Systematic Review of Efficacy of Recombinant Factor IX Products for Prophylactic Treatment of Hemophilia B

Scientific research question: To systematically review the evidence from Phase III clinical trials evaluating the use of rFIX products for prophylaxis in hemophilia B patients. The outcomes considered were total annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR).

Methodology: A systematic literature search was conducted in both EMBASE and PubMed. Phase III clinical trials of prophylactic rFIX treatment in previously treated, hemophilia B patients aged ≥12 years, with endogenous FIX levels ≤2% were included. Studies which did not meet these criteria, or did not report any of the outcomes mentioned above, were excluded. Relevant data were then extracted from these studies.

Findings: The search identified a total of 1,362 articles, with 35 passing the title and abstract screen. Following full-text review, 9 articles met the inclusion criteria. Data has been extracted from these articles and is summarized in [Table 1] (data marked * was obtained from the clinical study report); information is presented for the weekly infusion regimen where data was available for more than one prophylaxis schedule. ABR reported in the relevant studies ranged from a median of 0-3.0, AsBR ranged from 0-1.0, and AjBR ranged from 0-1.1. The median values reported for rIX-FP were 0 for ABR, AsBR and AjBR. Mean values ranged from 1.24-4.26 for ABR, 0.52-2.6 for AsBR, and 0.89-2.85 for AjBR, with rIX-FP at the lowest end for each value.

Conclusion: This review identified suitable data for an indirect comparison of rFIX products. Within the limitations of potential differences in patient population and study design, a formal meta-analysis may help to understand how these products compare with respect to the parameters of ABR, AsBR, and AjBR.

Table 1 Details of bleeding rates in rFIX studies identified by the systematic review

Study and regimen	rFIX product	No. prophylaxis subjects	Age, mean years (range)	ABR, median (IQR)	ABR, mean (SD)	AsBR, median (IQR)	AsBR, mean (SD)	AjBR, median (IQR)	AjBR, mean (SD)
Santagostino et al. 2016 (35-50 IU/kg weekly prophylaxis)	Albutrepenonacog alfa (rIX-FP)	40	31.6 (SD 15.2)	0 (0, 1.87)	1.24 (1.780)*	0 (0, 0)	0.52 (1.116)*	0 (0, 1.53)	0.89 (1.436)*
Powell et al. 2013 (50 IU/kg weekly prophylaxis)	rFIXFc INN	63	Median (range): 28 (12-71)	3.0 (1.0–4.4)	NR	1.0 (0.0–2.2)	NR	1.1 (0.0–4.0)	NR
Lambert et al. 2007 (regimen not reported)	Nonacog alfa	17	28.32 (12–61) [for all 34 patients in study]	NR	3.11	NR	0.72	NR	NR
Kavakli et al. 2016 (100 IU/kg weekly prophylaxis)	Nonacog alfa	25	31.3 (12.1–53.7)	2.0 (0, 13.8)	3.6 (4.6)	1.0 (0, 13.8)	2.6 (4.1)	0.0 (0, 9.8)	2.1 (3.2)
Windyga et al. 2014 (40–75 IU/kg twice-weekly prophylaxis)	BAX326 INN	56	Median (range): 33 (12–59) [for all 73 patients in study]	1.99 (0, 23.4)	4.26 (5.80)	0.0 (0, 15.6)	1.72 (3.26)	0.0 (0, 21.5)	2.85 (4.25)
Collins et al. 2014 (40 IU/kg weekly prophylaxis)	Nonacog beta pegol (N9-GP)	29	30.0 (SD 15.8)	1.04 (0.00–4.00)	NR	0.0 (0.0–0.98)	NR	NR	NR
Young et al. 2016 (40 IU/kg weekly prophylaxis)	Nonacog beta pegol (N9-GP)	52	32 (SD 14.2)	1.00 (0.00–2.03)	NR	0.00 (0.00–1.00)	NR	0.00 (0.00–1.97)	NR
Collins et al. 2017 (50–75 IU/kg twice-weekly prophylaxis)	Trenonacog alfa (IB1001)	58	28.8 (SD 14.2)	1.52 (0.00–3.46)	3.55 (SD 7.15)	NR	NR	NR	NR
Solano Trujillo et al. 2014 (20–40 IU/kg twice-weekly prophylaxis)	BAX326 INN	32	31.9 (14–55)	0.9 (0, 11.2)	2.3 (3.7)	0.0 (0, 10)	0.9 (1.95)	0.0 (0, 10)	1.5 (2.66)

No conflict of interest has been declared by the author(s).