scholarly journals An anti‐factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A

2020 ◽  
Vol 18 (4) ◽  
pp. 825-833 ◽  
Author(s):  
Masahiro Takeyama ◽  
Keiji Nogami ◽  
Tomoko Matsumoto ◽  
Mariko Noguchi‐Sasaki ◽  
Takehisa Kitazawa ◽  
...  
Keyword(s):  
Bispecific Antibody ◽  
Hemophilia A ◽  
Ex Vivo ◽  
Factor X ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Factor Ixa

scholarly journals Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

Blood ◽  
2014 ◽  
Vol 124 (20) ◽  
pp. 3165-3171 ◽  
Author(s):  
Atsushi Muto ◽  
Kazutaka Yoshihashi ◽  
Minako Takeda ◽  
Takehisa Kitazawa ◽  
Tetsuhiro Soeda ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Bispecific Antibody ◽  
Hemophilia A ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Primate Model ◽  
Factor Ixa ◽  
Key Points

Key Points A long-term acquired hemophilia A model expressing spontaneous joint bleeds and other bleeds was newly established in nonhuman primates. Weekly SC dose of the anti-FIXa/X bispecific antibody ACE910 prevented joint bleeds and other bleeds in the primate hemophilia A model.

Hemostatic Effect of a Novel Bispecific Antibody (ACE910) Against Activated Factor IX and Factor X in an Acquired Hemophilia A Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 42-42
Author(s):  
Atsushi Muto ◽  
Takehisa Kitazawa ◽  
Kazutaka Yoshihasi ◽  
Minako Takeda ◽  
Tetsuhiro Soeda ◽  
...  
Keyword(s):  
Single Dose ◽  
Bispecific Antibody ◽  
Hemophilia A ◽  
Factor Ix ◽  
Factor X ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Repeated Doses ◽  
Cofactor Activity

Abstract Abstract 42 Background: Hemophilia A is treated by intravenous replacement therapy with factor VIII (FVIII), either on demand to resolve bleeding or as a prophylactic to prevent bleeding. Recently, routine prophylactic treatment is recommended to effectively prevent bleeding and to reduce bleeding-related chronic joint damage. However, the need for frequent intravenous injections of FVIII negatively affects patients' quality of life and their adherence to the routine prophylactic regimen. More importantly, approximately 30% of severe hemophilia A patients develop inhibitory antibodies toward the injected FVIII, rendering the replacement therapy ineffective. To overcome these drawbacks, we generated a bispecific antibody (termed ACE910) against activated factor IX (FIXa) and factor X (FX), which mimics the cofactor function of FVIII. Objectives: The aims of the present study were to examine the FVIII-mimetic cofactor activity of ACE910 in vitro and its hemostatic activity in vivo. Methods: The FVIII-mimetic cofactor activity of ACE910 was evaluated by a thrombin generation assay in human FVIII-deficient plasma as well as by an enzymatic assay using purified coagulation factors. For in vivo studies, an acquired hemophilia A model was established in cynomolgus monkeys by a single intravenous injection of mouse monoclonal anti-FVIII neutralizing antibody, which was cross-reactive to cynomolgus monkey FVIII but not to porcine FVIII. After artificial bleeding had been induced, ACE910 or porcine FVIII was intravenously administered in a single dose or in twice-daily repeated doses, respectively. Bleeding symptoms, including anemia and skin bruising, were monitored for three days. A pharmacokinetic study of ACE910 was also performed with a single intravenous or subcutaneous administration to cynomolgus monkeys. Results: ACE910 concentration-dependently showed FVIII-mimetic cofactor activity in the enzymatic assay and improved thrombin generation parameters in human FVIII-deficient plasma. Intravenous administration of ACE910 (a single dose of 3 mg/kg) significantly reduced the bleeding symptoms in the acquired hemophilia A model of a non-human primate. This hemostatic effect was comparable to twice-daily intravenous administration of porcine FVIII (repeated doses of 10 U/kg). The half-life of ACE910 was approximately three weeks for both single intravenous and subcutaneous administrations. The subcutaneous bioavailability of ACE910 was nearly 100%. Conclusion: The bispecific antibody against FIXa and FX, ACE910, exerted FVIII-mimetic cofactor activity in vitro. Furthermore, a single dose of ACE910 demonstrated hemostatic activity comparable to twice-daily repeated doses of 10 U/kg porcine FVIII in vivo. Moreover, ACE910 exhibited high subcutaneous bioavailability and approximately three-week half-life in a non-human primate. Our bispecific antibody against FIXa and FX is a subcutaneously injectable, long-acting agent that removes the need to consider the induction or presence of FVIII inhibitors and may establish a novel principle for the prophylactic treatment of hemophilia A patients. Disclosures: Muto: Chugai Pharmaceutical Co., Ltd.: Employment. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment. Yoshihasi:Chugai Pharmaceutical Co., Ltd.: Employment. Takeda:Chugai Pharmaceutical Co., Ltd.: Employment. Soeda:Chugai Pharmaceutical Co., Ltd.: Employment. Igawa:Chugai Pharmaceutical Co., Ltd.: Employment. Sampei:Chugai Pharmaceutical Co., Ltd.: Employment. Sakamoto:Chugai Pharmaceutical Co., Ltd.: Employment. Okuyama-Nishida:Chugai Pharmaceutical Co., Ltd.: Employment. Saito:Chugai Pharmaceutical Co., Ltd.: Employment. Kawabe:Chugai Pharmaceutical Co., Ltd.: Employment. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment.

A case of rare inhibitory coagulopathy - acquired hemophilia A

2010 ◽  
Vol 94 (10) ◽  
pp. 775-779
Author(s):  
V. I. Ershov ◽  
Dar’ya A. Budanova ◽  
I. Yu. Gadaev ◽  
O. V. Bochkarnikova ◽  
I. Ya. Sokolova ◽  
...  
Keyword(s):  
Rare Disease ◽  
Blood Clotting ◽  
Hemophilia A ◽  
Coagulation System ◽  
Clotting Factor ◽  
Factor X ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Hemostatic Therapy ◽  
Blood Clotting Factor

Inhibitory coagulopathy is a rare variant of hemorrhagic syndrome. Acquired hemophilia A is caused by the formation of inhibitors (antibodies) to Factor VIII of the blood coagulation system leading to impaired activation of the key stage of blood clotting (factor X) and development of hemorrhagic syndrome of different severity. Acquired hemophilia A is a rare disease with an incidence of 1.38-1.48 per 1 million population per year. We report a case off severe idiopathic acquired hemophilia A in a 53 year-old woman manifest as skin hemorrhages, subcutaneous and intramuscular hematomas. Hemostatic therapy described in the article resulted in the elimination of hemorrhagic syndrome and complete remission. This case represents a rare disease the knowledge of which can be useful for preventing the development of debilitating complications, and sometimes saving the patient’s life.

Ex Vivo Prediction of Comprehensive Coagulation Potential Using Simulated Blood Concentrations of Emicizumab in Patients with Acquired Hemophilia A

2021 ◽  
Author(s):  
Masahiro Takeyama ◽  
Shoko Furukawa ◽  
Koji Yada ◽  
Kenichi Ogiwara ◽  
Naruto Shimonishi ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Clinical Course ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Waveform Analysis ◽  
Severe Bleeding ◽  
Maximum Plasma ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Blood Concentrations

Abstract Introduction Emicizumab prophylaxis improves coagulation function in congenital hemophilia A, regardless of inhibitor presence. We recently reported that emicizumab enhanced the coagulant potentials, ex vivo, in plasmas from patients with acquired hemophilia A (PwAHAs) at diagnosis. However, coagulant effects of emicizumab in PwAHAs during the clinical course remain unclear. Aim To assess ex vivo coagulant effects of emicizumab in PwAHAs during the clinical course. Methods/Results Blood samples were obtained from 14 PwAHAs on (median) days 0 and 6 during a severe-bleeding phase, and days 27 and 59 during a reduced-bleeding phase with elevated endogenous factor VIII (FVIII) and decreased inhibitor titers. If administered a single dose of 3 or 6 mg/kg, or two doses at 6 mg/kg followed by 3 mg/kg, estimated plasma emicizumab concentrations (10/5/2.5, 20/10/5, and 30/15/7.5 µg/mL on days 0–7/30/60, respectively) could be used to represent potential changes, based on the half-life (T 1/2: ∼30 days). Emicizumab concentrations that covered maximum plasma concentrations of each dosage were used for spiking on day 0. Ex vivo addition of estimated emicizumab to PwAHA's plasma containing endogenous FVIII and/or inhibitor, without and with recombinant (r)FVIIa administration during immunosuppressive therapy, increased the calculated Ad|min1| values, assessed by clot waveform analysis, and their coagulant potentials were below normal levels. Rotational thromboelastometry revealed that ex vivo emicizumab addition resulted in the further improvement of coagulant potentials in whole bloods when combined with rFVIIa administration. Conclusion Based on ex vivo and in vitro data, emicizumab has the potential to be effective in clinical situations for PwAHAs.

scholarly journals A Healthy Volunteer-Derived, Factor VIII-Neutralized, Acquired Hemophilia a-Mimetic Plasma Produces Similar Pharmacodynamic Responses of Emicizumab to Those in Patients with Congenital Hemophilia a with or without Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3190-3190
Author(s):  
Koichiro Yoneyama ◽  
Kazuo Tokuda ◽  
Tetsuhiro Soeda ◽  
Tomohisa Saito ◽  
Midori Shima
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Ex Vivo ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Advisory Committees ◽  
Chugai Pharmaceutical ◽  
Spiked Plasma

Abstract INTRODUCTION: Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII (FVIIIa) and is currently indicated for routine prophylaxis of bleeds in patients with congenital hemophilia A (PwCHA) regardless of factor VIII (FVIII) inhibitor status. Given its mechanism of action, the treatment response of emicizumab is expected to be similar between PwCHA and patients with acquired hemophilia A (AHA; PwAHA). However, it has not been well evidenced. We aimed to address this question by elucidating whether a healthy volunteer (HV)-derived, FVIII-neutralized, AHA-mimetic plasma produces similar pharmacodynamic (PD) responses of emicizumab to those in PwCHA. METHODS: In the phase I-I/II studies of emicizumab (Blood 2016;127:1633-41; N Engl J Med 2016;374:2044-53; Blood Adv 2017;1:1891-9; Haemophilia 2021;27:81-9), 40 Japanese HVs, 24 Caucasian HVs, 11 Japanese PwCHA with inhibitors (PwCHAwI), and 7 Japanese PwCHA without inhibitors (PwCHAwoI) were enrolled to receive emicizumab or placebo. These studies were conducted in accordance with relevant ethical standards as previously reported. Plasma samples were collected before first administration of the study drug, and they were spiked with emicizumab at 0, 0.3, 3, 30, or 300 μg/mL for HVs or 0, 3, or 300 μg/mL for PwCHA in combination with two anti-FVIII neutralizing antibodies (VIII-2236, anti-A2 type 1 inhibitor; VIII-9222, anti-C2 type 2 inhibitor) at approximately 300 μg/mL each (termed "ex vivo spiked plasma") for the measurement of activated partial thromboplastin time (APTT) and activated factor XI-triggered thrombin generation (TG). Separate plasma samples were collected before and after first administration (termed "in vivo exposed plasma") to be used for measuring APTT and TG, with ex vivo FVIII neutralization for HVs or without for PwCHA, as well as emicizumab concentration. Due to the difference in the given dosing regimens, observed plasma emicizumab concentrations did not largely overlap between HVs and PwCHA (up to 5.92 μg/mL as mean maximum concentration in HVs versus 10.3 to 120 μg/mL as mean steady-state trough concentration in PwCHA), which precluded simple comparison of the concentration-response (C-R) relationships between HVs and PwCHA in the in vivo exposed plasma. To overcome this limitation, nonlinear mixed-effect ("population") modeling was performed to analyze the C-R data from the ex vivo spiked plasma from HVs for APTT and TG each, and the developed population PD (PopPD) models were used to simulate C-R relationships in HVs over a wide range of plasma emicizumab concentration for comparison with those observed in the in vivo exposed plasma from PwCHA. RESULTS: In the ex vivo spiked plasma, the observed C-R relationships of APTT and TG were similar among Japanese HVs, Caucasian HVs, Japanese PwCHAwI, and Japanese PwCHAwoI, indicating similar FVIIIa-mimetic activity of emicizumab between HVs and PwCHA under the artificial FVIII-depleted condition ex vivo. The developed PopPD models adequately described the C-R data from HVs which were used for the model development. In the in vivo exposed plasma (Figure), the observed C-R relationships of APTT and TG were similar between Japanese HVs and Caucasian HVs as well as between Japanese PwCHAwI and Japanese PwCHAwoI. The observed C-R relationships in HVs were well captured by the PopPD model-based simulations despite these data being not directly used for the model development, which demonstrated the ability of the ex vivo data to be extrapolated in vivo. The PopPD models also well captured the observed C-R relationships in PwCHA, suggesting similar FVIIIa-mimetic activity of emicizumab between HVs and PwCHA in vivo. Some deviating observations from the PopPD model-based simulations might be attributed to the residual activity of given coagulation factor products, e.g., relatively short APTT and promoted TG at a plasma emicizumab concentration of 0 μg/mL (before first administration) in PwCHAwoI prior treated with FVIII prophylaxis. CONCLUSIONS: A HV-derived, FVIII-neutralized, AHA-mimetic plasma produced similar PD responses of emicizumab to those in PwCHA with or without inhibitors. Given its potential nature of mimicking AHA, i.e., coexistence of FVIII and multiple inhibitors including a type 2 one, the findings derived using this plasma may suggest similarity in the treatment response of emicizumab between PwCHA and PwAHA. Figure 1 Figure 1. Disclosures Yoneyama: Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Tokuda: Chugai Pharmaceutical Co., Ltd.: Current Employment. Soeda: Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Saito: Chugai Pharmaceutical Co., Ltd.: Current Employment. Shima: BioMarin Pharmaceutical Inc.: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk A/S: Honoraria, Speakers Bureau; Takeda: Research Funding; CSL Behring: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau; Sanofi S.A.: Speakers Bureau; Fujimoto Seiyaku: Consultancy, Speakers Bureau. OffLabel Disclosure: Emicizumab for acquired hemophilia A

scholarly journals Successful Management of Acquired Hemophilia A Associated with Bullous Pemphigoid: A Case Report and Review of the Literature

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Quentin Binet ◽  
Catherine Lambert ◽  
Laurine Sacré ◽  
Stéphane Eeckhoudt ◽  
Cedric Hermans
Keyword(s):  
Bullous Pemphigoid ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Rare Condition ◽  
Term Treatment ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Short Term Treatment ◽  
Life Threatening ◽  
Dose Levels

Background. Acquired hemophilia A (AHA) is a rare condition, due to the spontaneous formation of neutralizing antibodies against endogenous factor VIII. About half the cases are associated with pregnancy, postpartum, autoimmune diseases, malignancies, or adverse drug reactions. Symptoms include severe and unexpected bleeding that may prove life-threatening.Case Study. We report a case of AHA associated with bullous pemphigoid (BP), a chronic, autoimmune, subepidermal, blistering skin disease. To our knowledge, this is the 25th documented case of such an association. Following treatment for less than 3 months consisting of methylprednisolone at decreasing dose levels along with four courses of rituximab (monoclonal antibody directed against the CD20 protein), AHA was completely cured and BP well-controlled.Conclusions. This report illustrates a rare association of AHA and BP, supporting the possibility of eradicating the inhibitor with a well-conducted short-term treatment.

scholarly journals Persistent surgical wound bleeding: A rare condition related to acquired hemophilia A

2013 ◽  
Vol 46 (4) ◽  
pp. 135-139
Author(s):  
Chia-Wei Chang ◽  
Jiun-Ting Yeh ◽  
Shang-Yu Wang ◽  
Chun-Hsiang Ouyang ◽  
Chien-Hung Liao ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Rare Condition ◽  
Surgical Wound ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia

Two Cases of Acquired Hemophilia A Successfully Treated with Oral Steroid or Danazol

2005 ◽  
Vol 40 (1) ◽  
pp. 58 ◽  
Author(s):  
Sun Young Park ◽  
Jin Seok Kim ◽  
Yuri Kim ◽  
In Hae Park ◽  
June-Won Cheong ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Oral Steroid ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia
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