Editorial Borrowing (once again) from the animal kingdom Leonardo Pasalic, Emmanuel J. Favaloro Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology NSW, Westmead Hospital, NSW, Australia
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bleeding, is to bypass the effect of anti-FVIII antibodies with activated prothrombin complex concentrates (APCC; FEIBA NF)11 or recombinant activated factor VII (rFVIIa)12. Nevertheless, due to their short halflives, these agents appear less efficient in achieving haemostasis than FVIII in patients without inhibitors13. In addition, the use of APCC and rFVIIa may be associated with a small (3-4%) risk of thromboembolic complications14,which is significantly lower than that reported with off-label use15. In this issue of Blood Transfusion, Mannucci and Franchini16 provide a timely critical review of the clinical utility of porcine rFVIII in the management of AHA and in haemophilia A patients with inhibitors. The FVIII molecule consists of several structural domains (A1-A2-B-A3-C1-C2). Human anti-FVIII inhibitory antibodies are polyclonal IgG molecules, which are most often directed against epitopes in the A2 and/or C2 regions. These inhibitory antibodies block the haemostatic function of endogenous or exogenous FVIII leading to haemorrhagic complications. A potential solution would therefore be functional FVIII molecules "resistant" to inhibitors. This could be potentially achieved by modifying FVIII through recombinant DNA or other bioengineering techniques in such a way to minimise or hide these immunodominant epitopes whilst preserving or potentially even enhancing the procoagulant function. Porcine FVIII (pFVIII) represents a naturally occurring "modification" of human (h) FVIII17 that can support efficient generation of thrombin in human plasma but, structurally, is sufficiently different from hFVIII to result in low cross-reactivity (median 15%) by anti-hFVIII alloantibodies, with even less crossreactivity observed in patients with AHA8,18,19. A plasma-derived pFVIII (pd-pFVIII) product (Hyate:C; Speywood/Ipsen Ltd., Wrexham, United Kingdom) had been in clinical use since the 1980s, with a reported success rate of up to 90% of bleeds in haemophilia A with inhibitors, notwithstanding a degree of thrombocytopenia, thought to be caused by contaminating porcine von Willebrand factor (VWF)19. Hyate:C was withdrawn in the early 2000s following findings of porcine parvovirus in some batches20,21. This strengthened the impetus to develop a recombinant pFVIII (rpFVIII) with the desire for increased safety, reduced immunogenicity and absence of thrombocytopenic adverse effects. A recently
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Congenital deficiency or dysfunction of coagulation factor VIII (FVIII) leads to haemophilia A, an X-linked recessive bleeding disorder characterised by episodes of bleeding, especially into soft tissue joints and muscles1, with a global prevalence of around 6.6-12.8 cases per 100,000 males2. Without prophylactic treatment, recurrent intra-articular haemorrhages lead to chronic synovitis and debilitating arthropathies of the knee, elbow, ankle, hip and shoulder joints3,4. Acquired haemophilia A (AHA) is a rare (1.21.5/million/year) but potentially life-threatening bleeding disorder caused by inhibitory autoantibodies, directed against FVIII, which develop spontaneously in individuals with previously normal haemostasis5,6. Importantly, FVIII neutralising alloantibodies also complicate the treatment of around 20-30% of cases of genetic haemophilia A7, compromising the patients' care and resulting in increased morbidity and mortality. Replacement of deficient FVIII by infusion of plasma-derived and, increasingly, recombinant (r) FVIII concentrates has been the mainstay of treatment for moderate and severe haemophilia A. Over the last few decades, the therapeutic focus has been on increasing the safety of plasma-derived factor concentrates, and the development of rFVIII preparations, now with extended half-lives. There are currently a large number of actual, as well as potential therapies in development, which could radically improve delivery of optimal haemophilia care. In addition to ongoing efforts in gene therapy, novel strategies include extending the half-life of replacement FVIII through development of fusion molecules and modifying FVIII structure (glycosylation and protein stabilisation). Moreover, several potential non-factor therapies such as bispecific antibody mimicking function of FVIII, antagonising tissue factor pathway inhibitor and suppression of antithrombin production are in the pipeline8,9. Nevertheless, treatment of haemophilia A patients with inhibitors remains difficult, especially in those with high antibody titres, and the accessibility and efficacy of currently available therapeutic options are limited. Immune tolerance induction (ITI) regimens using large doses of FVIII products can result in eradication of FVIII inhibitors in up to 70% of patients10; however, due to the high cost of such therapy, especially in adults, ITI is not feasible in a great majority of patients worldwide, and it does not achieve immediate resolution of inhibitors. Another potential option, particularly in the urgent or acute setting to treat life-threatening
Blood Transfus 2017; 15: 294-5 DOI 10.2450/2016.0104-16 294
All rights reserved - For personal use only No other use without premission
© SIMTI Servizi Srl
Borrowing from the animal kingdom
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3) Di Minno MD, Ambrosino P, Franchini M, et al. Arthropathy in patients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost 2013; 39: 723-31. 4) Blobel CP, Haxaire C, Kalliolias GD, et al. Blood-induced arthropathy in hemophilia: mechanisms and heterogeneity. Semin Thromb Hemost 2015; 41: 832-7. 5) Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007; 109: 1870-7. 6) Coppola A, Favaloro EJ, Tufano A, et al. Acquired inhibitors of coagulation factors: part I-acquired hemophilia A. Semin Thromb Hemost 2012; 38: 433-46. 7) Darby SC, Keeling DM, Spooner RJ, et al. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99. J Thromb Haemost 2004; 2: 1047-54. 8) Peyvandi F, Garagiola I. Treatment of hemophilia in the near future. Semin Thromb Hemost 2015; 41: 838-48. 9) Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42: 526-32. 10) Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119: 1335-44. 11) Sjamsoedin LJM, Heijnen L, Mauser-Bunschoten EP, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. N Engl J Med 1981; 305: 717-21. 12) Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912-8. 13) Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39: 772-8. 14) Baudo F, Collins P, Huth-Kuhne A, et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120: 39-46. 15) Goodnough LT, Levy JH. The judicious use of recombinant factor VIIa. Semin Thromb Hemost 2016; 42: 125-32. 16) Mannucci PM, Franchini M. Porcine recombinant factor VIII: an additional weapon to handle anti-factor VIII antibodies. Blood Transfus 2017; 15: 365-8. 17) Healey JF, Lubin IM, Lollar P. The cDNA and derived amino acid sequence of porcine factor VIII. Blood 1996; 88: 4209-14. 18) Zakas PM, Vanijcharoenkarn K, Markovitz RC, et al. Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors. J Thromb Haemost 2015; 13: 72-81. 19) Hay CR. Porcine factor VIII: current status and future developments. Haemophilia 2002; 8 (Suppl 1): 24-7; discussion 28-32. 20) Soucie JM, Erdman DD, Evatt BL, et al. Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Transfusion (Paris) 2000; 40: 708-11. 21) Giangrande PL. Porcine factor VIII. Haemophilia 2012; 18: 305-9. 22) Kempton CL, Abshire TC, Deveras RA, et al. Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A. Haemophilia 2012; 18: 798-804. 23) Kruse-Jarres R, St-Louis J, Greist A, et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia 2015; 21: 162-70.
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developed rpFVIII molecule with a deleted B domain (Obizur [OBI-1]; Baxalta, Bannockburn, IL, USA) was shown in animal studies to be comparable to the plasmaderived Hyate:C with respect to immunogenicity, but with the added advantage of higher maximum plasma concentration16. In clinical studies in haemophilia A patients with alloantibodies and AHA with autoantibodies against hFVIII presenting with bleeding, OBI-1 led to measurable responses, resulting in reliable haemostasis without any severe drug-related adverse effects22,23. Mannucci and Franchini16 recognise the advantage of using a (relatively high) fixed loading dose (200 U/kg used in clinical trials22,23) of OBI-1 in providing urgent treatment, particularly when information about the degree of cross-reactivity of the patient's antibody with rpFVIII may not be available. However, the authors speculate that a lower fixed loading dose should be evaluated if possible, given that the majority of trial participants with AHA achieved unnecessarily high and potentially prothrombotic levels of plasma FVIII. One possible limitation to repeated use of rpFVIII includes potential development of specific anti-porcine antibodies (17.9% in a cohort of patients with AHA23), although once effective immunosuppression is established this is not expected to be a significant problem in patients with AHA. However, additional evidence for the efficacy and safety of this product is eagerly awaited from more accurate post-marketing surveillance studies. Due to inter-patient variation in inhibitor epitope specificity, assays for measuring the degree of cross-reactivity of the anti-hFVIII antibodies with rpFVIII are also needed to facilitate more tailored dosing of OBI-1. In addition to pFVIII, other FVIII orthologues from the animal kingdom18 or cross-species hybrid FVIII molecules, each with its own advantages and limitations are likely to expand our clinical armamentarium in the near future and facilitate provision of personalised haemophilia care. Naturally, this is not the first, nor the last, time that we will "borrow from the animal kingdom" in order to treat or manage human diseases, including those in the field of thrombosis and haemostasis. For example, unfractionated heparin, used to treat thrombotic disease, is generally also obtained from porcine (or bovine) sources. Vitamin K antagonists were originally "discovered" after cows suffered bleeding deaths from eating clover enriched in the drug. Animal sources of insulin to treat diabetes and thyroxin to treat thyroid-related problems provide a few other examples of our reliance on the animal kingdom for maintaining human health. The Authors declare no conflicts of interest.
References
1) Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J Med 2001; 344: 1773-9. 2) Stonebraker JS, Bolton-Maggs PH, Soucie JM, et al. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 2010; 16: 20-32.
Correspondence: Emmanuel J. Favaloro Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital Hawkesbury Road Westmead, NSW, 2145, Australia e-mail: [email protected]
Blood Transfus 2017; 15: 294-5 DOI 10.2450/2016.0104-16 All rights reserved - For personal use only No other use without premission
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bleeding, is to bypass the effect of anti-FVIII antibodies with activated prothrombin complex concentrates (APCC; FEIBA NF)11 or recombinant activated factor VII (rFVIIa)12. Nevertheless, due to their short halflives, these agents appear less efficient in achieving haemostasis than FVIII in patients without inhibitors13. In addition, the use of APCC and rFVIIa may be associated with a small (3-4%) risk of thromboembolic complications14,which is significantly lower than that reported with off-label use15. In this issue of Blood Transfusion, Mannucci and Franchini16 provide a timely critical review of the clinical utility of porcine rFVIII in the management of AHA and in haemophilia A patients with inhibitors. The FVIII molecule consists of several structural domains (A1-A2-B-A3-C1-C2). Human anti-FVIII inhibitory antibodies are polyclonal IgG molecules, which are most often directed against epitopes in the A2 and/or C2 regions. These inhibitory antibodies block the haemostatic function of endogenous or exogenous FVIII leading to haemorrhagic complications. A potential solution would therefore be functional FVIII molecules "resistant" to inhibitors. This could be potentially achieved by modifying FVIII through recombinant DNA or other bioengineering techniques in such a way to minimise or hide these immunodominant epitopes whilst preserving or potentially even enhancing the procoagulant function. Porcine FVIII (pFVIII) represents a naturally occurring "modification" of human (h) FVIII17 that can support efficient generation of thrombin in human plasma but, structurally, is sufficiently different from hFVIII to result in low cross-reactivity (median 15%) by anti-hFVIII alloantibodies, with even less crossreactivity observed in patients with AHA8,18,19. A plasma-derived pFVIII (pd-pFVIII) product (Hyate:C; Speywood/Ipsen Ltd., Wrexham, United Kingdom) had been in clinical use since the 1980s, with a reported success rate of up to 90% of bleeds in haemophilia A with inhibitors, notwithstanding a degree of thrombocytopenia, thought to be caused by contaminating porcine von Willebrand factor (VWF)19. Hyate:C was withdrawn in the early 2000s following findings of porcine parvovirus in some batches20,21. This strengthened the impetus to develop a recombinant pFVIII (rpFVIII) with the desire for increased safety, reduced immunogenicity and absence of thrombocytopenic adverse effects. A recently
©
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Se rv
Congenital deficiency or dysfunction of coagulation factor VIII (FVIII) leads to haemophilia A, an X-linked recessive bleeding disorder characterised by episodes of bleeding, especially into soft tissue joints and muscles1, with a global prevalence of around 6.6-12.8 cases per 100,000 males2. Without prophylactic treatment, recurrent intra-articular haemorrhages lead to chronic synovitis and debilitating arthropathies of the knee, elbow, ankle, hip and shoulder joints3,4. Acquired haemophilia A (AHA) is a rare (1.21.5/million/year) but potentially life-threatening bleeding disorder caused by inhibitory autoantibodies, directed against FVIII, which develop spontaneously in individuals with previously normal haemostasis5,6. Importantly, FVIII neutralising alloantibodies also complicate the treatment of around 20-30% of cases of genetic haemophilia A7, compromising the patients' care and resulting in increased morbidity and mortality. Replacement of deficient FVIII by infusion of plasma-derived and, increasingly, recombinant (r) FVIII concentrates has been the mainstay of treatment for moderate and severe haemophilia A. Over the last few decades, the therapeutic focus has been on increasing the safety of plasma-derived factor concentrates, and the development of rFVIII preparations, now with extended half-lives. There are currently a large number of actual, as well as potential therapies in development, which could radically improve delivery of optimal haemophilia care. In addition to ongoing efforts in gene therapy, novel strategies include extending the half-life of replacement FVIII through development of fusion molecules and modifying FVIII structure (glycosylation and protein stabilisation). Moreover, several potential non-factor therapies such as bispecific antibody mimicking function of FVIII, antagonising tissue factor pathway inhibitor and suppression of antithrombin production are in the pipeline8,9. Nevertheless, treatment of haemophilia A patients with inhibitors remains difficult, especially in those with high antibody titres, and the accessibility and efficacy of currently available therapeutic options are limited. Immune tolerance induction (ITI) regimens using large doses of FVIII products can result in eradication of FVIII inhibitors in up to 70% of patients10; however, due to the high cost of such therapy, especially in adults, ITI is not feasible in a great majority of patients worldwide, and it does not achieve immediate resolution of inhibitors. Another potential option, particularly in the urgent or acute setting to treat life-threatening
Blood Transfus 2017; 15: 294-5 DOI 10.2450/2016.0104-16 294
All rights reserved - For personal use only No other use without premission
© SIMTI Servizi Srl
Borrowing from the animal kingdom
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3) Di Minno MD, Ambrosino P, Franchini M, et al. Arthropathy in patients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost 2013; 39: 723-31. 4) Blobel CP, Haxaire C, Kalliolias GD, et al. Blood-induced arthropathy in hemophilia: mechanisms and heterogeneity. Semin Thromb Hemost 2015; 41: 832-7. 5) Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007; 109: 1870-7. 6) Coppola A, Favaloro EJ, Tufano A, et al. Acquired inhibitors of coagulation factors: part I-acquired hemophilia A. Semin Thromb Hemost 2012; 38: 433-46. 7) Darby SC, Keeling DM, Spooner RJ, et al. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99. J Thromb Haemost 2004; 2: 1047-54. 8) Peyvandi F, Garagiola I. Treatment of hemophilia in the near future. Semin Thromb Hemost 2015; 41: 838-48. 9) Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42: 526-32. 10) Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119: 1335-44. 11) Sjamsoedin LJM, Heijnen L, Mauser-Bunschoten EP, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. N Engl J Med 1981; 305: 717-21. 12) Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912-8. 13) Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39: 772-8. 14) Baudo F, Collins P, Huth-Kuhne A, et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120: 39-46. 15) Goodnough LT, Levy JH. The judicious use of recombinant factor VIIa. Semin Thromb Hemost 2016; 42: 125-32. 16) Mannucci PM, Franchini M. Porcine recombinant factor VIII: an additional weapon to handle anti-factor VIII antibodies. Blood Transfus 2017; 15: 365-8. 17) Healey JF, Lubin IM, Lollar P. The cDNA and derived amino acid sequence of porcine factor VIII. Blood 1996; 88: 4209-14. 18) Zakas PM, Vanijcharoenkarn K, Markovitz RC, et al. Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors. J Thromb Haemost 2015; 13: 72-81. 19) Hay CR. Porcine factor VIII: current status and future developments. Haemophilia 2002; 8 (Suppl 1): 24-7; discussion 28-32. 20) Soucie JM, Erdman DD, Evatt BL, et al. Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Transfusion (Paris) 2000; 40: 708-11. 21) Giangrande PL. Porcine factor VIII. Haemophilia 2012; 18: 305-9. 22) Kempton CL, Abshire TC, Deveras RA, et al. Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A. Haemophilia 2012; 18: 798-804. 23) Kruse-Jarres R, St-Louis J, Greist A, et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia 2015; 21: 162-70.
©
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Se rv
developed rpFVIII molecule with a deleted B domain (Obizur [OBI-1]; Baxalta, Bannockburn, IL, USA) was shown in animal studies to be comparable to the plasmaderived Hyate:C with respect to immunogenicity, but with the added advantage of higher maximum plasma concentration16. In clinical studies in haemophilia A patients with alloantibodies and AHA with autoantibodies against hFVIII presenting with bleeding, OBI-1 led to measurable responses, resulting in reliable haemostasis without any severe drug-related adverse effects22,23. Mannucci and Franchini16 recognise the advantage of using a (relatively high) fixed loading dose (200 U/kg used in clinical trials22,23) of OBI-1 in providing urgent treatment, particularly when information about the degree of cross-reactivity of the patient's antibody with rpFVIII may not be available. However, the authors speculate that a lower fixed loading dose should be evaluated if possible, given that the majority of trial participants with AHA achieved unnecessarily high and potentially prothrombotic levels of plasma FVIII. One possible limitation to repeated use of rpFVIII includes potential development of specific anti-porcine antibodies (17.9% in a cohort of patients with AHA23), although once effective immunosuppression is established this is not expected to be a significant problem in patients with AHA. However, additional evidence for the efficacy and safety of this product is eagerly awaited from more accurate post-marketing surveillance studies. Due to inter-patient variation in inhibitor epitope specificity, assays for measuring the degree of cross-reactivity of the anti-hFVIII antibodies with rpFVIII are also needed to facilitate more tailored dosing of OBI-1. In addition to pFVIII, other FVIII orthologues from the animal kingdom18 or cross-species hybrid FVIII molecules, each with its own advantages and limitations are likely to expand our clinical armamentarium in the near future and facilitate provision of personalised haemophilia care. Naturally, this is not the first, nor the last, time that we will "borrow from the animal kingdom" in order to treat or manage human diseases, including those in the field of thrombosis and haemostasis. For example, unfractionated heparin, used to treat thrombotic disease, is generally also obtained from porcine (or bovine) sources. Vitamin K antagonists were originally "discovered" after cows suffered bleeding deaths from eating clover enriched in the drug. Animal sources of insulin to treat diabetes and thyroxin to treat thyroid-related problems provide a few other examples of our reliance on the animal kingdom for maintaining human health. The Authors declare no conflicts of interest.
References
1) Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J Med 2001; 344: 1773-9. 2) Stonebraker JS, Bolton-Maggs PH, Soucie JM, et al. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 2010; 16: 20-32.
Correspondence: Emmanuel J. Favaloro Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital Hawkesbury Road Westmead, NSW, 2145, Australia e-mail: [email protected]
Blood Transfus 2017; 15: 294-5 DOI 10.2450/2016.0104-16 All rights reserved - For personal use only No other use without premission
295
