Haemophilia (2015), 1–3
DOI: 10.1111/hae.12612
COMMENTARY
Recombinant porcine factor VIII: a new instalment of a long story P. M. MANNUCCI Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
In the 1960s the standard of care of persons with haemophilia was very inadequate, even in high-income countries. Plasma concentrates of coagulation factors were produced in very small amounts, including cryoprecipitate after the seminal discovery of Judith Pool. They were barely sufficient to handle catastrophic bleeds, and even emergency surgery had to contend with the lack of the large amounts of factors needed to safely perform these procedures. Confronted with this dramatic situation Ethel Bidwell, a fine biochemist at the Oxford Haemophilia Centre, chose to fractionate in her own laboratory bovine and porcine plasma obtained at the abattoir to produce bovine and porcine factor VIII (FVIII) [1]. These home-made therapeutic products were not free from significant side effects: hypersensitivity reactions were almost constant and the platelet count fell in all recipients. This notwithstanding, animal FVIII allowed to perform successfully a number of major surgical operations [2,3]. On the basis of these early experiences, the UK-based pharmaceutical company Maw chose to produce a lyophilized porcine FVIII that became commercially available for compassionate use, not only in the UK but also in other countries. Even though the use of this second-generation product was not rid of the previous problems (thrombocytopenia and hypersensitivity reactions), on the whole the benefit/risk balance was favourable, because in the 1960s it did permit to handle life-threatening clinical situations that could not be tackled with the small amounts of FVIII available at that time [3]. In the 1970s the increasing availability of several commercial brands of human plasma-derived FVIII made less cogent the need to resort to products of animal origin, with a significant exception: patients with haemophilia A who had developed alloantibodies inacCorrespondence: Pier Mannuccio Mannucci, Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy Tel.: + 39 02 5503 5414; fax: + 39 02 54 100 125; e-mail: [email protected] Accepted after revision 14 November 2014 © 2015 John Wiley & Sons Ltd
tivating the infused human FVIII (inhibitors). A significant breakthrough was the observation that the degree of cross reactivity of anti-human FVIII antibodies with porcine FVIII was much smaller than that towards the human factor, in average 30% or less [4,5]. The fact that alloantibodies to human FVIII were less active towards porcine FVIII promoted the use of the latter in patients bleeding or undergoing surgical procedures that could not be handled with human FVIII, particularly when the inhibitor titre was too high to be neutralized and overcome by increasing the dosages of human FVIII. Thus, the lower cross reactivity of porcine FVIII with anti-human FVIII antibodies did help to increase the threshold of bleeding episodes that could be handled with FVIII. For instance, bleeding episodes in a hypothetical patient with 15 BU mL 1 of FVIII inhibitor are unlikely to be controlled with human FVIII, because the amount needed to neutralize the inhibitor and hence to obtain measurable plasma levels would be prohibitively high. On the other hand, assuming 30% cross-reactivity, the anti-porcine FVIII antibody of such an hypothetical patient could be 5 BU mL 1, a level that can be overcome with porcine FVIII, thereby attaining measurable plasma levels. The possibility to adapt the available inhibitor assays, and in particular the Bethesda assay in order to measure the degree of cross reactivity of the human antibody towards porcine FVIII, made this strategy tailored to the antibody titre and hence more accurate for the choice of the optimal dosage in each patient [4,5]. All in all, the approach to bleeding in patients with FVIII inhibitors that took advantage of the lower antibody reactivity towards porcine FVIII became and remained appealing even after the introduction of bypassing agents, because many of us felt more comfortable to treat life-threatening bleeds (and perform major surgery) with a product that could yield measurable FVIII in plasma, at variance with bypassing agents that can be hardly monitored in the laboratory. However, the Maw preparation of porcine FVIII was too much accompanied by substantial side effects to be widely accepted by the haemophilia community. The next instalment of the story stems from another English company (Speywood), that in the early 1980s 1
2
EDITORIAL
chose to produce a more refined FVIII fractionated from pig plasma. This third-generation product was definitely more easily dissolved, and gave less hypersensitivity reactions, even though thrombocytopenia continued to be a frequent occurrence owing to the platelet-aggregation effect of von Willebrand factor (VWF) contained in the preparation [6]. The first clinical studies based upon the use of Hyate:C were published in 1984 by Kernoff et al. [4] and Loredana Gatti with me [5]. A relatively large number of patients with severe haemophilia A complicated by inhibitors were treated successfully, side effects being limited in number and severity [4,5]. Following these early studies, the product was licensed and used quite extensively despite its high price (a feature that also applies to bypassing agents) [7,8]. Hints were put forward that porcine FVIII might also be used at home to induce immune tolerance [9], and for prophylaxis of bleeding in patients with FVIII inhibitors [10]. Hyate:C was also used in a patient who had an acquired FVIII deficiency postpartum as a consequence of FVIII autoantibodies [5]. In acquired haemophilia, the convenience of porcine FVIII was made more prominent by the fact that the degree of reactivity of autoantibodies towards porcine FVIII was found to be even smaller than that of alloantibodies. In a few instances cross reactivity was even absent, making the use of Hyate:C very convenient for the treatment or prevention of bleeding in these rare but difficult cases [11]. Unfortunately, at a time when the indications for this product were expanding, it was discovered that some batches were contaminated with porcine parvovirus [12–14]. After a few attempts made by the manufacturers to tackle this issue, they decided to stop production, in spite of the fact that the porcine parvovirus is not pathogenic in humans. Many of us felt we had lost an important weapon to manage patients with FVIII inhibitors and acquired haemophilia! The fourth instalment of the story of porcine FVIII is developing in the Third Millennium, when a pharmaceutical company chose to tackle by means of recombinant DNA technology the main limitations of the previous preparations: the content of VWF and of other porcine plasma proteins, and the risk of viral contamination. After a few preliminary studies had evaluated the new porcine FVIII in the frame of a pharmacokinetic study and in patients with severe haemophilia A complicated by inhibitors [15], this issue of Haemophilia includes a most recent study carried out by Kruse-Jarres et al. [16] in 28 patients with acquired haemophilia.
References 1 Bidwell E. The purification of bovine antihaemophilic globulin. Br J Haematol 1955; 1: 35–45.
Haemophilia (2015), 1--3
Not surprisingly, the recombinant product that contains only porcine FVIII is devoid of the side effects associated with the previous generations of plasma-derived products. Most importantly, the authors of the study provide us with convincing evidence that the product was efficacious in controlling severe bleeding episodes in 28 patients with acquired haemophilia. The authors’ approach to the choice of the dose regimen was astute and pragmatic, perhaps taking into account that these patients with a rare acquired disease are often initially seen in non-specialized clinical centres. According to Kruse-Jarres et al. [16] all the patients were initially treated with the same large dose of porcine FVIII (200 U kg 1), assuming that this dose, even without knowing inhibitor levels and cross reactivity with porcine FVIII, would overcome any inhibitor titre and quickly attain measurable FVIII levels. This goal was achieved in practically all instances, and measurable FVIII was accompanied by a satisfactory control of the bleeding episodes in the majority of cases. Kruse-Jarres et al. [16] also provides us with useful data on those cases who needed further FVIII doses, on antibody cross reactivity, anamnestic rise of pre-existing antibodies as well as de novo development of anti-FVIII after the first infusion. However, the main appeal of this study is the demonstration that the choice of a dose irrespective of the inhibitor titre is a clinically valid approach. One can envisage that in the frame of a consultation stemming from a distant clinical unit that has to tackle dramatic clinical situations such as those reported in this article, a simple schedule such as that proposed by the authors could be recommended even without immediate support from specialized laboratories. No rose is without thorn. In several instances, patients attained very high plasma levels of FVIII, which may be a cause of concern for the theoretical risk of venous thromboembolism in these often elderly patients. Even though it would be worthy to see the rate of bleeding control with a smaller fixed dose (for instance, 100 U kg 1), I surmise that perhaps the risk of thrombosis associated with high but transient plasma levels of FVIII is smaller than that associated with the sustained high levels shown in the literature to be a risk factor for venous thrombosis.
Disclosures The author has received speaker fees for participation as expert at educational meetings organized by Baxter, Bayer, Biotest, Grifols, Kedrion Biopharma and Novo Nordisk.
2 Macfarlane RG, Biggs R, Bidwell E. Bovine antihaemophilic globulin in the treatment of haemophilia. Lancet 1954; i: 1316–9. 3 Biggs R. Thirty years of haemophilia treatment in Oxford. Br J Haematol 1967; 13: 452–63.
4 Kernoff PB, Thomas ND, Lilley PA, Matthews KB, Goldman E, Tuddenham EG. Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII. Blood 1984; 63: 31–41.
© 2015 John Wiley & Sons Ltd
EDITORIAL 5 Gatti L, Mannucci PM. Use of porcine factor VIII in the management of seventeen patients with factor VIII antibodies. Thromb Haemost 1984; 51: 379–84. 6 Altieri DC, Capitanio AM, Mannucci PM. von Willebrand factor contaminating porcine factor VIII concentrate (Hyate C) causes platelet aggregation. Br J Haematol 1986; 63: 703–11. 7 Lozier JN, Santagostino E, Kasper CK, Teitel JM, Hay CR. Use of porcine factor VIII for surgical procedures in hemophilia A patients with inhibitors. Semin Hematol 1993; 2(Suppl. 1): 10–21. 8 Hay CR. Porcine factor VIII: past, present and future. Haematologica 2000; 85(Suppl. 1): 21–4. 9 Hay CRM, Laurian Y, Verroust F, Preston FE, Kernoff PA. Induction of immune tolerance in patients with haemophilia A and
© 2015 John Wiley & Sons Ltd
10
11
12
13
inhibitors treated with porcine factor VIII by home therapy. Blood 1990; 76: 882–6. Vyas P, Pasi J, Lee CA. Successful longterm treatment with porcine factor VIII of a patient with haemophilia and an inhibitor to factor VIII. Haemophilia 1996; 2: 240–3. Morrison AF, Ludlam CA, Kessler C. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 1993; 81: 1513–20. Soucie JM, Erdman DD, Evatt BL et al. Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Transfusion 2000; 40: 708–11. Takefman DM, Wong S, Maudru T, Peden K, Wilson CA. Detection and characterization of porcine endogenous retrovirus in
3
porcine plasma and porcine factor VIII. J Virol 2001; 75: 4551–7. 14 Giangrande PL, Kessler CM, Jenkins CE, Weatherill PJ, Webb PD. Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII. Haemophilia 2002; 8: 798–801. 15 Toschi V. OBI-1, porcine recombinant factor VIII for the potential treatment of patients with congenital hemophilia A and alloantibodies against human factor VIII. Curr Opin Mol Ther 2010; 12: 617–25. 16 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 2014; 20(Suppl. 3): 1–186.
Haemophilia (2015), 1--3
DOI: 10.1111/hae.12612
COMMENTARY
Recombinant porcine factor VIII: a new instalment of a long story P. M. MANNUCCI Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
In the 1960s the standard of care of persons with haemophilia was very inadequate, even in high-income countries. Plasma concentrates of coagulation factors were produced in very small amounts, including cryoprecipitate after the seminal discovery of Judith Pool. They were barely sufficient to handle catastrophic bleeds, and even emergency surgery had to contend with the lack of the large amounts of factors needed to safely perform these procedures. Confronted with this dramatic situation Ethel Bidwell, a fine biochemist at the Oxford Haemophilia Centre, chose to fractionate in her own laboratory bovine and porcine plasma obtained at the abattoir to produce bovine and porcine factor VIII (FVIII) [1]. These home-made therapeutic products were not free from significant side effects: hypersensitivity reactions were almost constant and the platelet count fell in all recipients. This notwithstanding, animal FVIII allowed to perform successfully a number of major surgical operations [2,3]. On the basis of these early experiences, the UK-based pharmaceutical company Maw chose to produce a lyophilized porcine FVIII that became commercially available for compassionate use, not only in the UK but also in other countries. Even though the use of this second-generation product was not rid of the previous problems (thrombocytopenia and hypersensitivity reactions), on the whole the benefit/risk balance was favourable, because in the 1960s it did permit to handle life-threatening clinical situations that could not be tackled with the small amounts of FVIII available at that time [3]. In the 1970s the increasing availability of several commercial brands of human plasma-derived FVIII made less cogent the need to resort to products of animal origin, with a significant exception: patients with haemophilia A who had developed alloantibodies inacCorrespondence: Pier Mannuccio Mannucci, Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy Tel.: + 39 02 5503 5414; fax: + 39 02 54 100 125; e-mail: [email protected] Accepted after revision 14 November 2014 © 2015 John Wiley & Sons Ltd
tivating the infused human FVIII (inhibitors). A significant breakthrough was the observation that the degree of cross reactivity of anti-human FVIII antibodies with porcine FVIII was much smaller than that towards the human factor, in average 30% or less [4,5]. The fact that alloantibodies to human FVIII were less active towards porcine FVIII promoted the use of the latter in patients bleeding or undergoing surgical procedures that could not be handled with human FVIII, particularly when the inhibitor titre was too high to be neutralized and overcome by increasing the dosages of human FVIII. Thus, the lower cross reactivity of porcine FVIII with anti-human FVIII antibodies did help to increase the threshold of bleeding episodes that could be handled with FVIII. For instance, bleeding episodes in a hypothetical patient with 15 BU mL 1 of FVIII inhibitor are unlikely to be controlled with human FVIII, because the amount needed to neutralize the inhibitor and hence to obtain measurable plasma levels would be prohibitively high. On the other hand, assuming 30% cross-reactivity, the anti-porcine FVIII antibody of such an hypothetical patient could be 5 BU mL 1, a level that can be overcome with porcine FVIII, thereby attaining measurable plasma levels. The possibility to adapt the available inhibitor assays, and in particular the Bethesda assay in order to measure the degree of cross reactivity of the human antibody towards porcine FVIII, made this strategy tailored to the antibody titre and hence more accurate for the choice of the optimal dosage in each patient [4,5]. All in all, the approach to bleeding in patients with FVIII inhibitors that took advantage of the lower antibody reactivity towards porcine FVIII became and remained appealing even after the introduction of bypassing agents, because many of us felt more comfortable to treat life-threatening bleeds (and perform major surgery) with a product that could yield measurable FVIII in plasma, at variance with bypassing agents that can be hardly monitored in the laboratory. However, the Maw preparation of porcine FVIII was too much accompanied by substantial side effects to be widely accepted by the haemophilia community. The next instalment of the story stems from another English company (Speywood), that in the early 1980s 1
2
EDITORIAL
chose to produce a more refined FVIII fractionated from pig plasma. This third-generation product was definitely more easily dissolved, and gave less hypersensitivity reactions, even though thrombocytopenia continued to be a frequent occurrence owing to the platelet-aggregation effect of von Willebrand factor (VWF) contained in the preparation [6]. The first clinical studies based upon the use of Hyate:C were published in 1984 by Kernoff et al. [4] and Loredana Gatti with me [5]. A relatively large number of patients with severe haemophilia A complicated by inhibitors were treated successfully, side effects being limited in number and severity [4,5]. Following these early studies, the product was licensed and used quite extensively despite its high price (a feature that also applies to bypassing agents) [7,8]. Hints were put forward that porcine FVIII might also be used at home to induce immune tolerance [9], and for prophylaxis of bleeding in patients with FVIII inhibitors [10]. Hyate:C was also used in a patient who had an acquired FVIII deficiency postpartum as a consequence of FVIII autoantibodies [5]. In acquired haemophilia, the convenience of porcine FVIII was made more prominent by the fact that the degree of reactivity of autoantibodies towards porcine FVIII was found to be even smaller than that of alloantibodies. In a few instances cross reactivity was even absent, making the use of Hyate:C very convenient for the treatment or prevention of bleeding in these rare but difficult cases [11]. Unfortunately, at a time when the indications for this product were expanding, it was discovered that some batches were contaminated with porcine parvovirus [12–14]. After a few attempts made by the manufacturers to tackle this issue, they decided to stop production, in spite of the fact that the porcine parvovirus is not pathogenic in humans. Many of us felt we had lost an important weapon to manage patients with FVIII inhibitors and acquired haemophilia! The fourth instalment of the story of porcine FVIII is developing in the Third Millennium, when a pharmaceutical company chose to tackle by means of recombinant DNA technology the main limitations of the previous preparations: the content of VWF and of other porcine plasma proteins, and the risk of viral contamination. After a few preliminary studies had evaluated the new porcine FVIII in the frame of a pharmacokinetic study and in patients with severe haemophilia A complicated by inhibitors [15], this issue of Haemophilia includes a most recent study carried out by Kruse-Jarres et al. [16] in 28 patients with acquired haemophilia.
References 1 Bidwell E. The purification of bovine antihaemophilic globulin. Br J Haematol 1955; 1: 35–45.
Haemophilia (2015), 1--3
Not surprisingly, the recombinant product that contains only porcine FVIII is devoid of the side effects associated with the previous generations of plasma-derived products. Most importantly, the authors of the study provide us with convincing evidence that the product was efficacious in controlling severe bleeding episodes in 28 patients with acquired haemophilia. The authors’ approach to the choice of the dose regimen was astute and pragmatic, perhaps taking into account that these patients with a rare acquired disease are often initially seen in non-specialized clinical centres. According to Kruse-Jarres et al. [16] all the patients were initially treated with the same large dose of porcine FVIII (200 U kg 1), assuming that this dose, even without knowing inhibitor levels and cross reactivity with porcine FVIII, would overcome any inhibitor titre and quickly attain measurable FVIII levels. This goal was achieved in practically all instances, and measurable FVIII was accompanied by a satisfactory control of the bleeding episodes in the majority of cases. Kruse-Jarres et al. [16] also provides us with useful data on those cases who needed further FVIII doses, on antibody cross reactivity, anamnestic rise of pre-existing antibodies as well as de novo development of anti-FVIII after the first infusion. However, the main appeal of this study is the demonstration that the choice of a dose irrespective of the inhibitor titre is a clinically valid approach. One can envisage that in the frame of a consultation stemming from a distant clinical unit that has to tackle dramatic clinical situations such as those reported in this article, a simple schedule such as that proposed by the authors could be recommended even without immediate support from specialized laboratories. No rose is without thorn. In several instances, patients attained very high plasma levels of FVIII, which may be a cause of concern for the theoretical risk of venous thromboembolism in these often elderly patients. Even though it would be worthy to see the rate of bleeding control with a smaller fixed dose (for instance, 100 U kg 1), I surmise that perhaps the risk of thrombosis associated with high but transient plasma levels of FVIII is smaller than that associated with the sustained high levels shown in the literature to be a risk factor for venous thrombosis.
Disclosures The author has received speaker fees for participation as expert at educational meetings organized by Baxter, Bayer, Biotest, Grifols, Kedrion Biopharma and Novo Nordisk.
2 Macfarlane RG, Biggs R, Bidwell E. Bovine antihaemophilic globulin in the treatment of haemophilia. Lancet 1954; i: 1316–9. 3 Biggs R. Thirty years of haemophilia treatment in Oxford. Br J Haematol 1967; 13: 452–63.
4 Kernoff PB, Thomas ND, Lilley PA, Matthews KB, Goldman E, Tuddenham EG. Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII. Blood 1984; 63: 31–41.
© 2015 John Wiley & Sons Ltd
EDITORIAL 5 Gatti L, Mannucci PM. Use of porcine factor VIII in the management of seventeen patients with factor VIII antibodies. Thromb Haemost 1984; 51: 379–84. 6 Altieri DC, Capitanio AM, Mannucci PM. von Willebrand factor contaminating porcine factor VIII concentrate (Hyate C) causes platelet aggregation. Br J Haematol 1986; 63: 703–11. 7 Lozier JN, Santagostino E, Kasper CK, Teitel JM, Hay CR. Use of porcine factor VIII for surgical procedures in hemophilia A patients with inhibitors. Semin Hematol 1993; 2(Suppl. 1): 10–21. 8 Hay CR. Porcine factor VIII: past, present and future. Haematologica 2000; 85(Suppl. 1): 21–4. 9 Hay CRM, Laurian Y, Verroust F, Preston FE, Kernoff PA. Induction of immune tolerance in patients with haemophilia A and
© 2015 John Wiley & Sons Ltd
10
11
12
13
inhibitors treated with porcine factor VIII by home therapy. Blood 1990; 76: 882–6. Vyas P, Pasi J, Lee CA. Successful longterm treatment with porcine factor VIII of a patient with haemophilia and an inhibitor to factor VIII. Haemophilia 1996; 2: 240–3. Morrison AF, Ludlam CA, Kessler C. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 1993; 81: 1513–20. Soucie JM, Erdman DD, Evatt BL et al. Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Transfusion 2000; 40: 708–11. Takefman DM, Wong S, Maudru T, Peden K, Wilson CA. Detection and characterization of porcine endogenous retrovirus in
3
porcine plasma and porcine factor VIII. J Virol 2001; 75: 4551–7. 14 Giangrande PL, Kessler CM, Jenkins CE, Weatherill PJ, Webb PD. Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII. Haemophilia 2002; 8: 798–801. 15 Toschi V. OBI-1, porcine recombinant factor VIII for the potential treatment of patients with congenital hemophilia A and alloantibodies against human factor VIII. Curr Opin Mol Ther 2010; 12: 617–25. 16 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 2014; 20(Suppl. 3): 1–186.
Haemophilia (2015), 1--3
