521
Views
9
CrossRef citations to date
0
Altmetric
Review

Safety of recombinant coagulation factors in treating hemophilia

&
Pages 75-85 | Received 14 Oct 2018, Accepted 22 Jan 2019, Published online: 22 Feb 2019

References

  • Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood. 2001;98:2571–2573.
  • Azzi A, Maggi F, Zakrzewska K, et al. Different behavior of erythrovirus B19 and torquetenovirus in response to a single step of albumin purification. Transfusion. 2006;46:1162–1167.
  • Hollak CE, Vom Dahl S, Aerts JM, et al. Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease. Blood Cells Mol Dis. 2010;44:41–47.
  • Schlesinger KW, Ragni MV. Safety of the new generation recombinant factor concentrates. Expert Opin Drug Saf. 2002;1:213–223.
  • Kahle J, Orlowski A, Stichel D, et al. Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A. Blood. 2017;130:808–816.
  • Franchini M, Lippi G, Montagnana M, et al. Anaphylaxis in patients with congenital bleeding disorders and inhibitors. Blood Coagul Fibrinolysis. 2009;20:225–229.
  • Verbruggen B, van Heerde WL, Laros-van Gorkom BA. Improvements in factor VIII inhibitor detection: from Bethesda to Nijmegen. Semin Thromb Hemost. 2009;35:752–759.
  • Sultan Y. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French hemophilia study group. Thromb Haemost. 1992;67:600–602.
  • Margaglione M, Castaman G, Morfini M, et al. The Italian AICE-genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008;93:722–728.
  • Schwaab R, Brackmann HH, Meyer C, et al. mutation type determines risk of inhibitor formation. Thromb Haemost. 1995;74:1402–1406.
  • Hall M. Haemophilia complicated by an acquired circulating anticoagulant: a report of three cases. Br J Haematol. 1961;7:340–348.
  • Bidwell E, Denson KW, Dike GW. Antibody nature of the inhibitor to antihaemophilic globulin (Factor 8). Nature. 1966;210:746–747.
  • Strauss HS, Merler E. Characterization and properties of an inhibitor of factor 8 in the plasma of patients with hemophilia A following repeated transfusions. Blood. 1967;30:137–150.
  • Kasper CK. Incidence and course of inhibitors among patients with classic hemophilia. Thromb Diath Haemorrh. 1973;30:263–271.
  • Yang HC, Kuzur M. Procoagulant specificity of factor VIII inhibitor. Br J Haematol. 1977;37:429–433.
  • Fulcher CA, de Graaf Mahoney S, Zimmerman TS. FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. Blood. 1987;69:1475–1480.
  • Shapiro SS. Characterization of factor VIII antibodies. Ann N Y Acad Sci. 1975;240:350–361.
  • Wight J, Paisley S. The epidemiology of inhibitors in hemophilia: a systematic review. Haemophilia. 2003;9:418–435.
  • Scandella D, Mattingly M, de Graaf S, et al. Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization. Blood. 1989;74:1618–1626.
  • Scandella DH. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients. Semin Thromb Hemost. 2000;26:137–142.
  • Schwarzinger I, Pabinger I, Korninger C, et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol. 1987;24:241–245.
  • Ehrenforth S, Kreuz W, Scharrer I, et al. Factor VIII inhibitors in haemophiliacs. Lancet. 1992;340:253.
  • Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992;339:594–598.
  • de Biasi R, Rocino A, Papa ML, et al. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost. 1994;71:544–547.
  • Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Hemost. 2002;28:273–276.
  • Lusher JM, Arkin S, Abildgaard CF, et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate previously untreated patient study group. N Engl J Med. 1993;328:453–459.
  • Gruppo RA, Brown D, Wilkes MM. Navickis RJ comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis–a meta-analysis. Haemophilia. 2003;9:251–260.
  • Gruppo RA, Brown D, Wilkes MM, et al. Increased breakthrough bleeding during prophylaxis with B-domain deleted factor VIII–a robust meta-analytic finding. Haemophilia. 2004;10:449–451.
  • Gruppo RA, Brown D, Wilkes MM, et al. Meta-analytic evidence of increased breakthrough bleeding during prophylaxis with B-domain deleted factor VIII. Haemophilia. 2004;10:747–750.
  • Rea C, Dunkerley A, Sørensen B, et al. Pharmacokinetics, coagulation factor consumption and clinical efficacy in patients being switched from full-length FVIII treatment to B-domain-deleted r-FVIII and back to full-length FVIII. Haemophilia. 2009;15:1237–1242.
  • Aledort LM, Navickis RJ. Wilkes MM best evidence on B-domain deletion and the immunogenicity of recombinant factor VIII. J Thromb Haemost. 2011;9:2325–2327.
  • Epstein J, Xiong Y, Woo P, et al. Retrospective analysis of differences in annual factor VIII utilization among haemophilia A patients. Haemophilia. 2012;18:187–192.
  • Gringeri A, Tagliaferri A, Tagariello G, et al. Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII. Br J Haematol. 2004;126:398–404.
  • Pollmann H, Externest D, Ganser A, et al. Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria. Haemophilia. 2007;13:131–143.
  • Delignat S, Repessé Y, Gilardin L, et al. Predictive immunogenicity of refacto AF. Haemophilia. 2014;20:486–492.
  • Mathias MC, Collins PW, Palmer BP, et al. The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom. Haemophilia. 2018;24:896–901.
  • Zhu FX, Liu ZL, Miao J, et al. Glycosylation modifications improve secretion and activity of intein spliced coagulation factor VIII]. Zhonghua Yi Xue Za Zhi. 2010;90:2570–2574.
  • Kreuz W, Ettingshausen CE, Zyschka A, et al. Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products. Semin Thromb Hemost. 2002;28:285–290.
  • Goudemand J, Laurian Y, Calvez T. Risk of inhibitors in haemophilia and the type of factor replacement. Curr Opin Hematol. 2006;13:316–322.
  • Chalmers EA, Brown SA, Keeling D, et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia. 2007;13:149–155.
  • Mancuso ME, Mannucci PM, Rocino A, et al. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost. 2012;10:781–790.
  • Gouw SC, van der Bom JG, Auerswald G, et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007;109:4693–4697.
  • Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med. 2013;368:231–239.
  • Fischer K, Lassila R, Peyvandi F, et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European haemophilia safety surveillance (EUHASS) project. Thromb Haemost. 2015;113:968–975.
  • Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost. 2010;8:1256–1265.
  • Franchini M, Coppola A, Rocino A, et al. Systematic review of the role of FVIII concentrates inhibitor development in previously untreated patients with severe hemophilia A: a 2013 update. Semin Thromb Hemost. 2013;39:752–766.
  • Marcucci M, Mancuso ME, Santagostino E, et al. Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A. A patient-level meta-analysis. Thromb Haemost. 2015;113:958–967.
  • Messori A, Peyvandi F, Mengato D, et al. Incidence of low-titre factor VIII inhibitors in patients with haemophilia A: meta-analysis of observational studies. Haemophilia. 2017;23:e87–e92.
  • Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374:2054–2064.
  • Kaveri SV, Dasgupta S, Andre S, et al. Factor VIII inhibitors: role of von willebrand factor on the uptake of factor VIII by dendritic cells. Haemophilia. 2007;13:61–64.
  • Dasgupta S, Repessé Y, Bayry J, et al. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors. Blood. 2007;109:610–612.
  • Delignat S, Dasgupta S, André S, et al. Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A. Haematologica. 2007;92:1423–1426.
  • Qadura M, Waters B, Burnett E, et al. Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice. Blood. 2009;114:871–880.
  • Peyvandi F, Garagiola I. Product type and other environmental risk factors for inhibitor development in severe hemophilia A. Res Pract Thromb Haemost. 2018;10(2):220–227.
  • Calvez T, Chambost H, d’Oiron R, et al. Analyses of the FranceCoag cohort support differences in immunogenicity among one plasma-derived and two recombinant factor VIII brands in boys with severe hemophilia A. Haematologica. 2018;103:179–189.
  • Strauss T, Lubetsky A, Ravid B, et al. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study. Haemophilia. 2011;17:625–629.
  • van Den Berg HM, Pipe S, Ljung R. Plasma products do not solve the inhibitor problem. Haemophilia. 2017;23:346–347.
  • Fischer K, Blatny J. Do the SIPPET study results apply to the patients I treat? Haemophilia. 2017;23:348–349.
  • Iorio A. Research and policy implications of a recently published controlled study in previously untreated haemophilia patients at high risk of inhibitor development. Haemophilia. 2017;23:350–352.
  • Mannucci PM, Peyvandi F, Rosendaal FR. Reply to the letter by Iorio. Haemophilia. 2017;23:e248–e249.
  • Peyvandi F, Mannucci PM, Palla R, et al. SIPPET: methodology, analysis and generalizability. Haemophilia. 2017;23:353–361.
  • EMA_1. [cited 2018 Oct 4]. Available from: https://www.ema.europa.eu/documents/press-release/factor-viii-medicines-no-clear-consistent-evidence-difference-risk-inhibitor-development-between_en.pdf
  • Neufeld EJ, Sidonio RF Jr, O’Day K, et al. Cost analysis of plasma-derived factor VIII/von willebrand factor versus recombinant factor VIII for the treatment of previously untreated patients with severe hemophilia A in the United States. J Med Econ. 2018;21:762–769.
  • Mohamed AF, Epstein JD, Li-McLeod JM. Patient and parent preferences for haemophilia A treatments. Haemophilia. 2011;17:209–214.
  • Franchini M, Coppola A, Rocino A, et al. Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey. Haemophilia. 2014;20:e128–e135.
  • Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for the prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126:1078–1085.
  • Liesner RJ, Abashidze M, Aleinikova O, et al. Immunogenicity, efficacy and safety of nuwiq® (Human-cl rhFVIII) in previously untreated patients with severe haemophilia A-interim results from the nuprotect study. Haemophilia. 2018;24:211–220.
  • Lentz SR, Janic D, Kavakli K, et al. Long-term safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: final results from the guardian 2 extension trial. Haemophilia. 2018;24:e391–e394.
  • Klukowska A, Szczepański T, Vdovin V, et al. Novel, human cell line-derived recombinant factor VIII (human-cl rhFVIII, nuwiq®) in children with severe haemophilia A: efficacy, safety and pharmacokinetics. Haemophilia. 2016;22:232–239.
  • Shah A, Coyle T, Lalezari S, et al. BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: comprehensive pharmacokinetic assessment from clinical studies. Haemophilia. 2018;24:733–740.
  • EMA_2. [cited 2018 Oct 4]. Available from: https://www.ema.europa.eu/documents/scientific-guideline/draft-guideline-clinical-investigation-recombinant-human-plasma-derived-factor-viii-products_en.pdf
  • EMA_3. [cited 2018 Oct 4]. Available from: https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-recombinant-human-plasma-derived-factor-ix-products-revision-1_en.pdf
  • Lillicrap D. Immunogenicity of new treatments: current status knowledge. 11th Annual Congress of the European Association for Haemophilia and Allied Disorders 2018; 2018 Feb 7–9; Madrid, Spain. Haemophilia 2018;24:S1.
  • Stidl R, Denne M, Goldstine J, et al. Polyethylene glycol exposure with antihemophilic factor (recombinant), PEGylated (rurioctocog alfa pegol) and other therapies indicated for the pediatric population : history and safety. Pharmaceuticals. 2018;11:75.
  • Zhang P, Sun F, Liu S, et al. Anti-PEG antibodies in the clinic: current issues and beyond PEGylation. J Control Release. 2016;244(Pt B):184–193.
  • Milton Harris J, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003;2:214–221.
  • Webster R, Didier E, Harris P, et al. PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos. 2007;35:9–16.
  • Kang JS, DeLuca PP, Lee KC. Emerging PEGylated drugs. Expert Opin Drug Discov. 2009;14:363–380.
  • Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2003;55:1261–1277.
  • Nakaoka R, Tabata Y, Yamaoka T, et al. Prolongation of the serum half-life period of superoxide dismutase by poly(ethylene glycol) modification. J Control Release. 1997;46:253–261.
  • Ivens IA, Baumann A, McDonald TA, et al. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia. 2013;19:11–20.
  • Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci. 1994;83:601–606.
  • Yamaoka T, Tabata Y, Ikada Y. Fate of water‐soluble polymers administered via different routes. J Pharm Sci. 1995;84:349–354.
  • Simone Fishburn C. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci. 2008;97:4167–4183.
  • Stidl R, Fuchs S, Bossard M, et al. Safety of PEGylated recombinant human full-length coagulation factor VIII (BAX 855) in the overall context of PEG and PEG conjugates. Haemophilia. 2016;22:54–64.
  • Rudmann DG, Alston JT, Hanson JC, et al. High molecular weight polyethylene glycol cellular distribution and PEG-associated cytoplasmic vacuolation is molecular weight dependent and does not require conjugation to proteins. Toxicol Pathol. 2013;41:970–983.
  • Rebinyn Package Insert. [cited 2018 Oct 4]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Product_Information/human/004178/WC500232816.pdf
  • Sternebring O, Christensen JK, Bjørnsdottir I. Pharmacokinetics, tissue distribution, excretion, and metabolite profiling of PEGylated rFIX (nonacog beta pegol, N9-GP) in rats. Eur J Pharm Sci. 2016;92:163–172.
  • Lubich C, Allacher P, de la Rosa M, et al. The mystery of antibodies against Polyethylene Glycol (PEG) - what do we know? Pharm Res. 2016;33:2239–2249.
  • Ganson NJ, Kelly SJ, Scarlett E, et al. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Therapy. 2006;8:R12.
  • Judge A, McClintock K, Phelps JR, et al. Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes. Mol Ther. 2006;13:328–337.
  • Armstrong JK, Hempel G, Koling S, et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007;110:103–111.
  • Hershfield MS, Ganson NJ, Kelly SJ, et al. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Therapy. 2014;16:R63.
  • Richter AW, Åkerblom E. Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. Int Arch Allergy Immunol. 1983;70:124–131.
  • Mehvar R. Modulation of the pharmacokinetics and pharmacodynamics of proteins by polyethylene glycol conjugation. J Pharm Pharm Sci. 2000;3:125–136.
  • Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10:1451–1458.
  • Hamidi M, Azadi A, Rafiei P. Pharmacokinetic consequences of pegylation. Drug Deliv. 2006;13:399–409.
  • Tillmann H, Ganson NJ, Patel K, et al. High prevalence of pre-existing antibodies against polyethylene glycol (PEG) in hepatitis C (HCV) patients which is not associated with impaired response to PEG-interferon. J Hepatol. 2010;52:S129.
  • Garay RP, Labaune JP. Immunogenicity of Polyethylene Glycol (PEG). Open Conf Proc J. 2011;2:104–107.
  • Garay RP, El-Gewely R, Armstrong JK, et al. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–1323.
  • Ganson NJ, Povsic TJ, Sullenger BA, et al. Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. Allergy Clin Immunol. 2016;137:1610–1613.
  • Ivens IA, Zierz R, Haaning J, et al. BAY 94–9027, a PEGylated Recombinant Human FVIII, Shows Less Immunogenicity Compared to Un-PEGylated Recombinant FVIII. Blood. 2010;116(2214):LP–2214.
  • Shubin AV, Demidyuk IV, Komissarov AA, et al. Cytoplasmic vacuolization in cell death and survival. Oncotarget. 2016;7:55863–55889.
  • Irizarry Rovira AR, Bennet BM, Bolon B, et al. Scientific and regulatory policy committee points to consider: histopathologic evaluation in safety assessment studies for PEGylated pharmaceutical products. Toxicol Pathol. 2018;46:616–635.
  • Halpern WG, Ameri M, Bowman CJ, et al. Scientific and regulatory policy committee points to consider review: inclusion of reproductive and pathology end points for assessment of reproductive and developmental toxicity in pharmaceutical drug development. Toxicol Pathol. 2016;44:789–809.
  • Fruijtier-Pölloth C. Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products. Toxicology. 2005;214:1–38.
  • Webster R, Elliott V, Park BK, et al. PEG and PEG conjugates toxicity: towards an understanding of the toxicity of PEG and its relevance to PEGylated biologicals. In: Veronese FM, editor, Pegylated protein drugs. Basic science and clinical applications. Milestone in Drug Therapy. Basel, Switzerland: Birkhauser Verlag; 2009. pp. 127–146.
  • Ivens IA, Achanzar W, Baumann A, et al. PEGylated biopharmaceuticals: current experience and considerations for nonclinical development. Toxicol Pathol. 2015;43:959–983.
  • Negrier C, Knobe K, Tiede A, et al. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: A first human dose trial in patients with hemophilia B. Blood. 2011;118:2695–2701.
  • Mei B, Pan C, Jiang H, et al. Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood. 2010;116:270–279.
  • Ivens IA, Zierz R, Haaning J, et al. 94–9027, a PEGylated recombinant human FVIII, shows less immunogenicity compared to Un-PEGylated recombinant FVIII. Blood. 2010;116:2214.
  • Ljung R, Karim FA, Saxena K, et al. 40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors. J Thromb Haemost. 2013;11:1260–1268.
  • Coyle TE, Reding MT, Lin JC, et al. Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J Thromb Haemost. 2014;12:488–496.
  • Kamphuisen PW, Eikenboom JCJ. Bertina RM elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21:731–738.
  • Rietveld IM, Lijfering WM, le Cessie S, et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von willebrand factor. J Thromb Haemost. 2019;17:99–109.
  • [cited 2019 Jan 16].  Available from: https://www.hemophilia.org/Newsroom/Industry-News/Statement-from-Genentech-Regarding-Hemlibra
  • [cited 2019 Jan 16]. Available from: https://news.wfh.org/first-case-anti-drug-antibody-reported-hemlibra-trial/

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.