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

Figures & data

Table 1. Literature search terms.

PubMed
1	Factor IX deficiencies OR Factor IX deficiency OR FIX deficiencies OR FIX deficiency
2	Hemophilia B OR Haemophilia B
3	“Factor IX/administration and dosage”[Mesh] OR “FIX/administration and dosage”[Mesh] OR “Factor 9/administration and dosage”[Mesh]
4	((Factor IX OR FIX OR Factor 9) AND (treatment OR drug OR therapy OR concentrate OR recombinant)) OR “rFIX”
5	rFIX OR IDELVION OR rIX-FP OR CSL654 OR albutrepenonacog OR beneFIX OR nonacog alfa OR RIXUBIS OR BAX 326 OR nonacog gamma OR ALPROLIX OR rFIXFc OR BIIB 029 OR eftrenonacog alfa OR Refixia OR REBINYN OR N9-GP OR NN-7999 OR nonacog beta pegol OR Ixinity OR IB1001 OR trenacog alfa
6	(bleed OR bleeding OR bleedings OR bleeds OR “Blood loss” OR hemorrhag* OR haemorrhag* OR “ABR” OR “AsBR” OR “jABR” OR “annualized bleeding rate” OR “annualized spontaneous bleeding rate” OR “joint annualized bleeding rate” OR “annualised bleeding rate” OR “annualised spontaneous bleeding rate” OR “joint annualised bleeding rate”)
Final	(1 OR 2) AND (3 OR 4 OR 5) AND (6)
EMBASE
1	Factor IX deficiencies OR Factor IX deficiency OR FIX deficiencies OR FIX deficiency
2	“Hemophilia B” OR “Haemophilia B”
3	((“Factor IX” OR “FIX” OR “Factor 9”) AND (treatment OR drug OR therapy OR concentrate OR recombinant)) OR “rFIX”
4	rFIX OR IDELVION OR rIX-FP OR CSL654 OR albutrepenonacog OR beneFIX OR nonacog alfa OR RIXUBIS OR BAX 326 OR nonacog gamma OR ALPROLIX OR rFIXFc OR BIIB 029 OR eftrenonacog alfa OR Refixia OR REBINYN OR N9-GP OR NN-7999 OR nonacog beta pegol OR Ixinity OR IB1001 OR trenacog alfa
5	bleed OR bleeding OR bleedings OR bleeds OR “Blood loss” OR hemorrhag* OR haemorrhag* OR “ABR” OR “AsBR” OR “jABR” OR “annualized bleeding rate” OR “annualized spontaneous bleeding rate” OR “joint annualized bleeding rate” OR “annualised bleeding rate” OR “annualised spontaneous bleeding rate” OR “joint annualised bleeding rate”
Final	(1 OR 2) AND (3 OR 4) AND (5)

Date range: 1966 (PubMed) or 1968 (EMBASE) to present.

Table 2. Inclusion and exclusion criteria for the analysis.

	Inclusion criteria	Exclusion criteria
Study type	Phase III trials Full original articles	Review papers Conference abstracts or proceedings Opinion pieces Guidelines Meta-analyses Systematic reviews Editorials Commentaries Case reports/series Extension studies Secondary articles Retracted papers
Subjects	Adolescent and adult human subjects (aged ≥12 years) Diagnosed with moderate/severe hemophilia B (FIX levels ≤2%) Previously treated Receiving rFIX prophylactically	Animal models In vitro or ex vivo studies Healthy volunteers Surgical patients Patients receiving pd-FIX

Figure 1. PRISMA diagram for the systematic literature review of articles that evaluated the treatment of previously treated adult human subjects diagnosed with moderate-to-severe hemophilia (FIX levels ≤2 %) receiving rFIX either prophylactically or on-demand. ^aSome articles met more than one criterion. ^bNine articles met the inclusion criteria initially, but Solano Trujillo et al.¹⁷ and Oldenburg et al.¹⁴ were excluded from further analysis as they included duplicate patients from Windyga et al.¹⁶ and Collins et al.¹⁰, respectively. ^cOf the remaining seven articles, Collins et al.¹⁰ was excluded from the statistical analysis as it did not include mean/SD data for analysis. ^dIneligible articles consisted of manuscripts which did not describe results of a Phase III study, including post-hoc analyses, meta-analyses, and post-marketing surveillance. ^eExclusions for non-human subjects included any study using animals or animal tissues or in vivo, in vitro, or ex vivo studies. ^fIneligible study types were those that were not Phase III clinical trials, including surgical sub-studies and extension studies. ^gAny study where the patients were not diagnosed with hemophilia B were excluded. ^hStudies not treating participants with a recombinant FIX product were excluded. ⁱEligible studies must include outcomes from at least one of the following; ABR, AsBR, AjBR. ^jPediatric studies were excluded, including those who combined adult and pediatric data.

Table 3. Study characteristics for included articles.

Study	Product	Design	Subjects (n)	Endogenous FIX level	Median treatment duration (weeks)
Santagostino et al.^8	rIX-FP (IDELVION)	Open-label, non-randomized	63	≤2%	38 (7-day regimen) 34 (10-day regimen) 55 (14-day regimen)
Powell et al.^9	rFIXFc (ALPROLIX)	Open-label, non-randomized	119^a	≤2%	52 (7-day regimen) 58 (interval-based regimen)
Lambert et al.^13	rFIX (BeneFIX)	Open-label, non-randomized prophylaxis following a randomized PK evaluation	34	≤2%	32
Kavakli et al.^15	rFIX (BeneFIX)	Open-label, non-randomized	25	≤2%	78
Windyga et al.^16	BAX 326 (RIXUBIS)	Open-label, non-randomized prophylaxis following a randomized PK evaluation	73	≤2%	26
Collins et al.^10	N9-GP (REFIXIA)	Randomized, single-blind trial to compare two prophylaxis doses	74	≤2%	52
Collins et al.^18	IB1001 (Ixinity)	Open-label, non-randomized prophylaxis following a randomized PK evaluation	76	≤2%	70

Abbreviations. ED, exposure day; PK, pharmacokinetic.

^aDoes not include four participants who were only enrolled in the surgical group.

Table 4. Details of bleeding rates of prophylaxis patients in rFIX studies identified by the systematic review.

Study and regimen	Regimen	Patients, n	Age (years), mean (SD)	ABR, median (IQR)	ABR, mean (SD)	AsBR, median (IQR)	AsBR, mean (SD)	AjBR, median (IQR)	AjBR, mean (SD)
Santagostino et al.^8 (rIX-FP)	7-day	40	31.6 (15.2)	0 (0–1.87)	1.24 (1.780)^a	0 (0–0)	0.52 (1.116)^a	0 (0–1.53)	0.89 (1.436)^a
	10-day	7		0 (0–1.78)	0.82 (1.195)^a	0 (0–0)	0.13 (0.334)^a	0 (0–0.88)	0.34 (0.615)^a
	14-day	14		1.08 (0–2.7)	1.96 (2.653)^a	0 (0–1.0)	1.07 (2.114)^a	0 (0–1.04)	1.42 (2.708)^a
Powell et al.^9 (rFIXFc)	7-day	63	28 (12–71)^b	3.0 (1.0–4.4)	3.07 (2.87)^c	1.0 (0.0–2.2)	NR	1.1 (0.0–4.0)	NR
	Interval-adjusted	29	33 (12–62)^b	1.4 (0.0–3.4)	NR	0.9 (0.0–2.3)	NR	0.4 (0.0–3.2)	NR
Lambert et al.^13 (rFIX)	1–>3× weekly^d	17	28.32 (12–61)^e^,^f	NR	3.11 (3.76)^c	NR	0.72	NR	NR
Kavakli et al.^15 (rFIX)	7-day	25	31.3 (12.6)	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.^16 (BAX 326)	2× weekly	56	33 (12–59)^b^,^f	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.^10 (N9-GP)	7-day (10 IU/kg)	30	32.4 (13.9)	2.93 (0.99–6.02)	NR	0.97 (0.0–4.01)	NR	NR	NR
	7-day (40 IU/kg)	29	30.0 (15.8)	1.04 (0.00–4.00)	NR	0.0 (0.0–0.98)	NR	NR	NR
Collins et al.^18 (IB1001)	2× weekly	58	28.8 (14.2)	1.52 (0.00–3.46)	3.55 (7.15)	NR	NR	NR	NR

Abbreviations. ABR, annualized bleeding rate; AsBR, annualized spontaneous bleeding rate; AjBR, annualized joint bleeding rate; NR, not reported.

^aData from clinical study report.

^bMedian (range).

^cData from Iorio et al.¹¹.

^dIncluding 7-day (n = 1), 2× weekly (n = 10), 2.5× weekly (n = 1), 3× weekly (n = 1), >3× weekly (n = 2), 2× weekly (n = 10), 2.5× weekly (n = 1), 3× weekly (n = 1), and >3× weekly (n = 2) prophylaxis regimens.

^eMean (range).

^fData from all patients in the study.

Figure 2. Analysis results for (a) ABR, (b) AsBR, and (c) AjBR (mean).

Table 5. Summary of statistical analysis results.

Outcome	Study and product	Prophylaxis regimen	Prophylaxis dose^a	Mean ± SD	rIX-FP diff,^b Mean (95% CI)	p-value
ABR	Santagostino et al.^8 (rIX-FP)	7-day	35–50 IU/kg	1.2 ± 1.8	—
	Powell et al.^9 (rFIXFc)	7-day^c	50 IU/kg	3.1 ± 2.9	1.8 (0.9–2.7)	<0.001
	Kavakli et al.^15 (rFIX)	7-day	100 IU/kg	3.6 ± 4.6	2.4 (0.5–4.2)	0.01
	Lambert et al.^13 (rFIX)	1–>3× weekly^c	20–<130 IU/kg	3.1 ± 3.8	1.9 (0.0–3.7)	0.05
	Collins et al.^18 (IB1001)	2× weekly	50–75 IU/kg	3.6 ± 7.2	2.3 (0.4–4.2)	0.02
	Windyga et al.^16 (BAX 326)	2× weekly	50 IU/kg	4.3 ± 5.8	3.0 (1.4–4.6)	<0.001
AsBR	Santagostino et al.^8 (rIX-FP)	7-day	35–50 IU/kg	0.5 ± 1.2	—
	Kavakli et al.^15 (rFIX)	7-day	100 IU/kg	2.6 ± 4.1	2.1 (0.1–4.0)	0.04
	Windyga et al.^16 (BAX 326)	2× weekly	50 IU/kg	1.7 ± 3.3	1.2 (−0.2–2.6)	0.09
AjBR	Santagostino et al.^8 (rIX-FP)	7-day	35–50 IU/kg	0.9 ± 1.4	—
	Kavakli et al.^15 (rFIX)	7-day	100 IU/kg	2.1 ± 3.2	1.2 (−0.1–2.5)	0.07
	Windyga et al.^16 (BAX 326)	2× weekly	50 IU/kg	2.9 ± 4.3	2.0 (0.8–3.2)	0.001

^aProphylaxis dose per infusion, as detailed in the methods for each study. For Lambert et al.¹³, the range of prescribed doses for prophylaxis was listed in the results.

^bDifference with rIX-FP results. Figures reported as values for indicated product minus values for rIX-FP.

^cData for mean/SD ABR for Powell et al.⁹ and SD for ABR for Lambert et al.¹³ reported in Iorio et al.¹¹; only data for the 7-day prophylaxis for Powell et al.⁹ was reported. As noted in the methods, the AsBR and AjBR data from Powell et al.⁹ (rFIXFc) and the ABR and AsBR data from Collins et al.¹⁰ (N9-GP) were excluded from the statistical comparison, as mean/SD data were not available for these outcomes.

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