Efficacy of rFIXFc versus N9-GP Prophylaxis in Patients with Hemophilia B: Matching-Adjusted Indirect Comparison of B-LONG and PARADIGM 2 Trials

Abstract

Maria Elisa Mancuso,1,2 Daniel Eriksson,3 Aletta Falk,3 Zalmai Hakimi,3 Piotr Wojciechowski,4,5 Marlena Wdowiak,4 Robert Klamroth6,7 1Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; 2Humanitas University, Pieve Emanuele, Milan, Italy; 3Swedish Orphan Biovitrum AB, Stockholm, Sweden; 4Creativ-Ceutical, Krakow, Poland; 5Assignity, Krakow, Poland; 6Department of Internal Medicine, Hemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Berlin, Germany; 7Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, GermanyCorrespondence: Robert Klamroth, Department of Internal Medicine – Angiology and Hemostaseology, Center for Vascular Medicine, Haemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Landsberger Allee 49, Berlin, D-10249, Germany, Tel [phone], Fax [phone], Email [email protected]: For patients with hemophilia B, extended half-life factor IX (FIX) products are available for prophylaxis and for treating bleeds. Different methods are used to extend the half-lives of recombinant FIX Fc fusion protein (rFIXFc) and nonacog beta pegol (N9-GP). This affects their biodistribution and plasma FIX levels, although differences do not always correlate with clinical outcomes. A matching-adjusted indirect comparison (MAIC) of prophylaxis with rFIXFc and N9-GP was performed, based on licensed dosing in the European Union.Patients and Methods: Combined rFIXFc data from the weekly and individualized interval prophylaxis arms of the B-LONG clinical trial, and N9-GP data from the 40 IU/kg once-weekly prophylaxis arm of PARADIGM 2 were used in a MAIC. Individual patient data for rFIXFc (n=87) were matched to aggregated data for N9-GP (n=29). Estimated annualized bleeding rates (ABRs) for rFIXFc were recalculated using a Poisson regression model with adjustment for over-dispersion, and compared with ABRs reported for N9-GP, using incidence rate ratios (IRRs) with 95% confidence interval (CI).Results: There was no evidence of significant differences in estimated ABRs between prophylaxis with rFIXFc and N9-GP. Analysis of pooled rFIXFc weekly and interval-adjusted dosing compared with N9-GP 40 IU/kg once weekly produced estimated ABRs of 2.59 versus 2.51 (IRR 1.03; 95% CI 0.56– 1.89), as well as 1.34 versus 1.22 (IRR 1.10; 95% CI 0.42– 2.91) and 1.13 versus 1.29 (IRR 0.88; 95% CI 0.47– 1.63) for overall, spontaneous, and traumatic bleeding events, respectively.Conclusion: The study did not reveal any significant differences in the efficacy of rFIXFc and N9-GP prophylaxis. Given differences in trough levels (rFIXFc dosing was targeted to achieve a trough 1– 3 IU/dL above baseline versus a reported estimated N9-GP mean trough of 27.3 IU/dL), interpreting plasma FIX levels as potential surrogate efficacy markers requires consideration of compound-specific pharmacokinetic profiles.Keywords: annualized bleeding rate, factor IX deficiency, factor IX Fc fusion protein, nonacog beta pegol, plasma factor IX activity, treatment outcome

Keywords

• annualized bleeding rate
• factor ix deficiency
• factor ix fc fusion protein
• nonacog beta pegol
• plasma factor ix activity
• treatment outcome