the treatment period as compared with the 6 months before enrollment. RESULTS Emicizumab was associated with neither serious adverse events nor clinically relevant coagulation abnormalities. Plasma concentrations of emicizumab increased in a dose-dependent manner. Activated partial-thromboplastin times remained short throughout the study. The median annualized bleeding rates in cohorts 1, 2, and 3 decreased from 32.5 to 4.4, 18.3 to 0.0, and 15.2 to 0.0, respectively. There was no bleeding in 8 of 11 patients with factor VIII inhibitors (73%) and in 5 of 7 patients without factor VIII inhibitors (71%). Episodic use of clotting factors to control bleeding was reduced. Antibodies to emicizumab did not develop. CONCLUSIONS Once-weekly subcutaneous administration of emicizumab markedly decreased the bleeding rate in patients who had hemophilia A with or without factor VIII inhibitors. (Funded by Chugai Pharmaceutical; JapicCTI number, 121934.).

Prevalence and persistence of a novel DNA TT virus (TTV) infection in Japanese haemophiliacs.

To clarify the clinical implication of a newly discovered ‘TT virus (TTV)’, we assayed TTV DNA in sera from 50 haemophiliacs by a seminested‐PCR. TTV DNA was detected in 75% (35/50), which was a much higher prevalence than for HBV (HBc‐Ab), HCV RNA, or HGV RNA. In particular, TTV DNA was found in 44.4% (4/8) of patients who had been treated only with virally inactivated factor VIII concentrates. Elevated ALT levels were observed in patients with HCV RNA and TTV DNA; however, the elevation in TTV DNA was obtained from patients co‐infected with HCV RNA (62.9%, 22/35). There was no significant difference in ALT levels between TTV DNA‐positive and DNA‐negative in patients without HCV RNA. 85.3% (35/41) of TTV DNA‐positive sera in 1990 were again positive for TTV DNA in 1995. These findings suggest that many haemophiliacs have been infected with TTV. Although TTV infection was not associated with serum ALT elevation, persistent TTV infection may contribute to cryptogenic hepatic failure in haemophiliacs.

Increasing Incidence of Critical Liver Disease among Causes of Death in Japanese Hemophiliacs with HIV-1

Critical liver diseases are now major causes of death in HIV-1-infected patients after the remarkable improvement in the clinical status resulting from highly active antiretroviral therapy. We report the results of an analysis on causes of deaths related to liver diseases based on our surveillance of hemophiliacs infected with HIV-1 up until May 31, 2002. A total of 1,405 patients (hemophilia A, 1,084, and hemophilia B, 321) were registered. The cumulative number of deaths was 534 (hemophilia A, 414, and hemophilia B, 120) by May 31, 2002. Hepatic disease due to HCV infection was found in 29.8% (95% confidence interval: 20.3–40.7%) of the total cases with known causes of death after 1997, whereas this value was 14.0% (95% confidence interval: 10.8–17.7%) before 1997 (p < 0.01). We observed an increasing incidence of critical hepatic diseases among HIV-1-infected hemophiliacs, thus suggesting that treatment of HCV infection is essential for HIV-1-infected hemophiliacs.

Consensus guideline for diagnosis and treatment of childhood idiopathic thrombocytopenic purpura.

A practice guideline aimed at standardizing the treatment for childhood idiopathic thrombocytopenic purpura (ITP) is presented. This consensus guideline is based on a survey carried out via a questionnaire prepared by the ITP Committee of the Japanese Society of Pediatric Hematology and sent to society members. The survey questionnaire included questions on the diagnosis of ITP submitted for the purpose of revising the ITP diagnostic guideline prepared in 1990 by the Research Group for Intractable Hematopoietic Disorders; a revised diagnostic guideline also is presented.

The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals.

Pre‐existing antibodies against adeno‐associated virus (AAV), caused by natural AAV infections, interfere with recombinant AAV vector‐mediated gene transfer. We studied the prevalence of neutralizing antibodies against AAV serotypes 1, 2, 5, 8, and 9 in healthy subjects (n = 85) and hemophilia patients (n = 59) in a Japanese population. For healthy subjects, the prevalence of neutralizing antibodies against AAV serotypes 1, 2, 5, 8, and 9 was 36.5%, 35.3%, 37.6%, 32.9%, and 36.5%, respectively, while that in hemophilia patients was 39.7%, 28.8%, 35.6%, 32.9%, and 27.4%, respectively. There was no difference in the prevalence of neutralizing antibody against each AAV serotype between the healthy subjects and the hemophilia patients. The prevalence of neutralizing antibodies against all AAV serotypes increased with age in both healthy subjects and hemophilia patients. High titers of neutralizing antibodies against AAV2 (≥1:224) and AAV8 (≥1:224) were more evident in older individuals (≥42 years old). Approximately 50% of all screened individuals were seronegative for neutralizing antibodies against each AAV tested, while approximately 25% of individuals were seropositive for each AAV serotype tested. The prevalence of seronegativity for all AAV serotypes was 67.0% (healthy subjects, 68.6%; hemophilia patients, 65.0%) and 18.6% (healthy subjects, 20.5%; hemophilia patients, 15.7%) in young (<42 years old) and older subjects (≥42 years old), respectively. The findings from this study suggested that young subjects are more likely to be eligible for gene therapy based on AAV vectors delivered via an intravascular route because of the low prevalence of antibodies to AAV capsids. J. Med. Virol. 86:1990–1997, 2014.

Successful treatment with vincristine of an infant with intractable Kasabach-Merritt syndrome.

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

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

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 remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195.

Current situation of regular replacement therapy (prophylaxis) for haemophilia in Japan.

Summary.  We conducted a questionnaire survey of haemophilia treaters participating in the Fourth Seminar on Regular Replacement Therapy (sponsored by Baxter Bioscience, 4 March 2006) to clarify the current status (up to January 2006) of replacement therapy for haemophilia. The haemophilia treaters including medical doctor, nurse belonged to 48 institutions located in the 23 prefectures of Japan. Topics included age at the initiation of regular replacement therapy (prophylaxis), and expected future situation of patients who are currently receiving prophylaxis. Data were collected from 1267 patients with haemophilia A and 273 patients with haemophilia B who had been treated at the represented institutions. Of these haemophilia A and B patients, 23% and 16% had received a prophylactic treatment regimen respectively. A breakdown of each disease by severity demonstrated that of the patients with severe haemophilia A and B patients, 27% and 18% of patients received a prophylaxis treatment, compared to 17% and 19% of patients with moderate type, and 1% and 3% of patients with mild type respectively. Of those severe haemophilia A and B patients receiving prophylaxis, the percentage of primary prophylaxis, which means prophylaxis begins under 2 years of age, was still small for 24% and 29% respectively. However, approximately half of the patients received prophylaxis during the age of 2–14 years, which suggests that secondary prophylaxis is widely spread in the age group in Japan. Problems in introduction of prophylaxis include difficulty in peripheral venous access, a lack of understanding of the therapy by the caregiver. In addition, the fear of inhibitor development, as well as the psychological anxiety in paediatric patients, was also mentioned as barriers to initiating and continuing prophylaxis.

Spontaneous platelet aggregation in Kawasaki disease using the particle counting method

Abstract Background : Platelet aggregation is generally measured by the optical density method. This method is not very sensitive in detecting platelet activation because of the poor correlation between the formation of platelet aggregates and light transmission, and inability to detect small platelet aggregates. Recently, a new method was developed that detects small platelet aggregates formed in the early phase of platelet aggregation by means of a particle counting technique using light scattering.

A Nationwide Survey of Newly Diagnosed Childhood Idiopathic Thrombocytopenic Purpura in Japan

Background We evaluated the clinical pictures, outcome for childhood idiopathic thrombocytopenic purpura (ITP) and the trends of the choice of management for childhood ITP in Japan. Method Every year, questionnaires were sent to all institutions that employ the active members of the Japanese Society of Pediatric Hematology. The questionnaires included age, sex, date of diagnosis, platelet count at diagnosis, the presence or absence of antecedent infection, hemorrhagic symptoms, initial management, and the outcome of all patients newly diagnosed with ITP. Results A total of 986 newly diagnosed as ITP patients were reported between January 2000 and December 2005. The occurrence of ITP peaked in boys less than 1 year of age, and at 1 year of age in girls. The male-to-female ratio was 1.24:1. Wet purpura was observed in more than half of the patients with platelet counts of <10,000/μL. The initial treatment varied among the patients with different platelet counts at diagnosis; most of the patients with platelet counts <20,000/μL received intravenous immunoglobulin or oral corticosteroids. Conversely, cases without any aggressive treatment increased to a larger degree in patients with ≥20,000/μL of platelet. Conclusions These findings indicate that overall compliance to the Japanese guideline is considered to be relatively good in Japan.