A phase <scp>III</scp> clinical trial of a mixture agent of plasma‐derived factor <scp>VII</scp>a and factor X (<scp>MC</scp>710) in haemophilia patients with inhibitors

Shirahata, Akira; Fukutake, Katsuyuki; Takamatsu, Junki; Shima, Midori; Hanabusa, Hideji; Mugishima, Hideo; Takedani, Hideyuki; Kawasugi, Kazuo; Taki, Masashi; Matsushita, Tadashi; Tawa, Akio; Nogami, Keiji; Higasa, Satoshi; Kosaka, Yoshiyuki; Fujii, Teruhisa; Sakai, Michio; Migita, Masahiro; Uchiba, Mitsuhiro; Kawakami, Kiyoshi; Sameshima, Koji; Ohashi, Yuichi; Saito, Hidehiko

doi:10.1111/hae.13050

Cited by 23 publications

(19 citation statements)

References 21 publications

(30 reference statements)

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“…Several promising alternatives for HA/HB inhibitor subset are under investigation. [120][121][122][123][124][125][126][127][128] However, it has to be highlighted that the exciting data from emicizumab studies are not applicable to HB patients. 128 Inhibition of tissue factor pathway inhibitor (TFPI) promotes FX activation and thrombin generation through TF and activated FVII, without the involvement of FIX and FVIII.…”

Section: New Therapeutic Agentsmentioning

confidence: 99%

Inhibitors in Hemophilia B

Quintavalle

Castaman

Baldacci

et al. 2018

Semin Thromb Hemost

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Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.

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Section: New Therapeutic Agentsmentioning

confidence: 99%

Inhibitors in Hemophilia B

Quintavalle

Castaman

Baldacci

et al. 2018

Semin Thromb Hemost

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“…104 Another FVIIa product, MC710, being developed by the Chemo-Sero Therapeutic Research Institute (Japan), is a 1:10 protein weight ratio mixture of plasma-derived activated FVIIa and FX. 105 In a phase 3, open-label study of 21 joint, muscle and subcutaneous bleeding episodes in 14 male patients, individuals received one or two doses of intravenously administered MC710 at 60 or 120 μg/kg once or twice (to a maximum of 180 μg/kg) for up to five bleeding episodes per patient. Nineteen episode treatments were rated 'excellent' or 'effective' 8 hours after the last treatment.…”

Section: Other Therapies In Developmentmentioning

confidence: 99%

“…Nineteen episode treatments were rated 'excellent' or 'effective' 8 hours after the last treatment. 105 The rFVIIa variant marzeptacog alfa (MarzAA; Catalyst Biosciences) was designed to combine higher clot-generating activity and longer activity at the site of bleeding and therefore improve efficacy. 106 It is anticipated that the compound could be used for both subcutaneous prophylactic treatment and intravenous acute treatment, and may be valuable for patients with HB with inhibitors, or patients with HA with inhibitors who failed emicizumab.…”

Section: Other Therapies In Developmentmentioning

confidence: 99%

Origins, Development, Current Challenges and Future Directions with Activated Prothrombin Complex Concentrate for the Treatment of Patients with Congenital Haemophilia with Inhibitors

Brackmann

Schramm²,

Oldenburg

et al. 2020

Hamostaseologie

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Congenital haemophilia A (HA) is caused by deficiency of coagulation factor VIII (FVIII) activity, leading to spontaneous or traumatic bleeding events. While FVIII replacement therapy can treat and prevent bleeds, approximately 30% of patients with severe HA develop inhibitor antibodies that render FVIII replacement therapy ineffective. The bypassing agents (BPAs), activated prothrombin complex concentrate (aPCC) and recombinant activated FVII, first approved in 1977 and 1996, respectively, act to generate thrombin independent of pathways that involve factors IX and VIII. Both may be used in patients with congenital haemophilia and inhibitors (PwHIs) for the treatment and prevention of acute bleeds and quickly became standard of care. However, individual patients respond differently to different agents. While both agents are approved for on-demand treatment and perioperative management for patients with congenital haemophilia with inhibitors, aPCC is currently the only BPA approved worldwide for prophylaxis in PwHI. Non-factor therapies (NFTs) have a mechanism of action distinct from BPAs and have reported higher efficacy rates as prophylactic regimens. Nonetheless, treatment challenges remain with NFTs, particularly regarding the potential for synergistic action on thrombin generation with concomitant use of other haemostatic agents, such as BPAs, for the treatment of breakthrough bleeds and in perioperative management. Concomitant use of NFTs with other haemostatic agents could increase the risk of adverse events such as thromboembolic events or thrombotic microangiopathy. This review focuses on the origins, development and on-going role of aPCC in the evolving treatment landscape in the management of PwHI.

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“…13,14 The main treatment of hemophilia patients with inhibitors is on-demand treatment or regular prophylaxis with bypassing agents (BPAs), 15,16 including recombinant FVIIa (rFVIIa), activated prothrombin complex concentrates (aPCC), and plasma-derived FVIIa/FX complex. 17 These protocols have limited success in controlling hemorrhage, however. 18,19 An alternative approach is immune tolerance induction (ITI), an option that aims to eradicate the inhibitors.…”

Section: Introductionmentioning

confidence: 99%

New therapies using nonfactor products for patients with hemophilia and inhibitors

Nogami

Shima

2019

Blood

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Regular prophylaxis with factor VIII (FVIII) or FIX products to prevent bleeding in patients with severe hemophilia A (HA) and HB, respectively, results in marked suppression of the onset of arthropathy and contributes greatly to improvements in quality of life. Some issues remain with the use of clotting factor replacement therapy, however. The need for multiple IV infusions is associated with a substantial mental and physical burden, and the hemostatic effect of bypassing agents (BPAs) in patients with inhibitor is inconsistent. The development of subcutaneous products with prolonged hemostatic efficiency, irrespective of the presence of inhibitors, has been a longtime wish for patients. A new class of therapeutic agents that act by enhancing coagulation (emicizumab) and inhibiting anticoagulant pathways (fitusiran and concizumab) have been established, and clinical trials using these nonfactor products are ongoing. The current findings have demonstrated that prophylaxis by nonfactor products supports marked reductions of bleeding episodes in hemophilia patients with or without inhibitor. Emicizumab has already been approved for use internationally. Some concerns are evident, however. Thrombotic microangiopathy and thromboembolism have occurred in 5 emicizumab-treated patients receiving repeated infusions of activated prothrombin complex concentrates, and a sinus vein thrombosis has occurred in a fitusiran-treated patient receiving repeated infusions of FVIII product. Moreover, reliable techniques to monitor hemostatic function in patients receiving nonfactor products with concomitant BPA or FVIII/FIX therapies require further assessment. These novel therapeutic agents have promising hemostatic properties, although wider experience in hemophilia centers is warranted to establish appropriate therapeutic strategies.

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A phase III clinical trial of a mixture agent of plasma‐derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors

Abstract: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.

Cited by 23 publications

References 21 publications

Inhibitors in Hemophilia B

Inhibitors in Hemophilia B

Origins, Development, Current Challenges and Future Directions with Activated Prothrombin Complex Concentrate for the Treatment of Patients with Congenital Haemophilia with Inhibitors

New therapies using nonfactor products for patients with hemophilia and inhibitors

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