The benefits of prophylaxis in patients with hemophilia B

Figures & data

Table 1. Currently available coagulation factor IX replacement products.

FIX product (generic name)			Manufacturer
Plasma-derived FIX (pdFIX)
	Intermediate purity pdFIX
		Bebulin®	Baxalta
		Profilnine® SD	Grifols
		Proplex-T®	Baxter
	High-purity pdFIX
		AIMAFIX®	Synergy Diagnostics
		AlphaNine®	Grifols
		Berinin®	CSL Behring
		Betafact®	LFB/OBI
		Factor IX Grifols®	Grifols
		FIXNOVE®	Baxter
		Haemonine®	Biotest Pharma
		Immunine®	Baxter
		Monofix®	CSL Behring
		Octanine®	Octapharma
	Ultra-high-purity monoclonal-purified pdFIX
		Mononine®	CSL Behring
		Nanotiv®	Octapharma
		Nonafact®	Sanquin
		Replenine-vf®	BPL
Recombinant FIX (rFIX)
	Standard-acting rFIX
		BeneFIX® (nonacog alfa)	Pfizer
		Ixinity® (trenonacog alfa)	Aptevo
		RIXUBIS® (nonacog gamma)	Shire
	Long-acting rFIX
		ALPROLIX® (rFIXFc)	Bioverativ Therapeutics/Sobi
		IDELVION® (rIX-FP)	CSL Behring
		Rebinyn®/Refixia® (N9-GP)	Novo Nordisk

FIX, factor IX

Table 2. Definition of factor replacement protocols (adapted from a communication from the SSC of the International Society of Thrombosis and Haemostasis) [7].

Treatment Protocol	Definition
Episodic (on-demand) replacement therapy	Replacement therapy administered at the time of clinically evident bleeding
Primary prophylaxis	Regular, continuous* replacement therapy in the absence of documented joint disease, (determined by physical examination and/or imaging studies) and initiated before age 3 years and the second clinically evident joint bleed
Secondary prophylaxis	Regular, continuous* replacement therapy initiated after two or more large joint bleeds but before the onset of joint disease (determined by physical examination and/or imaging studies)
Tertiary prophylaxis	Regular continuous* replacement therapy started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints
Intermittent (periodic) prophylaxis	Replacement therapy given to prevent bleeding for periods not exceeding 45 weeks in a year

*Continuous is defined as the intent of treating for 52 weeks/year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under consideration.

Table 3. Impact of prophylaxis versus on-demand treatment on bleeding rates in clinical trials with recombinant factor IX.

					ABR			AsBR		AJBR
rFIX	Study design	N subjects	Mean (SD) age, years	Px regimen	OD	Px	Percent reduction in ABR (Px vs. OD)	OD	Px	OD	Px	Reference
Nonacog alfa	Randomized, cross-over study	50	27.7 (13.9)	50 IU/kg twice weekly	35.1^†	2.6^†	89**	21.8^†	1.7^†	25.4^†	1.9^†	Valentino et al. 2014 [30]
				100 IU/kg once weekly		4.6^†			3.5^†		3.6^†
	Open-label, randomized cross-over study	25	31.3 (12.6)	100 IU/kg once weekly	33.6^‡	2.0^‡	n.r.**	22.4^‡	1.0^‡	28.7^‡	0.0^‡	Kavakli et al. 2016 [31]
Trenonacog alfa	Non-randomized, open-label study (Px or OD)	73 (61 Px, 12 OD)	30.5 (14.4)	50−75 IU/kg twice weekly	16.1^‡	1.5^‡	n.r.	n.r.	n.r.	n.r.	n.r.	Collins et al. 2018 [32]
rFIXFc	Non-randomized, open-label study (Px or OD)	119 (92 Px, 27 OD)	30 (12–71)^§	50 IU/kg weekly	17.7^‡	3.0^‡	83*	11.8^‡	1.0^‡	13.6^‡	1.1^‡	Powell et al. 2013 [33]
				Interval-adjusted^‖		1.4^‡	87*		0.9^‡		0.4^‡
rIX-FP	Non-randomized, open-label study (cross-over arm)	63 (23 in cross-over arm)	33.0 (13.9)	35–50 IU/kg weekly (cross-over arm)	19.2^‡	1.6^‡	91**	15.4^‡	0.0^‡	n.r.	n.r.	Santagostino et al. 2016 [34]
				35–50 IU/kg weekly		0.0^‡	n.r		0.0^‡		0.0^‡
				75 IU/kg every 10 days		0.0^‡	n.r		0.0^‡		0.0^‡
				75 IU/kg every 14 days		1.1^‡	n.r		0.0^‡		0.0^‡
N9-GP	Randomized (Px or OD)	74 (59 Px, 15 OD)	31.4 (14.2)	10 IU/kg once weekly	15.6^‡	2.9^‡	n.r.	11.1^‡	1.0^‡	n.r.	n.r.	Collins et al. 2014 [35]
				40 IU/kg once weekly		1.0^‡			0.0^‡		n.r.

*p < 0.001; ** p < 0.0001 ^†Data shown are mean ^‡Data shown are median

^§Data shown are median (range) ^‖From 100 IU/kg every 10 days; dose could be adjusted as needed;

ABR: annualized bleeding rate; AJBR: annualized joint bleeding rate; AsBR: annualized spontaneous bleeding rate; n.r.: not reported; OD: on-demand treatment; Px: prophylaxis; SD: standard deviation.

Table 4. Summary of long-acting coagulation factor IX products.

		Approved prophylaxis indications
Product	Half-life extension method	Europe	USA	Half-life	Median ABR with weekly prophylaxis in patients ≥ 12 years (dose)
rIX-FP	rFIX linked to human albumin, which has a long half-life and utilizes the Fc receptor-mediated lysosomal recycling pathway	Patients ≥ 12 years of age [37]: 35–50 IU/kg once weekly Patients who are well-controlled on a once-weekly regimen might be treated with ≤ 75 IU/kg on an interval of 10 or 14 daysPatients < 12 years of age [37]: 35–50 IU/kg once weekly	Patients ≥ 12 years of age [38]: 25–40 IU/kg once weekly Patients who are well-controlled on a 7-day regimen may be switched to a 14-day interval at 50–75 IU/kgPatients < 12 years of age [38]: 40–55 IU/kg once weekly	102 h (4.3-fold longer than previous FIX treatment) [34]	0 (40 IU/kg) [34]
rFIXFc	rFIX linked to Fc region of IgG which delays lysosomal degradation, recycling it back into circulation	In patients ≥ 12 years of age [39]: 50 IU/kg once weekly* or 100 IU/kg once every 10 days^† Some patients who are well-controlled on a once every 10 days regimen might be treated on an interval of 14 days or longerIn patients < 12 years [39]: Starting dose is 50–60 IU/kg every 7 days Highest recommended prophylaxis dose is 100 IU/kg	In patients ≥ 12 years of age [40]: 50 IU/kg once weekly or 100 IU/kg once every 10 days^‡Patients < 12 years of age [40]: Starting dose of 60 IU/kg once weekly^‡	82.1 h versus 33.8 for rFIX [33]	3.0 (45 IU/kg) [33]
N9-GP	Addition of PEG to rFIX by glycoPEGylation increases size thus reducing elimination	In patients ≥ 12 years only [41]: 40 IU/kg once weekly	No indication	107–111 h [35]	1.04 (40 IU/kg) [35]

*Adjust dose based on individual response

^†Adjust interval based on individual response

^‡Adjust dosing regimen based on individual response; ABR, annualized bleeding rate; PEG, polyethylene glycol; rFIX, recombinant factor IX.

Table 5. Prevalence of prophylaxis in hemophilia B patients is lower than in hemophilia A patients.

			Hemophilia B patients on prophylaxis (%)				Hemophilia A patients on prophylaxis (%)
Country	Number of HTCs	Number of subjects	All	Severe	Moderate	Mild	All	Severe	Moderate	Mild	Reference
Australia	Registry	HB: 718; HA: 166	46	75	14	NA	69	82	25	NA	Mason et al. 2018 [61]
Canada	22	HB: 502; HA: 2161	11	32	5	1	23	69	18	1	Biss et al. 2008 [62]
Japan	48	HB: 273; HA: 1267	16	18	19	3	23	27	17	1	Taki et al. 2009 [63]
USA	138	HB: 3320; HA: 11,071	32.3	74.8	19.8	5.5	50	80.7	35.8	6	ATHN dataset [64]
Europe*	11 (2 registries)	HB: 312; HA: 1346	49	58	38	NA	66	n.r.	n.r.	NA	Berntorp et al. 2017 [65]

*Belgium, France, Germany, Italy, Spain, Sweden, and UK

HA, hemophilia A; HB, hemophilia B; HTC, hemophilia treatment center; NA, not applicable; n.r., not reported.

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