Plasma-derived human factor X concentrate for on-demand and perioperative treatment in factor X-deficient patients: pharmacology, pharmacokinetics, efficacy, and safety

ABSTRACT

Introduction: Hereditary factor X (FX) deficiency is a rare autosomal recessive bleeding disorder characterized mainly by mild-to-severe bleeding into the mucous membranes, muscles or joints. Previously, treatment options for hereditary FX deficiency were limited mostly to products that may not specify FX content (i.e. fresh frozen plasma and prothrombin complex concentrates) and that have associated safety concerns. To meet the need for a single-factor replacement therapy specifically for use in FX-deficient patients, a high-purity, high-potency, human plasma-derived FX concentrate (pdFX; Coagadex®; Bio Products Laboratory, Elstree, UK) has been developed and approved for treatment of perioperative bleeding and on-demand treatment in FX-deficient patients.

Areas covered: The pharmacology, efficacy, and safety of pdFX are discussed, with a review of preclinical studies and clinical trial data that led to regulatory approval of pdFX in the United States and Europe.

Expert opinion: As the first single-factor replacement therapy indicated for hereditary FX deficiency, pdFX is a safe and efficacious treatment option in patients aged ≥12 years with hereditary FX deficiency. Clinical studies of pdFX provide a dosing regimen for use in cases of bleeding episodes, surgery, and prophylaxis. Further studies are ongoing regarding use of pdFX long term and in patients aged ≤12 years.

KEYWORDS:

• Clotting factor concentrate
• efficacy
• factor X deficiency
• orphan drug
• pharmacokinetics
• rare bleeding disorders
• safety

1. Introduction

Hereditary factor (F) X deficiency is a rare blood coagulation disorder [1], with a global population prevalence of approximately 1:1,000,000 for the severe form [2]. FX deficiency may be hereditary (autosomal recessive [1]) or acquired [3]. Acquired FX deficiency may have a number of causes (e.g. amyloidosis, tumors, and infections) and may be self-limiting; the need for treatment of acquired FX deficiency depends on the cause and severity of the deficiency [3]. In contrast, hereditary FX deficiency presentation may occur throughout life [4], depending on the level of the deficiency, and disease severity is variable, as are associated bleeding symptoms [2,5]. While mucocutaneous symptoms (e.g. epistaxis) tend to occur frequently in FX-deficient patients [6,7], patients can also suffer from severe hemarthroses and resultant arthropathy [2,5], severe postoperative hemorrhage, central nervous system (CNS) hemorrhage [2], and gastrointestinal (GI) bleeding [4]. In women, menorrhagia is common [6] and may be observed at all severity levels [4]. Risks during pregnancy include miscarriage, uterine bleeding, postpartum hemorrhage, and preterm labor [5,8].

FX deficiency can present as a mild, moderate, or severe deficiency state [2,5,6]. Mild FX deficiency (FX functional activity [FX:C] 6–10 IU/dL) is characterized by easy bruising and/or menorrhagia and is normally diagnosed during routine screening or from family history. In moderate FX deficiency (FX:C 1–5 IU/dL), bleeding is observed in association with trauma or surgery and therefore usually presents after hemostatic challenge has occurred. Severe FX deficiency (FX:C <1 IU/dL) may present in neonates (e.g. CNS and umbilical-stump bleeding) and tends to exhibit the most severe phenotype. FX deficiency can be further divided into two forms, type I deficiency (low FX activity and low antigen levels) and type II deficiency (low FX activity and normal antigen levels) [5].

Hereditary FX deficiency is diagnosed via coagulation testing and is suggested when both the prothrombin time (PT) and activated partial thromboplastin time (APTT) are prolonged [2,5]. Diagnosis is confirmed by testing specific FX activity levels. As part of the differential diagnosis, it is also important to rule out vitamin K deficiency or an acquired deficiency, most often seen in older patients [2].

Due to the relatively small patient population and a sparse body of clinical evidence to guide best practice, options and guidelines for treatment of hereditary FX deficiency have been limited [1,2,5]. For treatment of bleeding episodes in FX-deficient patients, guidelines have typically recommended antifibrinolytics (e.g. tranexamic acid) and/or intermittent FX replacement via plasma or non-specific plasma-derived products (e.g. prothrombin complex concentrate [PCC]) that also contain other clotting factors [1,5,9,10]. These therapies have also been used successfully as prophylactic replacement of deficient FX in at-risk patient groups and/or high-risk clinical scenarios [1,2,5]. Additionally, expert consensus now considers that optimal therapy for rare coagulation disorders is the use of single-factor concentrates for specific replacement of the deficient factor wherever possible to reduce the risk of adverse reactions and accumulation of other non-deficient coagulation factors [11]. Accordingly, the 2016 updates to the Medical and Scientific Advisory Council of the National Hemophilia Foundation treatment recommendations for bleeding disorders included the addition of a plasma-derived FX concentrate (pdFX) for treatment of FX deficiency [12].

A high-purity, high-potency, human pdFX (Coagadex®; Bio Products Laboratory, Elstree, UK) has recently been developed and approved in the United States [13] and Europe [14] (Box 1). Here, we review the pharmacology, pharmacokinetics (PK), efficacy, and safety of pdFX and describe data from key preclinical and clinical studies.

Box 1. Drug summary: pdFX

Table

Drug name (generic)	Plasma-derived, human FX concentrate
Phase	Licensed in the United States and Europe
Indication	United States: indicated in adults and children (aged ≥12 years) with hereditary FX deficiency for (1) on-demand treatment and control of bleeding episodes and (2) perioperative management of bleeding in patients with mild FX deficiency (Limitation: perioperative management of bleeding in major surgery in patients with moderate and severe hereditary FX deficiency has not been studied [13]) Europe: indicated for the treatment and prophylaxis of bleeding episodes and for perioperative management in patients with hereditary FX deficiency [14]
Mechanism of action	Temporarily replaces missing FX in patients with hereditary FX deficiency to achieve hemostasis [13,14]
Route of administration	Intravenous administration at 10–20 mL/min [13,14] (Virally inactivated [15], lyophilized formulation, reconstituted before use [13])
Pivotal trials	Ten01: conducted in subjects ≥12 years with moderate-to-severe hereditary FX deficiency with ≥1 bleed occurring in the past year that required FX replacement therapy. Efficacy, safety and PK data were obtained for on-demand and perisurgical use of pdFX [15–17] Ten03: conducted in subjects ≥12 years with mild-to-severe hereditary FX deficiency. Efficacy of pdFX as perioperative management of bleeding for planned surgery was assessed [17]

FX: factor X; pdFX: plasma-derived FX concentrate; PK: pharmacokinetics.

2. Market overview

2.1. Non-specific FX replacement therapy

FX replacement therapy is indicated for the prompt resolution of bleeding symptoms and may also be beneficial as prophylaxis in patients with severe FX deficiency, especially in cases of severe bleeding in the CNS, GI tract, or joints [1,5,9,18,19]. A recent analysis of 489 patients with rare bleeding disorders from the European Network of Rare Bleeding Disorders database (including 45 patients diagnosed with FX deficiency) found that FX levels of 56 IU/dL correspond to an asymptomatic state and levels of 40 IU/dL correspond with Grade I bleeding (i.e. bleeding occurring after trauma or drug ingestion) [4,20]. Several non-specific methods for FX replacement are available, each of which have limitations (see in the following sections).

2.1.1. PCCs

PCCs are virally inactivated plasma-derived concentrates that typically include three (FII, FIX, and FX) or four (FII, FVII, FIX, and FX) coagulation factors [1,5,10] and the natural coagulation inhibitors protein C and protein S [21]. PCCs have been used for treatment of acute bleeds [2] as well as severe bleeding or major surgery [1]. PCCs have also been used prophylactically in severe cases [1,2,5] and prior to surgery [2]. However, PCCs have been associated with reports of thrombosis, which may be dependent on product quality, dosage, infusion rates, and patient circumstances and risk profile [5,22]; therefore, PCCs may not be suitable for all patients [22] or in all circumstances. Despite the variable activities of other coagulation factors present, variation between products, and variation within individual product batches, PCC dosing is often defined in terms of FIX activity [1].

2.1.2. Fresh-frozen plasma

Virally inactivated forms of fresh-frozen plasma (FFP) are preferable to non-virally inactivated forms for use as a non-specific replacement therapy but are not available in all countries [2,10,23]. FFP is a potential alternative to PCCs if PCCs are unavailable [1]. Because FFP contains a low concentration of each coagulation factor, a large volume must be given over several hours to achieve minimally hemostatic FX levels, leading to potential circulatory overload [23]. Other potential FFP-related issues include allergic reactions and transfusion-related lung injury [5].

2.1.3. FIX product

FIX plasma concentrates, which contain approximately 1200 IU of FIX as well as therapeutic amounts of FX (approximately 800 IU) have been used prophylactically in FX-deficient patients [19,24]; thrombosis may occur in some patients [22]. A number of FIX plasma concentrates also containing FX are in clinical development or have recently been approved [25–27].

2.2. FX replacement therapies: treatment selection

A specific pdFX is preferable to PCCs and FFP [1,11,12]. pdFX is the only approved specific FX replacement therapy containing FX as the sole hemostatic agent [15].

3. Introduction to a high-purity human pdFX

As a high-purity, high-potency human plasma-derived FX concentrate, pdFX is the first single-factor FX therapy to replace the deficient FX needed for effective hemostasis in patients with FX deficiency.

3.1. Chemistry

FX, the first enzyme in the common pathway of blood coagulation (Figure 1) [5,28], is vitamin K dependent [5] and hepatically synthesized [2,5]. FX is an inactive zymogen that is activated by activated FIX or activated FVII [5]; activated FX (FXa) associates with activated FV to form the prothrombinase complex, which proteolytically cleaves prothrombin to its active form, thrombin [5,28].

Figure 1. Blood coagulation pathway [28].

TF, tissue factor. Reprinted and adapted from Semin Hematol, volume 38(Suppl 4), Mikaelsson M et al., Measurement of factor VIII activity of B-domain deleted recombinant factor VIII, pages 13–23, Copyright (2011), with permission from Elsevier.

pdFX is manufactured from healthy US donor plasma that has tested negative for hepatitis A, B, and C viruses, human immunodeficiency virus (HIV)-1 and antibodies to HIV-1/-2, hepatitis C virus, and hepatitis B surface antigen, with human parvovirus B19 ≤ 10⁴ IU/mL [13]. Donor plasma is further subjected to solvent/detergent treatment, nanofiltration, and terminal heat treatment to remove/inactivate viruses [13,29]. Isolated, purified, filtered, and virally inactivated pdFX is supplied as a lyophilized powder; upon reconstitution with sterile water for injection, pdFX is formulated to contain 100 IU/mL of FX, <1 IU/mL of FII or FIX, and no added proteins [13,15,29]. The specific activity of pdFX is >100 IU/mg protein; pdFX functional activity is measured by the chromogenic substrate-based FX activity assay [29,30]. Following reconstitution, pdFX is administered intravenously at a rate of 10–20 mL/min for on-demand treatment and bleeding episode control and perioperative management of bleeding in patients with hereditary FX deficiency [13,14].

3.2. Pharmacodynamics

In vitro non-clinical coagulation tests (PT, APTT, thrombin generation assay, and thromboelastography) have demonstrated that pdFX corrects plasma FX deficiency in a dose-dependent manner [29,30]. In vivo non-clinical efficacy studies, however, have not been conducted, due to the lack of a suitable animal model of FX deficiency [29,30].

4. PK and metabolism

Due to the fact that pdFX is an endogenous human protein, preclinical PK data are limited. PK studies conducted in rats found pdFX to elicit a dose-dependent, linear increase in maximum plasma concentration and area under the plasma concentration time curve [29]. Preclinical toxicokinetics (in repeat-dose rat studies) were dose dependent, with no observed gender difference [30].

The clinical PK of pdFX was investigated in study Ten01 (Table 1), a pivotal phase III trial (first in human study; ClinicalTrials.gov NCT00930176; EudraCT 2009–011145-18) conducted in patients aged ≥12 years with moderate-to-severe hereditary FX deficiency (FX:C <5 IU/dL) and ≥1 bleed occurring in the previous year that required FX replacement therapy (i.e. PCC, FFP, or FIX/FX concentrate) (Figure 2) [15]. This study was small (N = 16) due to the rarity of the disease yet represents the most comprehensive PK study of FX performed to date. In Ten01, patients received pdFX 25 IU/kg for the baseline PK assessment (PK1) and underwent on-demand pdFX treatment for ≥6 months and until ≥1 bleed had been treated with pdFX, after which they completed a repeat PK assessment (PK2) [15]. Because PK2 (n = 15) results were similar to PK1 (n = 16) results, final PK data are based on the combination of PK1 and PK2 (N = 31) data (Table 2). These results were similar to previous FX PK results obtained in healthy volunteers following administration of PCC or FIX/FX concentrate [19,31]. The pdFX half-life measured in this study (29.4 h) suggests that in a prophylactic regimen, pdFX could be administered once or twice per week, depending on the trough FX activity level required. When adjusted for discrepancies between the one-stage clotting assay (used to monitor FX:C in clinical laboratories [29]) and the chromogenic assay (used to measure pdFX potency per regulatory guidelines [13,14]), the observed incremental recovery of 2.07 IU/dL per IU/kg (Table 2) was revised to a final value of 2.00 IU/dL per IU/kg.

Table 1. Completed and ongoing clinical studies of pdFX.

Study name	Design	Population	Key assessments	Key pdFX findings
Ten01 [15,16]	Prospective, open-label, multicenter, non-randomized, phase III study	Patients aged ≥12 years with moderate or severe hereditary FX deficiency (plasma FX:C <5 IU/dL) (N = 16)	PK after a single dose (25 IU/kg) Efficacy and safety in the treatment of bleeding episodes up to 2 years Perioperative management of bleeding for planned surgery	Mean IR: 2.00 IU/dL per IU/kg Mean half-life: 29.4 h Excellent or good efficacy for on-demand treatment of bleeds: 98% of patients Mean dose per infusion: 25.3 IU/kg Most common AE: mild headache (14 cases in 8 subjects) Possibly treatment-related AEs: one subject with infusion-site pain and one subject with fatigue, infusion-site erythema and back pain
Ten02 [32]	Prospective, open-label, multicenter, non-randomized, phase III study	Patients aged <12 years with moderate or severe hereditary FX deficiency (FX:C <5 IU/dL)	PK after a single dose (50 IU/kg) Efficacy and safety in routine prophylaxis over 6 months	Not yet available
Ten03 [17]	Prospective, open-label, multicenter, non-randomized, phase III study	Patients aged ≥12 years with mild-to-severe hereditary FX deficiency (FX:C <20 IU/dL) (N = 2)	Perioperative management of bleeding for planned surgery	Excellent efficacy for control of perioperative blood loss: 100% Postoperative bleeding: none Need for blood transfusions: none Blood loss: as expected or less than expected Possibly treatment-related AEs: none
Ten05 [33]	Retrospective, multicenter, data-collection study	Patients who have received ≥1 dose of pdFX on compassionate-use basis	Long-term prophylactic use	Not yet available
Ten06 [34]	Postmarketing registry study	Patients with moderate to severe hereditary FX deficiency	Perioperative management for major surgical procedures	Not yet available

AE: adverse event; FX: factor X; FX:C: FX functional activity; IR: incremental recovery; pdFX: plasma-derived FX concentrate; PK: pharmacokinetics.

Table 2. Summary of clinical PK parameters of human pdFX concentrate [15].

Clinical PK parameter	pdFX PK parameter value^a
t½ (h)	29.4
Cmax (IU/dL)	50.0
IR (IU/dL per IU/kg)	2.07
AUC (IU/h/dL)	1675
CL (mL/kg/h)	1.38
MRT (h)	40.50
Vdss (mL/kg)	55.8

AUC: area under the plasma concentration time curve; CL: clearance; C_max: maximum plasma concentration; IR: incremental recovery; MRT: mean residence time; pdFX: plasma-derived factor X concentrate; PK: pharmacokinetics, t_½: half-life; V_dss: volume of distribution at steady state.

^aData are geometric means of 31 datasets from 16 subjects with moderate-to-severe hereditary FX deficiency. pdFX was administered as an intravenous bolus dose of 25 IU/kg.

Reprinted from [15], Copyright (2016), with permission from John Wiley and Sons.

Figure 2. Study design of a phase III clinical trial of pdFX PK, efficacy, and safety [15,16].

BL: baseline; IV: intravenous; pdFX: plasma-derived factor X concentrate; PK: pharmacokinetics.

*In cases of prophylaxis, pdFX was administered by IV infusion 1–4 hours presurgery to raise plasma FX functional activity (FX:C) to 70–90 IU/dL. Additional infusions were given during surgery, if required. Postsurgery infusions were administered as required to achieve plasma FX:C ≥50 IU/dL.

5. Clinical efficacy

The clinical efficacy of pdFX was assessed in two phase III trials, Ten01 (described earlier) and Ten03 (ClinicalTrials.gov NCT01086852, EudraCT 2009 015086–31). In Ten01, 16 subjects experienced 228 bleeds, of which 187 required replacement therapy and were assessable for efficacy [16]. In this study, use of pdFX replacement therapy was administered on an as needed basis. Overall efficacy was rated as ‘excellent’ or ‘good’ (i.e. ‘treatment success’) by 98% of subjects, and 83% of bleeds were treated with a single pdFX infusion. An independent data review committee assessing the severity of bleeds determined that 98 bleeds (52%) were ‘major’ and 88 bleeds (47%) were ‘minor’ (one bleed [0.5%] was not evaluated). Fourteen of 16 subjects received pdFX at the standard dose (25 IU/kg), while the remaining two subjects received doses up to 30 and 33 IU/kg. Overall, subjects were treated with a mean total dose of 30.4 IU/kg pdFX per bleed and received a mean of 1.2 infusions per bleed.

pdFX efficacy for perioperative management of bleeding for planned surgery was also assessed in five subjects undergoing seven surgeries [17]. Ten01 subjects eligible for this analysis received pdFX to prevent bleeding and achieve hemostasis in ≥1 surgical procedures during the Ten01 study (n = 2, two major surgeries each). Ten03 was a small study in subjects aged ≥12 years with mild-to-severe hereditary FX deficiency (FX:C <20 IU/dL) who received pdFX to prevent bleeding and achieve hemostasis during planned surgery (n = 3, one minor surgery each). Dosing, efficacy assessments, and safety assessments for surgical procedures were identical between studies. For each of the seven procedures, blood loss was as, or less than, expected compared with a patient without a bleeding disorder undergoing a similar surgery, and no blood transfusions were required. Although one subject/procedure was excluded from the efficacy analysis due to having required an on-demand dose of pdFX the day before the procedure (i.e. subject’s FX:C was not <20 IU/dL immediately prior to the presurgical dose), pdFX efficacy in perioperative management of bleeding was rated as excellent in all six remaining procedures. Table 3 summarizes pdFX doses and numbers of infusions required for each type of surgery. During the surgeries, no subjects received additional pdFX infusions or other FX-containing products, and tranexamic acid was used as an adjunct to pdFX therapy in all but one subject. Two subjects with coronary artery disease routinely took aspirin as thromboprophylaxis during the study, and one subject who underwent triple coronary artery bypass graft received heparin (day of surgery), tinzaparin (day after surgery), and aspirin (from day of surgery until end of study).

Table 3. Clinical efficacy parameters of human pdFX concentrate in factor-deficient patients undergoing surgery [17].

Parameter	Value
Presurgical pdFX (n = 6)
Median pdFX dose (IU/kg)	48.85 (range: 30.88–54.41)
Median IR for pdFX infusion (IU/dL per IU/kg)	2.21 (range: 1.67–2.34)
Median plasma FX:C level (IU/dL)	109 (range: 73–134)
Major surgery (n = 4)^a
Median infusions per procedure	13 (range: 2–15)
Median pdFX dose per infusion (IU/kg)	16.1 (range: 10.1–22.3)
Minor surgery (n = 2)^b
Median infusions per procedure	2.5 (range: 1–4)
Median pdFX dose per infusion (IU/kg)	41.5 (range: 32–51)

FX:C: factor X functional activity; IR: incremental recovery; pdFX: plasma-derived factor X concentrate.

^aMajor surgeries included left total knee replacement, right total knee replacement, triple coronary artery bypass graft, and extraction of six teeth (each procedure, n = 1).

^bMinor surgeries included extraction of one tooth (n = 2).

F10 genotyping was also performed for all Ten01 and Ten03 subjects [35]. In these, 18 subjects (Turkey [n = 6], the United Kingdom [(n = 4], Spain [n = 4], the United States [n = 3], and Germany [n = 1]), a total of 17 mutations were identified (12 missense mutations, 2 deletions, 2 splice-site mutations, and 1 nonsense mutation), including nine novel mutations. Eleven subjects were homozygous for a single F10 mutation and seven had compound heterozygous mutations. Due to the low numbers of each mutation, no conclusions could be drawn regarding the relationship between genotype and clinical symptoms or PK parameters.

Two post hoc analyses of Ten01 have been performed; the first examined the six Turkish subjects [36], who all shared the same homozygous missense mutation in F10 (p.Gly262Asp), and the second examined the 10 female subjects [37]. In each subpopulation, treatment success was comparable to that in the overall population (Turkish, 100%; females, 98%), and pdFX was well tolerated and effective for on-demand treatment [16,36,37].

6. Safety, tolerability, and toxicity

6.1. Preclinical studies

As was the case for preclinical PK studies, because pdFX is an endogenous human protein [14], preclinical safety studies have been limited. In vitro safety pharmacology data (Table 4) indicate that pdFX dose-dependently normalized APTT, PT, and thrombin-generating activity to levels similar to those observed in normal plasma [13,14,29,30]. Data from in vivo safety pharmacology studies in rats or rabbits similarly demonstrated no dose-dependent changes with pdFX in APTT or PT, no thrombotic response, and no significant treatment-related effects on mortality, viability, clinical signs, food consumption, body weight, ophthalmoscopy, urine analysis, or organ weights; repeat doses were generally well tolerated, and the no-observed-effect-level (i.e. the highest concentration at which no effect is observed) was established at 2400 IU/kg [29,30].

Table 4. In vitro safety pharmacology studies of human pdFX concentrate [30].

Study type (detects)	Assay	Result
Global hemostasis (thrombogenic activity)	NAPTT	No evidence of increased thrombogenic activity
	TGA, TEG	No greater reactivity than normal plasma
Specific clotting assay (thrombin)	FCT	All assays within the reference range
Activated FX (endogenous FXa)	FXa assay (SDS-PAGE Western blot; specific clotting factor assay)	Very low levels detected: approximately 0.001% of total FX is in the activated form
General proteolytic activity (endogenous protease activity against substrates)	Generic activity	No greater reactivity than normal plasma

FCT: fibrinogen clotting time; FX: factor X; FXa: activated FX; NAPTT: non-activated partial thromboplastin time; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; pdFX: plasma-derived factor X concentrate; TGA: thrombin generation assay; TEG: thromboelastography.

Adapted from Table 3 in the Coagadex assessment report from the European Medicines Agency Committee for Medicinal Products for Human Use. Available online at: http://www.ema.europa.eu/docs/en_GB/document_‌library/EPAR_-_Public_assessment_report/human/003855/WC500204191.pdf

Elevated sodium, calcium, and phosphorous levels were present in some animals at mid-to-high pdFX doses, but no clinical findings or related biochemical or microscopic findings of the kidneys or bones were found [30]. No immune impairment was observed in rats based on a repeat-dose immunotoxicity study evaluating immune response to sheep erythrocytes [30]. A rabbit model used to evaluate local tolerance demonstrated that pdFX was well tolerated, with reversible local tissue reactions [30]. Preclinical studies evaluating the carcinogenic or mutagenic potential of pdFX have not been conducted [13,14,29]. Although no formal preclinical fertility studies have been performed, no macroscopic or microscopic pathologies in reproductive organs were found in a rat study where pdFX was dosed every 2 days at six times the maximum recommended clinical dose (60 IU/kg for 28 days) [13,14].

An in vitro study found no presence of damage-induced FX neoantigens in pdFX [38]. In vivo studies found pdFX antibodies in nearly all animals tested, but this was not dose dependent and no neutralizing antibodies were present; this effect was therefore believed to be due to the introduction of foreign (human) protein into the animals, rather than an immunotoxic effect of pdFX [30].

6.2. Clinical studies

In the pdFX phase III clinical trials, treatment was well tolerated [16,17]. In study Ten01, the most frequent adverse event (AE) was mild headache, with 14 cases occurring in eight subjects [16]. Of all reported AEs, only 3.4% were judged to be possibly treatment-related; these occurred in two subjects and included one case of predose infusion-site pain in one subject and two cases of fatigue, two cases of infusion-site erythema, and one case of back pain in the other subject. Of the 31 AEs observed in pooled perisurgical safety data from Ten01 and Ten03, none were judged to be treatment-related [17].

In study Ten01, 15 of the 16 subjects in the study had type I FX deficiency (lowest basal of the FX antigen [FX:Ag]: median, 9 U/dL; range, <1–15 U/dL), and one subject had type II FX deficiency (lowest basal FX:Ag: 77 U/dL) [15]. Neither hypersensitivity reactions nor FX inhibitor development were observed with pdFX treatment in Ten01 or Ten03 [16,17], even in 15 patients from study Ten01 with type I FX deficiency. However, because hypersensitivity reactions, including anaphylaxis and formation of neutralizing antibodies (inhibitors), are possible, pdFX-treated patients should be monitored for hypersensitivity reactions and inhibitor development [13,14]. In Ten01, coagulation activation markers (i.e. thrombin–antithrombin complex [TAT], d-dimer, and prothrombin fragments 1 and 2 [F1 + 2]) were regularly assessed, and no thrombogenic effect of pdFX was observed [16]. In both Ten01 and Ten03, no indication of a possible thrombogenic effect of pdFX and no clinical symptoms suggestive of thrombosis were observed in any subject [16,17].

7. Drug–drug interactions

Drug–drug interaction studies have not been performed, but pdFX should be used with caution in patients receiving other FX-containing products [13]. Additionally, direct and indirect FXa inhibitors are likely to counteract the effect of pdFX, and pdFX has been found to reverse delayed PT in vitro caused by the specific FXa inhibitor rivaroxaban [39].

8. Regulatory affairs

pdFX is approved in the United States [13] and Europe [14] for on-demand treatment of bleeding episodes and perioperative management of bleeding in patients with hereditary FX deficiency. In the United States, the indication for perioperative management of bleeding is limited to patients with mild hereditary FX deficiency [13], whereas in Europe, prophylactic use in bleeding episodes is also approved [14] (Box 1). Studies of pdFX for prophylactic use in patients <12 years of age (at recommended doses of 40–50 IU/kg twice weekly) [32] and on a compassionate-use basis (including developing longer-term safety data) [33] are ongoing, and final study data will be available in 2017 (Table 1).

9. Conclusion

pdFX is the first human plasma-derived single-factor concentrate for the treatment of hereditary FX deficiency approved in the United States [13] and Europe [14]. Clinical studies have shown that a pdFX dose of 25 IU/kg is safe and efficacious for on-demand treatment and short-term prophylaxis in patients with moderate-to-severe hereditary FX deficiency [16]. The clinical half-life of pdFX is 29.4 h, indicating a potential for once- or twice-weekly prophylactic administration [15]. Additionally, pdFX administered at higher doses to support pre- and postoperative hemostasis management demonstrated the efficacy and tolerability of pdFX for perioperative use in patients with mild-to-severe hereditary FX deficiency [17].

10. Expert opinion

As the first human plasma-derived single-factor replacement therapy specifically for hereditary FX deficiency, pdFX provides advantages for the treatment of hereditary FX deficiency over other previously used therapies such as PCCs and FFP, which contain multiple coagulation factors, often do not specify FX content and, in many cases, may not achieve adequate hemostatic levels due to risks of volume overload, anaphylaxis, and thrombosis [5,23].

To date, clinical studies of pdFX have provided a dosing regimen for use in bleeding episodes, surgery and prophylaxis [15–17]. While increased use of prophylactic therapy in hereditary FX deficiency is warranted to prevent/suppress bleeding episodes [9,20] and multifactor products have already been used with some success [1,2,4,19,24,40], pdFX has been used effectively as a prophylactic agent [16,17], and is licensed for prophylactic use in Europe [14].

The availability of pdFX will allow physicians to optimize therapy especially with increased ongoing experience. Although pdFX is currently being marketed in the United States and the European Union, the manufacturer is aware of the need to increase access to this product worldwide and sees no reason to expect that pdFX would not be available in more countries in the future. Expert consensus guidelines recommend the use of single-factor concentrates for replacement of deficient coagulation factors wherever possible [11]. Nevertheless, pdFX optimal treatment regimens and durations of therapy for FX replacement therapy have yet to be determined. Further data are needed on the use of pdFX long term and in patients aged ≤12 years, but additional studies are in progress (Table 1) and further information will become available over the coming years.

Declaration of interest

A Shapiro is an advisory board member for Baxter BioScience, Biogen, Novo Nordisk; consultant for Baxter BioScience, Biogen, Kedrion Biopharma, Novo Nordisk, ProMetic Life Sciences; speaker’s bureau participant for Biogen; member of the International Network for Pediatric Hemophilia funded by Bayer Healthcare; member of the Novo Nordisk Hemophilia Foundation funded by Novo Nordisk; contributed to clinical research protocols for Baxter BioScience, Bayer Healthcare, Biogen, CSL-Behring, Daiichi Sankyo, Kedrion Biopharma, Novo Nordisk, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, Selexys; all grant/research funding and consultant fees associated with the above activities are paid to the Indiana Hemophilia & Thrombosis Center. 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.

Writing assistance was utilized in the preparation of this manuscript; it was funded by Bio Products Laboratory Ltd (Elstree, UK) and carried out by Hannah Mace, MSc, and Morgan C. Hill, PhD (QXV Communications, Haddam, CT, USA), who drafted and revised the manuscript based on input from authors, and Paula Stuckart (QXV Communications) who copyedited and styled the manuscript per journal requirements.

Acknowledgments

The author would like to thank Bio Products Laboratory Ltd (Elstree, UK) for its review of the pdFX data included in this manuscript.

Additional information

Funding

Bio Products Laboratory Ltd (Elstree, UK) provided funding for medical writing and editorial support in the development of this manuscript.