Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A

Summary

We report a prospective trial of 55 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe/moderately severe haemophilia A (baseline factor VIII [FVIII] ≤2%) treated with a single FVIII replacement product. It was the objective of this study to evaluate the immunogenicity, efficacy, and safety of rAHF-PFM (Advate^®). Ondemand or prophylactic treatment regimens were determined at the discretion of the investigator. rAHF-PFM was also permitted for perioperative management. There were 633 bleeding episodes (BEs), including 517 treated, and 466 rated for efficacy. Haemostatic efficacy was considered excellent/good in 93% of 466 rated treatments. Of 517 treated BEs, 463/517 (90%) were managed with one (356/517 [69%]) or two infusions (107/517 [21%]). There were 27 surgeries. Intraoperative (n=22) and postoperative (n=25) haemostatic efficacies were considered excellent or good in 100% of rated surgeries. Related serious adverse events (SAEs) were inhibitor development in 16/55 (29.1%) subjects who received at least one infusion of rAHF-PFM. Nonserious, related adverse events (AEs) were few in number (14 in eight subjects). The odds ratio (OR [95% Confidence Interval, CI]) of developing inhibitors was significantly higher in subjects with a family history of inhibitor (4.95 [1.29–19.06]), non-Caucasian ethnicity (4.18, [1.18–14.82]), and intensive treatment at high dose (4.5 [1.05–19.25]) within ≤20 exposure days (EDs). In conclusion, rAHF-PFM was safe and effective for the management and perioperative coverage of PUPs/MTPs with severe/moderately severe haemophilia A. This report supports previous findings from studies in which family history of inhibitor, non-Caucasian ethnicity, and high intensity treatment were associated with high risk of inhibitor development.

Keywords

Haemophilia A - previously untreated patients - paediatric - minimally treated patients - factor VIII - factor VIII inhibitor

^* Currently at The Hemophilia Center, Oregon Health and Science University, Portland, OR, USA.

⁵ Currently in Portland, OR, USA.

• References

• 1 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.
• 2 Blanchette VS, Shapiro AD, Liesner RJ. et al. Plasma and albumin free recombinant factor VIII (rAHF-PFM): pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost 2008; 6: 1319-1326.
• 3 Negrier C, Shapiro A, Berntorp E. et al. Surgical evaluation of a recombinant Factor VIII prepared using a plasma/albumin-free method: Efficacy and safety of Advate in previously treated patients. Thromb Haemost 2008; 100: 217-223.
• 4 Franchini M, Tagliaferri A, Mengoli C. et al. Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: A critical systematic review. Crit Rev Oncol Hematol 2012; 81: 82-93.
• 5 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.
• 6 Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A pa-tients-a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999; 5: 145-154.
• 7 Committee for Proprietary Medicinal Products (CPMP). Note for guidance on the clinical investigation of recombinant factor VIII and IX products. CPMP/ BPWG/1561/99. October 19, 2000. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500067560.pdf
• 8 European Medicines Agency. EMEA Public Statement: Review of Recombinant Factor VIII (FVIII) Products and Inhibitor Development. October 18, 2005 London: Available at: http://www.ema.europa.eu/pdfs/human/press/pus/33131605en.pdf Accessed March 22, 2012.
• 9 White GC, DiMichele D, Mertens K. et al. Utilization of previously treated patients (PTPs), noninfected patients (NIPs), and previously untreated patients (PUPs) in the evaluation of new factor VIII and factor IX concentrates. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1999; 81: 462.
• 10 Committee for Medicinal Products for Human Use (CHMP). Note for guidance on the clinical investigation of recombinant and human plasma-derived factor VIII products. London: European Medicines Agency; 2011. Jul 21. Report No.: EMA/CHMP/BPWP/144533/2009. Available at: http:\\www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109692.pdf Accessed March 22, 2012.
• 11 Pavlova A, Delev D, Lacroix-Desmazes S. et al. Impact of polymorphisms of the MHC class II, IL-10, TNF-a and CTLA-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost 2009; 7: 2006-2015.
• 12 Hay CRM, Mauser-Bunschoten EP, DiMichele DM. the International ITI Study Group. Protocol: An International, Randomised, Controlled Trial of Immune-Tolerance Induction.(US). The International ITI Study Group. 2009 September 20(Amendment 2: 07 April 2003)Available from: URL: http://www.itistudy.com/Protocol_introduction.asp
• 13 National Hemophilia Foundation. MASAC Guidelines for Emergency Department Management of Individuals with Hemophilia. National Hemophilia Foundation; 2006 Oct 14. Report No.: MASAC 175. Available at: www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=691 Accessed March 22, 2012.
• 14 Kreuz W, Gill JC, Rothschild C. et al. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of an international clinical investigation. Thromb Haemost 2005; 93: 457-467.
• 15 Bray GL, Gomperts ED, Courter S. et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994; 83: 2428-2435.
• 16 Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously treated patients. Semin Hematol 2001; 38 (Suppl. 04) 44-51.
• 17 Shapiro A, Gruppo R, Pabinger I. et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther 2009; 9: 273-283.
• 18 Pollmann H, Richter H, Ringkamp H. et al. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr 1999; 158 (Suppl. 03) S166-170.
• 19 Onwuzurike N, Warrier I, Lusher JM. Types of bleeding seen during the first 30 months of life in children with severe haemophilia A and B. Haemophilia 1996; 2: 137-140.
• 20 Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109: 4648-4654.
• 21 Königs C, Kessel C, Scholz S. et al. Identification of Inhibitor Epitopes in Acquired Hemophilia by Phage Display. Inge Scharrer, Wolfgang Schramm. 36th Hemophilia Symposium Hamburg 2005. Springer Berlin Heidelberg; 2007: 118-128.
• 22 Astermark J, Berntorp E, White GC. et al. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 2001; 7: 267-272.
• 23 ter Avest PC, Fischer K, Mancuso ME. et al. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost 2008; 6: 2048-2054.
• 24 Santagostino E, Mancuso ME, Rocino A. et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005; 130: 422-427.
• 25 Maclean PS, Richards M, Williams M. et al. Treatment related factors and inhibitor development in children with severe haemophilia A. Haemophilia 2011; 17: 282-287.
• 26 Gouw SC, van den Berg HM, le Cessie S. et al. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J Thromb Haemost 2007; 5: 1383-1390.
• 27 Aledort LM, DiMichele DM. Inhibitors occur more frequently in African-American and Latino haemophiliacs. Haemophilia 1998; 4: 68.
• 28 Carpenter S, Soucie JM, Sterner S. et al. Increased Prevalence of Inhibitors in Mexican-Hispanic Patients with Severe Hemophilia A Enrolled in the Universal Data Collection Project. ASH Annual Meeting Abstracts. Blood 2009; 114: 3488 (Abstract).
• 29 Kurnik K, Bidlingmaier C, Engl W. et al. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16: 256-262.