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Massimo Morfini, Carlo Antonio Paolo Rapisarda
during the last decade, new FVIII/IX concentrates have been developed for the treatment of patients affected by hemophilia A/B. Significant progress has been achieved regarding their half-life, but the old issue of immunogenicity and new concerns about safety need to be addressed. Areas covered: after the implementation of virucidal methods, both plasma-derived and recombinant clotting factor concentrates achieved a very safe profile. The development of anti-FVIII antibodies is the major adverse event of replacement therapy with both FVIII concentrates...
January 25, 2019: Expert Opinion on Drug Safety
Giuseppe Lippi, Emmanuel J Favaloro
Congenital hemophilia A, a relatively common and sometimes life-threatening bleeding disorder, is caused by inherited deficiency of clotting factor (F) VIII. The adoption of an appropriate medical and environmental prophylaxis is critical for long-term management of hemophilia because it will considerably reduce the number of both mild and severe bleeding episodes. Among the many therapeutic options that have become available over the past decades, ACE910 (also known as emicizumab) is a bispecific immunoglobulin G antibody characterized by its unique ability to bind FIX or FIXa on one arm and FX on the other, thus abrogating FVIII activity in vivo...
2019: Advances in Clinical Chemistry
E Carlos Rodriguez-Merchan, Leonard A Valentino
INTRODUCTION: Emicizumab-kywh (ACE910) is a recombinant, humanized, asymmetric bispecific antibody that functions to bring activated FIX (FIXa) and zymogen FX into an appropriate steric conformation to medicate the activation of FX to FXa thereby mimicking the cofactor function of FVIIIa. AIM: The objective of this manuscript was to review the development and potential role for emicizumab in the treatment of patients with haemophilia A with and without inhibitors...
November 15, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Naoki Kotani, Koichiro Yoneyama, Nobuhiko Kawakami, Tohru Shimuta, Hiroyuki Fukase, Takehiko Kawanishi
Emicizumab (ACE910) is a bispecific antibody that is a novel, subcutaneously injectable treatment for patients with hemophilia A. This study assessed the relative bioavailability of emicizumab between old and new drug products (DPs) and among 3 commonly used subcutaneous injection sites (abdomen, upper arm, and thigh), together with its absolute bioavailability in healthy volunteers. Forty-eight healthy volunteers were randomized into 4 groups to receive a single subcutaneous injection of 1 mg/kg with the old or new DP, and another 12 volunteers each received a single, 90-minute, intravenous infusion of 0...
September 19, 2018: Clinical Pharmacology in Drug Development
Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Ryu Kasai, Koichiro Yoneyama, Hiroki Yoshida, Keiji Nogami
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...
October 10, 2017: Blood Advances
Koichiro Yoneyama, Christophe Schmitt, Naoki Kotani, Gallia G Levy, Ryu Kasai, Satofumi Iida, Midori Shima, Takehiko Kawanishi
BACKGROUND: Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. METHODS: Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency...
September 2018: Clinical Pharmacokinetics
Peter J Lenting, Cécile V Denis, Olivier D Christophe
During the last decade, the development of improved and novel approaches for the treatment of hemophilia A has expanded tremendously. These approaches include factor VIII (FVIII) with extended half-life (eg, FVIII-Fc and PEGylated FVIII), monoclonal antibodies targeting tissue factor pathway inhibitor, small interfering RNA to reduce antithrombin expression and the bispecific antibody ACE910/emicizumab. Emicizumab is a bispecific antibody recognizing both the enzyme factor IXa and the substrate factor X. By simultaneously binding enzyme and substrate, emicizumab mimics some part of the function exerted by the original cofactor, FVIII, in that it promotes colocalization of the enzyme-substrate complex...
December 7, 2017: Blood
Keiji Nogami
In the treatment of hemophilia patients, factor (F) VIII or FIX product prophylaxis results in arthropathy prevention and quality of life (QOL) improvement. Serious issues concerning hemostatic treatment of hemophilia include frequent intravenous administration of products, inhibitor development, and hemostatic treatment of patients with inhibitors. To overcome these challenges, products with extended half-life were developed. Furthermore, alternative products based on new concepts of hemostatic therapy were developed...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Johannes Oldenburg, Johnny N Mahlangu, Benjamin Kim, Christophe Schmitt, Michael U Callaghan, Guy Young, Elena Santagostino, Rebecca Kruse-Jarres, Claude Negrier, Craig Kessler, Nancy Valente, Elina Asikanius, Gallia G Levy, Jerzy Windyga, Midori Shima
BACKGROUND: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. METHODS: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B)...
August 31, 2017: New England Journal of Medicine
Robert Klamroth
Treatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bi-specific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII...
August 8, 2017: Hämostaseologie
Midori Shima
The principle of hemophilia treatment is replacement therapy with factor VIII and factor IX concentrates. Recently, extended half-life factor VIII and factor IX concentrates have been developed. With these concentrates, improvements in patient QOL can be expected. More recently, a novel hemophilia therapy based on a very new concept was developed. ACE910 (emicizumab) is a humanized bispecific antibody recognizing factor IXa and X mimicking factor VIII function. The half-life is reportedly 4-5 weeks and remarkably decreased annual bleeding rates have been achieved with subcutaneous weekly injections in the phase 1 clinical trial...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
F Peyvandi, I Garagiola, E Biguzzi
Historically, the bleeding episodes in subjects with coagulation disorders were treated with substitution therapy, initially with whole blood and fresh frozen plasma, and more recently with specific factor concentrate. Currently, patients with hemophilia have the possibility of choosing different effective and safe treatments, including novel extended half-life and alternative hemostatic drugs. The availability of novel extended half-life products could probably overcome current prophylaxis limitations, particularly in hemophilia B patients, by reducing the frequency of injections, achieving a higher trough level, and improving the quality of life of the patients...
November 2016: Journal of Thrombosis and Haemostasis: JTH
M Shima, D Lillicrap, R Kruse-Jarres
The development of inhibitors to factor VIII (FVIII) or factor IX (FIX) remains a major treatment complication encountered in the treatment of haemophilia. Not all patients with even the same severity and genotype develop inhibitors suggesting an underlying mechanism of tolerance against FVIII- or FIX-related immunity. One mechanism may be central tolerance observed in patients in whom the FVIII mutation enables some production of the protein. The other is a peripheral tolerance mechanism which may be evident in patients with null mutation...
July 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
Keiji Nogami
Serious issues in current hemostatic treatment of hemophilia A are the requirement for frequent intravenous administrations of factor (F) VIII, FVIII inhibitor development, and hemostatic treatment for patients with this inhibitor. For the purpose of overcoming these challenges, the FVIIIa-substituting bispecific antibody against FIXa/FX (ACE910, INN emicizumab) was produced. Emicizumab demonstrated marked hemostatic effects on both ongoing and spontaneous joint bleeding in the acquired hemophilia A primate model...
June 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Naoki Fukazawa, Koichiro Yoneyama, Hiroki Yoshida, Keiji Nogami
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...
May 26, 2016: New England Journal of Medicine
Keiji Nogami
There are some issues in the current factor (F)VIII replacement therapy for severe hemophilia A. One is mental and physical burden for the multiple intravenous infusions, and the other is difficulty in the hemostatic treatment for the patients with FVIII inhibitor. The development of novel drug with fully hemostatic effect, simply procedure, and long-acting reaction has been expected. Recently, FVIIIa-mimicking humanized recombinant bispecific antibody (ACE910) against FIXa and FX was developed. In the non-human clinical study, primate model of acquired hemophilia A demonstrated that the ACE910 was effective on both on-going and spontaneous bleedings...
May 2016: Thrombosis Research
Paul E Monahan
For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B...
2015: Hematology—the Education Program of the American Society of Hematology
Naoki Uchida, Takehiko Sambe, Koichiro Yoneyama, Naoki Fukazawa, Takehiko Kawanishi, Shinichi Kobayashi, Midori Shima
ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group)...
March 31, 2016: Blood
Midori Shima
Unmet needs of current hemophilia A treatment include the requirement for frequent intravenous infusions, inhibitor development, and containment of high medical costs. In order to overcome these issues, we produced FVIII which mimics a bispecific antibody against FIXa/FX. ACE910 demonstrated hemostatic effects on both ongoing and spontaneous joint bleeding in the primate acquired hemophilia A model. Recently, a phase 1 study for PK, PD, and the safety of ACE910 was initiated. The t1/2 was approximately 30 days...
June 2015: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Zenjiro Sampei, Tomoyuki Igawa, Tetsuhiro Soeda, Miho Funaki, Kazutaka Yoshihashi, Takehisa Kitazawa, Atsushi Muto, Tetsuo Kojima, Satoshi Nakamura, Kunihiro Hattori
While antibody engineering improves the properties of therapeutic antibodies, optimization of regions that do not contact antigens has been mainly focused on modifying the effector functions and pharmacokinetics of antibodies. We recently reported an asymmetric anti-FIXa/FX bispecific IgG4 antibody, ACE910, which mimics the cofactor function of FVIII by placing the two factors into spatial proximity for the treatment of hemophilia A. During the optimization process, we found that the activity was significantly affected by IgG subclass and by modifications to the inter-chain disulfide bonds, upper hinge region, elbow hinge region, and Fc glycan, even though these regions were unlikely to come into direct contact with the antigens...
2015: MAbs
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