The benefits of prophylaxis in patients with hemophilia B

ABSTRACT

Introduction: The health benefits of prophylactic dosing regimens for clotting factor therapy in patients with hemophilia include reduced joint damage and improved quality of life; as such, prophylaxis is recommended in treatment guidelines. However, many patients with hemophilia B are treated on demand, and prophylaxis has been utilized less frequently than in hemophilia A.

Areas covered: This review discusses the opportunities and evidence for prophylaxis in hemophilia B, in the context of treatment guidelines and with regard to factor IX (FIX) replacement therapies, including long-acting recombinant FIX (rFIX).

Expert commentary: Long-acting rFIX concentrates may increase uptake of and adherence to prophylaxis regimens through attainment of higher trough levels with longer dosing intervals. In this new era of hemophilia B treatment, physicians may be able to achieve better clinical outcomes for their patients and reconsider treatment goals. Maintaining higher FIX trough levels will undoubtedly have long-term benefits for patients, such as preserving joint function. The long-acting rFIX concentrates support robust prophylaxis regimens and offer physician’s flexibility in treating patients to best suit their needs, whether to enable an active lifestyle, to achieve higher trough levels for better bleed protection, or simply to decrease the burden of treatment by reducing injection frequency.

KEYWORDS:

• Factor IX
• hemophilia B
• coagulation factor replacement therapies
• prophylaxis
• long-acting

1. Introduction

Hemophilia B (also known as Christmas disease) is the second-most common form of hemophilia and is an X chromosome-linked recessive disorder that results in a deficiency in coagulation factor IX (FIX) activity. The most recent global annual survey conducted by the World Federation of Hemophilia (WFH) estimated that there are approximately 30,000 people with hemophilia B worldwide, constituting approximately 16% of all hemophilia-reported cases in the 113 represented countries [1]. As such, hemophilia B is regarded as a rare disease with a prevalence varying from (mean ± standard deviation) 2.69 ± 1.61 per 100,000 males in developed countries to 1.20 ± 1.33 per 100,000 in the rest of the world [2]. Prevalence is expected to continue to increase due to better diagnosis, improved access to hemophilia care, migration of patients to countries with better care, and improved data collection and reporting.

Hemophilia severity is classified according to the level of circulating clotting factors (severe < 1%, moderate 1–5%, and mild > 5–< 40% of normal activity), with severe hemophilia characterized by frequent spontaneous bleeding and joint hemarthrosis [3]. Hemophilia B is currently managed using FIX replacement therapy, using either plasma-derived (pdFIX) or recombinant (rFIX) therapies. Currently available FIX concentrates are summarized in Table 1. Treatment may be administered in an episodic/on-demand manner to treat bleeding episodes, prior to surgical interventions, or using a prophylactic regimen, whereby FIX is administered on a regular basis to prevent or reduce bleeds. Prophylaxis is associated with improved patient outcomes, including reduced joint damage (the major long-term complication of hemophilia) [4] and improved quality of life [5]. However, there are a number of barriers to adherence to prophylaxis regimens including the burden of frequent injections [6]. This article will discuss the opportunities and evidence for prophylaxis in hemophilia B, in the context of the recommended treatment guidelines and with regard to FIX replacement therapies, including long-acting rFIX.

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

2. Overview of prophylaxis

The aim of prophylaxis is to raise the background levels of circulating coagulation FIX to prevent spontaneous bleeds. Prophylaxis can be sub-categorized as primary, secondary, or tertiary depending at what stage in the disease it is initiated, as defined in Table 2 [7]. Primary prophylaxis is considered as the optimal treatment for prevention of joint bleeds in severe hemophilia patients with the aim of maintaining a moderate hemophilia phenotype (factor levels 1−5%) [8]. Prophylaxis can potentially facilitate a more active lifestyle for patients and reduce the incidence of irreversible joint damage caused by bleeding into joints. Hemarthrosis, which may be subclinical, eventually leads to arthropathy and is associated with pain and disability, limits physical activity and thus impacts considerably upon quality of life [8,9].

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.

Following early observations by Ahlberg that hemophilia patients with factor levels higher than 3% rarely experienced chronic arthropathy [10], the goal of prophylaxis in severe hemophilia is generally accepted to be to maintain coagulation factor levels above 1% at all times, thereby converting severe hemophilia into a moderate phenotype of the disease [11]. However, due to the relatively short half-life of pdFIX and standard-acting rFIX concentrates (~ 20 h) [12,13], prophylactic management approaches with these products usually require at least two injections per week to raise factor levels above 1%. This high frequency of injections is a burden to patients, especially those of pediatric age, and their caregivers [14].

Prophylaxis for hemophilia has a long history and was first described in the 1940s and 1950s using whole blood transfusions [15,16]. Early protocols were developed in Sweden using high doses (25–40 IU/kg twice weekly in hemophilia B) [17], in the Netherlands using intermediate doses with longer dose intervals (15–20 IU/kg one to two times per week) [18] and in Germany, where prophylaxis is started early, dosing is individualized, and the importance of treatment continuity is recognized [19–21]. Despite this long history, much of the evidence for the efficacy of prophylaxis in hemophilia B has, until recently, been anecdotal or based on limited data, with typically a small number of patients with hemophilia B included in a study predominantly conducted in patients with hemophilia A [10,18].

3. Prophylaxis in hemophilia B – what is the evidence?

Studies investigating prophylaxis in hemophilia B are summarized in Supplementary Table 1. In many of the observational studies conducted to date, the impact of prophylaxis has been reported in a combined group of patients with hemophilia A or B. Additionally, a number of these studies were conducted prior to highly purified FIX concentrates being available, and therefore do not include rFIX, which is commonly used in developed countries today [10,22]. Morfini et al. investigated the use of FIX-containing prothrombin complex concentrate in two prophylaxis regimens (weekly and twice weekly) in a one-year cross-over trial [22]. Fewer bleeding episodes occurred during the trial compared with the preceding year, when patients were treated on demand, and twice-weekly dosing was shown to result in fewer bleeding episodes than once-weekly dosing [22]. However, it should be noted that significantly lower doses of FIX were used in this study compared with what is generally advised today. The study by Morfini et al. was the only study in hemophilia B patients included in a Cochrane review comparing prophylaxis to on-demand treatment in hemophilia in six randomized, controlled studies. The Cochrane review, published in 2011, concluded that prophylaxis results in better preservation of joint function in children with hemophilias A and B compared with on-demand treatment [23].

A retrospective, observational study in Swedish children showed that initiating prophylaxis at a younger age (< 3 years) was associated with fewer joint bleeds per year and less arthropathy compared with those starting at 3–5 years of age [24]. The lack of an association between reduced bleeding and increased dosing in this study (once weekly versus twice weekly) is considered as a result of the clinical variability between patients and the need for individualization of a dosing regimen. It should be noted that the majority of patients in this study had hemophilia A (n = 108) and only 13 hemophilia B patients were included [24]. Several other studies assessing prophylactic regimens in patients with hemophilia B concluded that prophylaxis results in fewer bleeding episodes compared with on-demand treatment [25], or reduced/prevented the progression of joint damage [17,18,26,27]; however, these studies were not randomized and some did not have an on-demand arm for direct comparison.

A two-year trial was conducted in hemophilia B patients receiving either on-demand treatment or secondary prophylaxis with standard-acting rFIX (regimen selected by the investigator). Of the 19 patients undergoing prophylaxis two or three times a week with an average dose of 40.3 IU/kg (range 13–78 IU/kg), prophylaxis was rated as “excellent” or “effective in 93% of cases” [28]. A second trial assessed the use of standard-acting rFIX in 63 previously untreated children (aged 0–14 years) over a median treatment period of 37 months [29]. Routine prophylaxis in 32 patients prevented bleeding in 16% of cases and the regimens were rated as “excellent” in 94.1% of those dosed ≥ 2 times per week compared with 84.9% of those receiving once-weekly dosing. More frequent dosing also led to fewer patients experiencing spontaneous bleeds (13% [3/24] with injections ≥ 2 times per week versus 25% [2/8] in patients receiving one weekly injection) [29].

3.1. Evidence from clinical trials: standard-acting rFIX

The majority of the compelling evidence that demonstrates large reductions in bleeding rates with prophylaxis, compared with on-demand treatment, comes from clinical trials for registration of new rFIX concentrates, which has emerged in the last few years. This is due to the Food and Drug Administration (FDA) regulatory requirement that new products compare prophylactic with on-demand regimens. The findings from key clinical trials comparing prophylaxis regimens to on-demand treatment with rFIX are summarized in Table 3. These studies clearly demonstrate a dramatic reduction in bleeding episodes with prophylaxis, with significant reductions in the annualized bleeding rate (ABR) compared with on-demand treatment ranging from 83 to 91%, depending on the product used and dosing regimen [30,31,33,34]. Of even greater clinical relevance are the large reductions in the rates of spontaneous and joint bleeds that have also been reported with prophylaxis in these trials. The annualized spontaneous bleeding rate (AsBR) ranged from 11.1 to 22.4 with on-demand treatment and from 0.0 to 3.5 with prophylaxis and joint ABRs ranged from 13.6 to 28.7 with on-demand treatment and from 0.0 to 3.6 with prophylaxis [30,31,33–35].

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.

In three of these trials, a cross-over design was used, enabling direct comparison of on-demand treatment with prophylaxis regimens in the same patients [30,31,34]. Two of these trials were conducted with the rFIX nonacog alfa (Pfizer Inc. Pfizer Inc, New York, NY, USA) [30,31] and the third with the long-acting rFIX rIX-FP [34]. In the nonacog alfa pivotal study, 50 patients with hemophilia B (FIX ≤ 2%) aged 6–65 years who had experienced a minimum of 12 bleeding episodes in the previous year received prophylaxis (50 IU/kg twice weekly and 100 IU/kg once weekly) and on-demand treatment. Each patient was treated on demand for 16 weeks, followed by one of the two prophylaxis regimens, then another 8 weeks treated on demand, and then 16 weeks on the alternate prophylaxis regimen. A lower mean ABR was reported with 50 IU/kg twice-weekly regimen but this was not statistically significantly different to the ABR reported with the 100 IU/kg once-weekly regimen (p = 0.22). However, this difference may be clinically relevant particularly as the AsBR and joint ABR were also lower with the 50 IU/kg twice-weekly regimen [30], indicating that more frequent dosing may be beneficial when treating with standard-acting rFIX.

A second cross-over trial was conducted in which 25 hemophilia B patients were treated on demand for 6 months with nonacog alfa and then with 100 IU/kg once-weekly prophylaxis for 12 months [31]. When assessed over a longer treatment duration, the 100 IU/kg once-weekly regimen resulted in low bleeding rates: a median ABR of 2.0, a median AsBR of 1.0, and a joint ABR of 0; and demonstrated a dramatic reduction in bleeding rates compared with on-demand treatment [31].

Nonacog alfa has been available for 15 years but has only recently gained the additional indication for prophylaxis in Europe and it is not currently approved for prophylaxis in the USA. It was also the only rFIX available for prophylaxis until 2014 when nonacog gamma (Baxter Healthcare Corporation, Westlake Village, CA, USA) reached the market. In the pivotal study for nonacog gamma, the twice-weekly prophylaxis regimen (median dose 50.5 IU/kg) was compared with a historical control group treated on demand and reported a 79% reduction in ABR [36]. More recently, a clinical study of trenonacog alfa (Aptevo Therapeutics Inc., Seattle, WA) observed that twice-weekly prophylaxis resulted in a much lower median ABR (1.5) than on-demand treatment (median ABR = 16.1) [32].

3.2. Evidence from clinical trials: long-acting rFIX

Prophylaxis is gaining increased interest as the treatment of choice for hemophilia B with the increasing availability of new long-acting products, which provide improved pharmacokinetic parameters, allowing less frequent dosing and the potential for better patient outcomes than standard-acting rFIX or pdFIX products. These new rFIX concentrates have been modified by fusion or binding to another component that results in a dramatic extension of the half-life of rFIX (up to ~ 5-fold) compared with standard-acting rFIX [33–35]. This enables the dosing interval to be extended due to the longer time taken to reach the desired trough level as well as trough levels being sustained at a higher level than expected to be achieved with standard-acting rFIX. It is, therefore, predicted that the use of prophylaxis will become more widespread. Key information on the long-acting rFIX concentrates is detailed in Table 4.

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.

The first of the long-acting rFIX concentrates to become available was rFIXFc (Bioverativ Therapeutics, Waltham, MA, USA), which was approved for use in the USA in 2014. The rFIXFc is a recombinant fusion protein linking FIX to the Fc fragment of immunoglobulin G. In the pivotal phase III study, hemophilia B patients were treated with either prophylaxis (50 IU/kg weekly or with an interval-adjusted regimen starting at 100 IU/kg every 10 days) or on-demand treatment, with prophylaxis resulting in ≥ 83% reduction in ABR compared with on-demand treatment [33]. The second long-acting rFIX concentrate to market was rIX-FP (CSL Behring, King of Prussia, PA, USA) in 2016. In rIX-FP, rFIX is fused to recombinant albumin for half-life extension [42]. In the pivotal study, 40 patients received routine prophylaxis (once every seven days for six months, followed by either 7-, 10- or 14-day regimen for six months) and 23 patients, in a cross-over arm, received on-demand treatment with rIX-FP for six months followed by prophylaxis every seven days for six months [34]. The median ABR was reduced by 91% when patients switched from on-demand treatment to 7-day prophylaxis [34].

Another approach to half-life extension that has been utilized in hemophilia is the addition of a polyethylene glycol (PEG) moiety. In N9-GP (Novo Nordisk A/S, Bagsvaerd, Denmark), a 40 kDa-branched PEG is bound to rFIX by glycoPEGylation. In a multinational, randomized, phase III trial (n = 74), patients were treated for one year with weekly prophylaxis (10 IU/kg or 40 IU/kg) or on demand for 28 weeks. Once-weekly prophylaxis with 40 IU/kg or 10 IU/kg N9-GP resulted in median ABRs of 1.0 and 2.9, respectively, versus 15.58 in the on-demand arm [35]. N9-GP has been approved for use in prophylaxis in patients ≥ 12 years in Europe but has no prophylaxis indication in the USA and is not currently in clinical use [35].

All trials have consistently demonstrated the superior efficacy of prophylaxis regimens compared with on-demand treatment with significant reductions in bleeding rates in patients ≥ 12 years. Clinical studies have also demonstrated that long-acting rFIX concentrates can be used for prophylaxis in pediatric patients (< 12 years), with dosing intervals of seven days, while maintaining low bleeding rates [43–45]. Prolonged dosing intervals of up to 14 days in pediatric patients with moderate-to-severe hemophilia are currently being investigated [46,47]. In addition, prophylaxis regimens in hemophilia B with long-acting rFIX concentrates have demonstrated a clinical benefit on joint health. In those patients with target joints at baseline, 97.3% of target joints had resolved one year later in patients receiving rFIXFc prophylaxis [48]. When patients ≥ 12 years were switched from on-demand treatment to 7-day prophylaxis with rIX-FP all target joints were resolved [34]. N9-GP also substantially decreases target joint bleeds when used in prophylaxis with a dose of 40 IU/kg weekly [49]. Prophylaxis with long-acting rFIX concentrates has also been shown to resolve target joints in pediatric patients [43–45].

4. Guidelines

In accordance with the evidence from clinical trials, national and international guidelines are unanimous in their recommendation that primary prophylaxis should be the preferred therapeutic approach in phenotypically severe hemophilia B. This strategy has been recommended by the Medical and Scientific Advisory Council (MASAC) of the US National Hemophilia Foundation, who recommend that prophylaxis be initiated as early as possible with the aim of keeping FIX levels above 1% between doses using an individualized doing regimen determined by appropriate laboratory monitoring [50]. The European Association for Haemophilia and Allied Disorders state that prophylaxis should be available to all patients with hemophilia [51], and the World Health Organization (WHO) and the WFH recommend that prophylaxis should be individualized based on bleeding phenotype, with the severity of bleeding generally correlating with clotting factor level [3,52]. The German Medical Association recommends routine prophylaxis in children and adults with hemophilia B [20,53]. The Italian Association of Hemophilia Centers (AICE) recommend primary prophylaxis, and the consideration of secondary or tertiary prophylaxis on an individualized basis [54], and prophylaxis is recommended in the national guidelines of New Zealand and Canada [55,56].

However, a major challenge to the implementation of prophylaxis is that there is no general agreement on the optimal treatment targets for hemophilia B, with different targets proposed by the different bodies. A report by the WHO, WFH, and International Society for Thrombosis and Haemostasis (ISTH) recommend that prophylaxis treatment is individualized, with maintenance of trough levels above 1% FIX activity with high-dose prophylaxis or avoidance of joint bleeds with intermediate-dose prophylaxis [52]. Trough levels of 1–2% and above 1% are advocated by AICE and MASAC, respectively [50,54], while the other guidelines do not discuss trough levels.

It is also recognized that there is heterogeneity in bleeding patterns and severity in patients with severe and moderate hemophilia, which are not specifically covered in the guidelines; the reasons behind this heterogeneity appear to be multifactorial [7,57,58]. The classification of hemophilia severity is based on endogenous clotting factor level, which is correlated with the severity of bleeding [3]. However, the pharmacokinetics of administered clotting factor concentrates can vary between hemophilia patients [59]. This impacts the clinical severity of bleeding due to the variation in factor consumption required to prevent bleeds. Consequently, annual clotting factor consumption has been used to characterize the phenotypic variation seen in severe hemophilia, along with incidence of joint bleeds and joint scores [60]. Therefore, in addition to considering the clinical bleeding phenotype, the PK of a given FIX concentrate in an individual and their previous FIX consumption may be helpful tools to consider when determining the optimal prophylaxis regimen for a hemophilia B patient. An individualized approach to treatment, that also considers the lifestyle of the patient, may help to address the known heterogeneity in bleeding patterns.

5. Overcoming challenges to prophylaxis

Despite the guideline recommendations, the use of prophylaxis in hemophilia B is less widespread than in hemophilia A (Table 5). A large-scale survey conducted in Canada in 2006 showed that hemophilia B patients were less likely to be treated with prophylaxis than hemophilia A patients (severe hemophilia: 32% vs. 69%; moderate hemophilia: 5% vs. 18%) [62]. More recent data indicates that the proportion of hemophilia B patients treated with prophylaxis is increasing but it remains lower than in hemophilia A. In the USA, data from 138 hemophilia treatment centers (HTCs) showed that 75% and 20% of severe and moderate hemophilia B patients were treated with prophylaxis, respectively, compared with 81% and 36% of severe and moderate hemophilia A patients [64]. Similarly, in Europe 49% of severe or moderate hemophilia B patients were treated with regular prophylaxis compared with 66% of severe or moderate hemophilia A patients, in a retrospective study of 11 HTCs and two registries in seven countries [65]. A very similar pattern was recently reported from a registry survey of treatment in Australia where 46% of moderate or severe hemophilia B patients were being treated with prophylaxis compared with 69% of moderate or severe hemophilia A patients [61]. This situation, coupled with recent genetic, clinical and radiologic evidence, including an observed less frequent need for orthopedic surgery in hemophilia B [66,67], has led some to question whether hemophilia B is less severe than hemophilia A [68,69]. In addition to hemophilia B severity, other factors that have been associated with higher rates of prophylaxis use include younger age, ethnicity and having a normal body mass index [70].

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.

The age at which prophylaxis is started in hemophilia B is also of considerable importance due to the potential impact of early joint bleeds on long-term joint health [71]. A study of previously untreated hemophilia patients observed that there was no difference in age at first bleed, age at first joint bleed or exposure to factor between severe hemophilia B and severe hemophilia A patients, indicating that early treatment should be the same [72]. However, an observational study of adult patients from seven HTCs in Canada conducted between 2009 and 2011 indicated that of the 52% of adult (≥ 18 years) severe hemophilia B patients receiving continuous prophylaxis, in all cases, was tertiary and was not started in childhood [73].

The uptake of prophylaxis for all patients is limited for a variety of reasons, including medical, social, and cost issues [74,75]. The major challenge has been the short half-life of rFIX; the peak activity level of 25 to 50% is only transient, followed by a steady decline in activity necessitating frequent administration. FIX has a half-life of around 20 h, so prophylaxis traditionally required two or three injections per week to maintain trough levels above 1%. Additionally, in younger children, the half-life of FIX is typically lower due to faster clearance, meaning that higher doses or more frequent dosing is required [57]. Most patients who fail to follow their prescribed regimen report the time commitment and inconvenience of prophylaxis as the biggest barriers to adherence [75–77]. A prophylactic treatment regimen should be developed in partnership between the physician and patient to ensure that the patient understands the importance of prophylaxis and feels confident in administering treatment [6]. The introduction of long-acting FIX products is likely to overcome many of these challenges by enabling maintenance of high trough levels with extended dosing intervals [33–35] and may therefore improve adherence [6]. Data from clinical studies of long-acting rFIX also indicate that hemophilia B patients may benefit from an improved quality of life [78–80] as a result of the reduced burden of treatment.

A second issue is treatment cost, which is primarily related to the dose and frequency of injections, and therefore factor consumption, required for prophylaxis. This was emphasized in a retrospective study of prophylaxis in hemophilia B at a single treatment center in which the number of bleeding episodes was reduced by 90%. At the same time, there was a three-fold higher consumption of FIX concentrates and a four-fold higher frequency of injections [81]. Another study showed that the increase in clotting factor consumption when switching to prophylaxis was 1.3-fold [82]. In terms of follow-up costs for management and treatment of damaged joints, prophylaxis has a clear benefit, and a 2005 study concluded that the use of prophylaxis treatment was overall more effective than on-demand treatment in young hemophilia patients, albeit at higher cost [83].

Prophylaxis with long-acting rFIX concentrates has been shown to reduce mean FIX consumption compared with prophylaxis with standard-acting rFIX by almost 50% [84]. Also, in clinical studies with long-acting rFIX concentrates, weekly FIX consumption was considerably lower (~ 30–50%) than with patients’ previous prophylaxis regimens with standard-acting rFIX or pdFIX [34,85]. Therefore, switching from on-demand treatment to prophylaxis with a long-acting rFIX would result in a lesser increase in FIX consumption than switching from on-demand treatment to prophylaxis with a standard-acting rFIX or pdFIX.

Another issue in prophylaxis is the optimal trough level. While maintaining trough factor levels above 1% with prophylaxis (the traditional goal of prophylaxis) represents a substantial advance over on-demand treatment, it does not prevent all bleeding [11]. Interestingly, studies comparing magnetic resonance imaging (MRI) scores with clinical data on joint bleeds found that some joints had high MRI scores despite no clinically evident bleeds, suggesting that subclinical bleeds occur due to apparent under-treatment [4,86]. Additionally, the long-term impact of subclinical bleeding is not yet known, and while there is limited information on the optimal trough level that will prevent joint arthropathy, it is assumed that higher levels would translate into long-term clinical benefits [87]. A report by the WFH suggested that moving to a higher trough level, for example 3–5%, would be a step in the right direction toward eliminating joint damage [11]. Furthermore, a study analyzing the association between joint bleeds and trough levels in 433 patients with mild or moderate hemophilia A concluded that there was an 18% reduction in bleeding frequency for every 1% increase in residual FVIII activity, and in patients with trough levels above 10% the risk of joint bleeds was extremely low, highlighting the benefit of aiming for higher trough levels [88]. Data from clinical trials demonstrate that the new long-acting rFIX concentrates enable patients to maintain higher trough levels over a longer period of time [33,34,89].

To summarize, while the benefits of prophylaxis are well recognized, a number of questions remain regarding optimum treatment of hemophilia B patients, including when to start primary prophylaxis, the minimum effective dose, and timing, and individualizing dosing according to the age of the patient [86,90]. It is also unknown whether prophylaxis influences the development of inhibitors in hemophilia B. It has been suggested that initiating low-dose prophylaxis early in patients with high-risk for developing inhibitors may be protective against the development of inhibitors by tolerizing them, but additional studies are needed to confirm this [91,92]. However, as inhibitors are much less common in hemophilia B than in hemophilia A [93], the impact of prophylaxis versus on-demand treatment on inhibitor development in hemophilia B has not been investigated. It is worth noting that in clinical studies reported to date, no previously treated patients have developed inhibitors in response to treatment with a long-acting rFIX concentrate [34,35,43,45,46,94].

6. Conclusion

Severe hemophilia B is a rare and challenging condition. Clinical phenotypes are heterogeneous and some patients with severe deficiency bleed very little, while others may experience frequent spontaneous bleeding. Despite robust clinical evidence demonstrating that prophylaxis offers many advantages to patients with hemophilia B, it has not been utilized as widely as is recommended by the numerous treatment guidelines. The publication of the first randomized trial comparing prophylaxis versus on-demand in hemophilia B [30], plus the recent approval of new long-acting rFIX concentrates (rFIXFc, rIX-FP and N9-GP) for prophylaxis, gives patients and physicians more product choice and flexibility in dosing regimens. Long-acting rFIX may overcome the disadvantages of prophylaxis regimens with standard-acting rFIX by offering a much longer dosing interval, which is more convenient for patients and their caregivers and should help improve adherence. As well as longer dosing intervals, long-acting products offer the opportunity to maintain significantly higher trough levels (e.g. up to 20% with once-weekly dosing of rIX-FP or N9-GP) [34,35], which could be tailored for individual patients and lead to improved joint status and the ability to maintain an active lifestyle. Reports of real-world clinical experience with these new products are now needed to examine the effectiveness of prophylaxis regimens with dosing intervals of 14 days or longer. Clinical guidelines may also need to be updated to reflect these new products, including advice on individualizing treatment to ensure the best outcomes for patients.

7. Expert commentary

Hemophilia B has been somewhat over looked in favor of hemophilia A due to its rarity and the perception that it is less severe, which has resulted in fewer treatments being developed. As a result, prophylaxis has not been as widely used to treat hemophilia B as hemophilia A. Clinical trials of new FIX replacement products have been required to compare prophylaxis with on-demand treatment despite guidelines recommending prophylaxis to maintain FIX levels above 1%. These clinical trials have provided robust clinical evidence that treating hemophilia B prophylactically is essential to protect against bleeds which will be a key to maintaining joint function long term in our patients. As a result, prophylaxis is now considered as the standard of care.

We are currently experiencing a shift in treatment practice in hemophilia B, thanks to long-acting rFIX concentrates becoming available, which may increase uptake of prophylaxis and improve adherence. These modified rFIX concentrates have an extended half-life, which means they can be dosed weekly or less frequently, while maintaining trough levels far above the generally accepted target of 1% FIX. Now it is perhaps the time that we should be reconsidering this target and our goals and expectations for treatment in hemophilia B. Research has indicated that maintaining higher trough levels, equivalent to a mild hemophilia phenotype, offers better protection from joint bleeds, which may be critical to preserving joint function long term. Prevention of subclinical bleeding will also be important in this regard. Furthermore, this fosters a more active lifestyle from early childhood including protected physical activity, which improves the general health status of the patients.

Undoubtedly, the perceptions and expectations that our patients have about their treatment will also change in light of these new options. In this modern era, patients have a great deal of access to information about their disease and treatment choices and many will be eager to embrace a less burdensome treatment regimen. Others may be happy with their current treatment and prefer not to change.

With the current armamentarium, we truly have flexibility in how we can treat patients to best suit their needs, whether to help a patient to maintain an active lifestyle by attaining higher trough levels or simply to reduce the frequency of injections. Real-world clinical experience with long-acting rFIX will determine how to maximize the effectiveness of these products in different patients with different needs. Of note, the long-acting rFIX concentrates have not yet been tested in previously untreated patients (PUPs), where there is a potential risk of inhibitor development, albeit a relatively low risk in hemophilia B. Ongoing extension studies, exploring the long-term efficacy and safety of long-acting rFIX, and other post-marketing studies will help to indicate the full potential of these products.

8. Five-year view

It is likely that in five years from now treating severe hemophilia B with prophylaxis will have become even more widespread and that the majority of patients will be treated with long-acting rFIX, where these treatments are accessible. As physicians, our expectations as to what constitutes adequate care for our hemophilia B patients will be higher than they are currently. Our patients will also expect to be able to live a relatively normal life without fear of bleeds and with treatment regimens that are minimally disruptive. Although the advances in hemophilia B treatment that we have seen in the last couple of years represent a major step forward, new therapeutics options are on the horizon. In five years’ time, we should know the full potential of these new treatments, which may include subcutaneous FIX, siRNA to anti-thrombin (fitusiran), an anti-TFPI antibody (concizumab), and FIX gene therapy. The future of hemophilia B treatment is extremely exciting and will potentially involve dramatic changes to treatment practice due to a wealth of new treatment options.

Key issues

• Prophylaxis with factor replacement therapy has not been widely utilized in hemophilia B despite robust clinical evidence of its benefits and its recommendation in guidelines.

• Clinical studies of rFIX therapies have clearly demonstrated that prophylaxis dramatically lowers bleeding rates (83−91%) compared with on-demand treatment.

• Treatment paradigms are shifting in hemophilia B due to the availability of long-acting rFIX concentrates, which enable higher trough levels and longer dosing intervals than standard-acting rFIX.

• Physicians now have more in their armamentarium to treat hemophilia B patients, enabling them to tailor treatment to an individual’s specific clinical needs or lifestyle.

• Hemophilia B patients now have more flexibility in dosing regimens offering them greater convenience and the possibility of a less burdensome treatment regimen.

Declaration of interest

G Castaman has served on advisory boards for CSL Behring, Kedrion, Pfizer, Baxter/Shire, Bayer, Novo Nordisk, Uniqure, Roche, and Sobi. Writing and editorial assistance was provided by Meridian HealthComms UK funded by CSL Behring. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementary Material

Supplemental data for this article can be accessed here.

Additional information

Funding

This manuscript was supported by CSL Behring.