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Research Article

30 May 2017

A new modeling approach allowing prediction and comparison of the long-term outcomes of treatments for hemophilia B

Authors: Marjolijn van Keep [email protected], Christina Stentoft Hoxer, Matthew Hemstock, Andreas Velsing Groth, and Christopher KnightAuthor Info & Affiliations

Publication: J. Comp. Eff. Res.

Volume 7, Number 1

https://doi.org/10.2217/cer-2017-0028

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Abstract

Aim: To develop a modeling approach to compare clinical outcomes of nonacog beta pegol to a standard-acting factor IX (FIX) product. Methods: Regression analysis linked FIX activity to bleed rates. Pharmacokinetic parameters were used to estimate FIX activity over time. The probability of bleeds was estimated for both treatment arms. A Markov model estimated the presence of target joints and annualized bleed rates (ABRs). Results: Higher FIX activity showed reduced ABRs (p < 0.001). Target joints resulted in higher bleed rates (p < 0.001). When FIX activity levels and bleed risks were applied to the Markov model, ABRs for nonacog beta pegol and its comparator were 2.40 and 6.36, respectively. Conclusion: This model provides a starting point for assessing the added value of new FIX products.

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References

Papers of special note have been highlighted as: • of interest; •• of considerable interest

1.

European Medicines Agency (EMA). Guideline on clinical investigation of recombinant and human plasma-derived factor IX products (2015). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187413.pdf

• Shows that comparison with other factor IX products is not required following the EMA guidelines for clinical trials in this disease area.

2.

Srivastava A, Brewer A, Mauser-Bunschoten E et al. Guidelines for the management of hemophilia. Haemophilia 19(1), e1–e47 (2013).

3.

Guidelines for the Management of Haemophilia in Australia. Australian Haemophilia Centre Directors’ Organisation, National Blood Authority Australia (2016). www.blood.gov.au/haemophilia-guidelines

4.

Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. Haemophilia 9(1), 1–23 (2008).

5.

Nordic Hemophilia Guidelines. Nordic Hemophilia Council Guideline Working Group (2015). http://nordhemophilia.org/library/Files/PDF-skjol/NordicGuidelinesCongenitalHemophilia2015.pdf

6.

Manucci PM, Mancuso ME, Santagostino E. How we choose factor VIII to treat hemophilia. Blood 119(18), 4108–4114 (2012).

7.

Berntorp E, Andersson N. Prophylaxis for hemophilia in the era of extended half-life factor VIII/factor IX products. Semin. Thromb. Hemost. 42(5), 518–525 (2016).

8.

Clinical trials database: NCT01333111. https://clinicaltrials.gov/ct2/show/NCT01333111

9.

Powell JS, Pasi KJ, Ragni MV et al. Phase III study of recombinant factor IX Fc fusion protein in hemophilia B. N. Engl. J. Med. 369(24), 2313–2323 (2013).

10.

Santagostino E, Martinowitz U, Lissitchkov T et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a Phase III trial. Blood 127(14), 1761–1769 (2016).

11.

Den Uijl I, Fischer K, Van Der Bom J, Grobbee D, Rosendaal F, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 17(1), 41–44 (2011).

•• Publication showing the link between factor activity levels and joint bleed rates, which has been the basis for the key assumption for our model.

12.

Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 12513 2038–2044, (2015).

13.

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. 357(6), 535–544 (2007).

14.

Soucie M, Monahan PE, Mazepa M, Kulkarnni R, Konkle BA. Relations between factor level activity and joint bleeding in a large cohort of males with mild and moderate hemophilia in the United States. Presented at: 2015 ISTH Congress. Toronto, Canada, 20–25 June 2015.

•• Hypothesis for the link between factor activity levels and joint bleed rates in hemophilia B.

15.

Collins PW, Young G, Knobe K et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomised Phase III trial. Blood 124(26), 3880–3886 (2014).

16.

Zeileis A, Kleiber C, Jackman S. Regression models for count data in R. J. Stat. Softw. 27(8), 1–25 (2008).

17.

Windyga J, Lissitchkov T, Stasyshyn O et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre Phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level </=2%) haemophilia B. Haemophilia 20(1), 15–24 (2014).

18.

Pfizer Limited. BeneFIX summary of product characteristics (SPC) (2016). www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000139/human_med_000671.jsp&mid=WC0b01ac058001d124

19.

Negrier C, Young G, Abdul Karim F et al. Recombinant long-acting glycoPEGylated factor IX (nonacog beta pegol) in haemophilia B: assessment of target joints in multinational Phase III clinical trials. Haemophilia 22(4), 507–513 (2016).

20.

Mazza G, O'hara J, Carroll L, Camp C, Hoxer C, Wilkinson L. The relationship between target joints and direct resource use in severe haemophilia. Presented at: ISPOR 19th Annual European Congress (PSY53), Vienna, Austria, 29 October–2 November 2016.

21.

Rodriguez-Merchan E, Wiedel J. General principles and indications of synoviorthesis (medical synovectomy) in haemophilis. Haemophilia 7(Suppl. 2), 6–10 (2001).

22.

Blanchette V, Key N, Ljung L, Manco-Johnson M, Van Den Berg H, Srivastava A. Definitions in hemophilia: communication from the SSC of the ISTH. J. Thromb. Haemost. 12(11), 1935–1939 (2014).

23.

Blanchette V, Mccready M, Achnu C, Abdolell M, Rivard G, Manco-Johnson M. A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres. Haemophilia 9(Suppl. 1), 19–26 (2003).

24.

Ota S, Mclinont M, Carcao M et al. Definitions for haemophilia prophylaxis and its outcomes: the Canadian consensus study. Haemophilia 13(1), 12–20 (2007).

25.

Gupta S, Siddiqi A, Soucie J et al. The effect of secondary prophylaxis versus episodic treatment on the range of motion of target joints in patients with haemophilia. Br. J. Haematol. 161(3), 424–433 (2013).

26.

Valentino LA, Rusen L, Elezovic I, Smith LM, Korth-Bradley JM, Rendo P. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects. Haemophilia 20(3), 398–406 (2014).

27.

Amby LK, Seremetis S, Obergfell A, Bjerre J. Challenges of defining reliable clinical surrogate end points in haemophilia trials: a critical review. Blood Coagul. Fibrinolysis 20(7), 488–493 (2009).

• Discusses that it is difficult to define good surrogate clinical end points for trials in hemophilia.

28.

Nugent D, Kalnins W, Querol F et al. Haemophilia Experiences, Results and Opportunities (HERO) study: treatment-related characteristics of the population. Haemophilia 21(1), e26–e38 (2015).

29.

Croteau SE, Neufeld EJ. Transition considerations for extended half-life products. Haemophilia 21(3), 285–288 (2015).

30.

Croteau SE, Saxenna K, Neufeld EJ. Correlation between dispensed and prescribed doses of factor products for bleeding disorder: can a small, centre-based pharmacy hit the mark? Haemophilia 21(2), 190–195 (2015).

31.

Krishnan S, Buckley B, Brennan A, Wong WY. Response to Croteau and Neufeld Editorial: ‘transition considerations for extended half-life factor products’. Haemophilia 21(5), e41–e453 (2015).

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