Treatment of hemophilia B: focus on recombinant factor IX

Figures & data

Table 1 Recommended dosages of factor IX (FIX) concentrates for the treatment or prevention of bleeding episodes in hemophilia B patients

Type of hemorrhage	FIX dose (U/kg)
Mild or moderate hemarthroses or hematomas	20–40
Severe hemarthroses or hematomas	40–60
External bleeding with anemia
Moderate posttraumatic bleeding
Cranial trauma	50–100*
Cerebral hemorrhage
Surgery prophylaxis
Primary prophylaxis	30–40 (two times weekly)

Note:

* For surgical prophylaxis, FIX levels should be maintained above 50% for 7–15 days after surgery.

Table 2 Characteristics of licensed factor IX concentrates

Brand name	Company	Source	Fractionation	Viral inactivation	Specific activity (IU/mg)
Aimafix^®	Kedrion	Plasma	Anion exchange, DEAE Sephadex^®/Sepharose^®, and heparin affinity chromatography	TNBP/polysorbate 80; dry heat, 100°C for 30 minutes; nanofiltration, 35 + 15 nm	>100
AlphaNine^® SD	Grifols	Plasma	Dual polysaccharide ligand affinity chromatography	S/D: TNBP/polysorbate 80; nanofiltration	210
Berinin^® P	CSL Behring	Plasma	DEAE Sephadex and heparin affinity chromatography	Pasteurization at 60°C for 10 hours	146
Betafact^®	LFB	Plasma	Ion exchange and affinity chromatography	TNBP/polysorbate 80; nanofiltration, 15 nm	110
Factor IX Grifols^®	Grifols	Plasma	Precipitation and multiple chromatography	S/D; nanofiltration, 15 nm	>150
Haemonine^®	Biotest	Plasma	Anion exchange, immunoaffinity, and hydrophobic interaction chromatography	TNBP/polysorbate 80; nanofiltration, 15 nm	>70
Hemo-B-RAAS	Shanghai RAAS	Plasma	Ion exchange and affinity chromatography	S/D; dry heat; nanofiltration	>50
Immunine^®	Baxter BioScience	Plasma	Ion exchange and hydrophobic interaction chromatography	Polysorbate 80; vapor heating, 60°C for 10 hours, 190 mbar, then 80°C for 1 hour, 375 mbar	~100
Mononine^®	CSL Behring	Plasma	Immunoaffinity chromatography	Sodium thiocyanate; ultrafiltration	>190
Nanotiv^®	Octapharma	Plasma	Ion exchange and affinity chromatography	TNBP/Triton^® × 100; nanofiltration	>150
Nonafact^®	Sanquin	Plasma	Immunoaffinity and hydrophobic interaction chromatography	TNBP/polysorbate 80; nanofiltration, 15 nm	≥200
Octanine F^®	Octapharma	Plasma	Ion exchange and affinity chromatography	TNBP/polysorbate 80; nanofiltration	>120
Replenine^®-VF	Bio products laboratory	Plasma	Metal chelate chromatography	S/D; nanofiltration, 15 nm	200
TBSF FIX	CSL biotherapies	Plasma	Ion exchange and heparin affinity chromatography	TNBP/polysorbate 80; nanofiltration	>50
BeneFIX^®	Pfizer	Recombinant	Anionic chromatography	Nanofiltration	≥200

Abbreviations: DEAE, diethylaminoethanol; S/D, solvent–detergent; TNBP, tri-n-butyl phosphate.

Table 3 Summary of the main clinical studies on recombinant factor IX (rFIX) concentrates

Reference	Study design (patient population)	Main results
White et al^Citation34	Double-blind, randomized, crossover (rFIX. n = 11; pdFIX, n = 11)	Significantly lower recovery for rFIX; safe and effective
Roth et al^Citation32	Prospective PK, safety, and efficacy (rFIX, n = 56)	Low recovery; safe and effective
Poon et al^Citation25	Retrospective observational (rFIX, n = 126; pdFIX, n = 75)	Significantly lower recovery for rFIX; in boys aged < 15 years, decreased recovery for both products; inhibitors, 2/244 (0.8%)
Ewenstein et al^Citation26	Double-blind, two-period crossover (rFIX, n = 43; pdFIX, n = 43)	Wide product-related (decreased for rFIX) and patient-related variability in recovery
Kisker et al^Citation38	Double-blind, two-period crossover (rFIX, n = 15; pdFIX, n = 15)	Decreased recovery for rFIX rFIX more expensive because of higher doses
Shapiro et al^Citation27	Open-label, single-cohort (rFIX, n = 63)	Recovery depending on age; safe and effective
Lambert et al^Citation39	Double-blind, randomized, PK crossover (rFIX, n = 34)	Recovery, safety, and efficacy of reformulated rFIX is comparable with original
Monahan et al^Citation40	Prospective PK, safety, and efficacy (rFIX, n = 25)	One or two rFIX infusions per week as prophylaxis is well tolerated
Recht et al^Citation41	Retrospective, safety (rFIX, n = 163; pdFIX, n = 88; rFIX and pdFIX, n = 71)	No difference in the frequency of allergic reactions or inhibitor development between pd- and rFIX concentrates
Berntorp et al^Citation33	Prospective, observational cohort (rFIX, n = 218)	A low incidence of SAEs was detected (inhibitors 0.9%, thrombosis 0.5%, allergic events 3.7%)

Abbreviations: pdFIX, plasma-derived factor IX; PK, pharmacokinetic; SAEs, serious adverse events.

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