Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP

Abstract

Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged !12 years (FIX 2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means ¼ 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.

The Australian experience with switching to extended half‐life factor VIII and IX concentrates: On behalf of the Australian Haemophilia Centre Directors' Organisation

“…EHLs were safe in our cohort of mainly PTPs, with no patient developing a clinically significant inhibitor during the 6‐month study period. The benefits of EHL concentrates in the Australian population are in keeping with clinical trial results and the growing ‘real‐world’ data showing improved bleeding outcomes despite fewer injections 2‐4. The improvement in bleeding outcomes is likely due to a combination of increased adherence, longer time at higher factor levels and achievement of higher trough factor levels 2.…”

IDELVION: A Comprehensive Review of Clinical Trial and Real-World Data

“…Furthermore, while direct comparisons between products cannot be made, it has been observed that the prophylactic efficacy of rIX-FP is favorable over other standard half-life rFIX and extended half-life products [25]. A systematic literature review indirectly compared the efficacy of rFIX products in adult patients and showed that ABR with 7-day rIX-FP prophylaxis was significantly lower than with standard half-life (p ≤ 0.05) and other extended half-life (p < 0.001) rFIX products (Figure 3) [25]. [8]; rFIXFc, 45 IU/kg (7-day dosing) [26]; rFIX, 100 IU/kg (7-day dosing) [27]; BAX 326, 50.5 IU/kg (2×/weekly dosing) [28]; IB1001, 53 IU/kg (2×/weekly dosing) [29].…”

Expert opinion paper on the treatment of hemophilia B with albutrepenonacog alfa

“…An indirect comparison with N9-GP was neither possible, since mean ABR, AsBR, and AjBR were not provided in the pivotal study [27]; however, rIX-FP achieved a lower median ABR than N9-GP, on 7-day regimen (0.00 vs 1.04). rIX-FP also achieved lower mean ABR values than the SHL-FIX products encompassed in the systematic review [9,28,29].…”

“…A systematic review conducted by Davis and collaborators compared, through indirect statistical comparison, the efficacy of rIX-FP to that of other SHL-FIX and EHL-FIX for prophylaxis treatment of adult patients [9]. On a 7-day regimen, the mean ABR was significantly lower with 35-50 IU/kg of rIX-FP than with 50 IU/kg of rFIX-Fc (1.2 [1.8] vs 3.1 [2.9], p < 0.001).…”

“…SHL-FIX products typically need to be administered two or three times per week. On the other hand, EHL-FIX have half-lives three to six times longer than SHL-FIX, and therefore entail less injections and a potential improvement in adherence [1,2,9,10].…”