Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia AFinancial support: This trial was sponsored by Novo Nordisk A/S (Bagsværd, Denmark).
Received:10 June 2016
Accepted after major revision:19 October 2016
13 November 2017 (online)
Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20–75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00–4.61), the mean ABR was 3.70 (95 % confidence interval 2.94–4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.
- 1 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-544.
- 2 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-47.
- 3 Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379: 1447-1456.
- 4 Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia 2001; 07: 392-396.
- 5 Thim L, Vandahl B, Karlsson J. et al. Purification and characterization of a new recombinant factor VIII (N8). Haemophilia 2010; 16: 349-359.
- 6 Agerso H, Stennicke HR, Pelzer H. et al. Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia 2012; 18: 941-947.
- 7 Tiede A, Brand B, Fischer R. et al. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost 2013; 11: 670-678.
- 8 World Medical Association. Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects Available at: http://www.wma.net/en/30publications/10policies/b3/ Accessed May 16, 2016.
- 9 International Conference on Harmonisation. Harmonised tripartite guideline: Guideline for good clinical practice. Consolidated Guidelines. E6(R1) Available at: http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice.html Accessed May 16, 2016.
- 10 Giles AR, Verbruggen B, Rivard GE. et al. A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor VIII:C inhibitors in the haemophilia A population of Canada. Association of Hemophilia Centre Directors of Canada. Factor VIII/IX Subcommittee of Scientific and Standardization Committee of International Society on Thrombosis and Haemostasis. Thromb Haemost 1998; 79: 872-875.
- 11 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
- 12 European Medicines Agency. Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109692.pdf Accessed May 16, 2016.
- 13 Committee for Medicinal Products for Human use (CHMP). Guideline on clinical trials in small populations Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003615.pdf Accessed May 16, 2016.
- 14 Shankar G, Shores E, Wagner C. et al. Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol 2006; 24: 274-280.
- 15 US Food and Drug Administration. Guidance for Industry Assay Development for Immunogenicity Testing of Therapeutic Proteins. Draft Guidance Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM192750.pdf Accessed May 16, 2016.
- 16 Mahlangu J, Powell JS, Ragni MV. et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123: 317-325.
- 17 Manco-Johnson MJ, Kempton CL, Reding MT. et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost 2013; 11: 1119-1127.
- 18 Recht M, Nemes L, Matysiak M. et al. Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia 2009; 15: 869-880.
- 19 Valentino LA, Mamonov V, Hellmann A. et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10: 359-367.
- 20 Abshire TC, Brackmann HH, Scharrer I. et al. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group. Thromb Haemost 2000; 83: 811-816.
- 21 Lentz SR, Misgav M, Ozelo M. et al. Results from a large multinational clinical trial (guardian1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy. Haemophilia 2013; 19: 691-697.
- 22 Lusher JM, Lee CA, Kessler CM. et al. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 09: 38-49.
- 23 Tarantino MD, Collins PW, Hay CR. et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004; 10: 428-437.
- 24 Skinner MW. Haemophilia care - past, present and future from a patient perspective. Haemophilia 2012; 18 (Suppl. 05) 3-5.
- 25 Hay CR, Palmer B, Chalmers E. et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood 2011; 117: 6367-6370.
- 26 Stennicke HR, Kjalke M, Karpf DM. et al. A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood 2013; 121: 2108-2116.
- 27 Klintman J, Hillarp A, Donfield S. et al. Antibody formation and specificity in Bethesda-negative brother pairs with haemophilia A. Haemophilia 2013; 19: 106-112.
- 28 Whelan SF, Hofbauer CJ, Horling FM. et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood 2013; 121: 1039-1048.