Safety, Efficacy and Treatment Patterns of rIX‐FP in Previously Untreated Paediatric Haemophilia B Patients: A Retrospective Chart Review in Japan

ABSTRACT

Background

Limited real‐world data exist on recombinant fusion protein‐linking coagulation factor IX (FIX) with albumin (rIX‐FP) in paediatric previously untreated patients (PUPs) with haemophilia B, particularly in infants.

Aims

To evaluate the treatment patterns, safety and efficacy of rIX‐FP in paediatric PUPs in Japan.

Methods

Retrospective chart review of 21 PUPs who initiated rIX‐FP between May 2017 and September 2023, with follow‐up to June 2024.

Results

At first administration, 95% (19/20) of patients were <2 years old, and 84% (16/19) weighed <10 kg. The mean treatment duration was 27 months. Prophylaxis was received by 90% (18/20), with 56% (10/18) on every 2 weeks and 44% (8/18) on a weekly regimen. The proportion of patients with ≥25 exposure days was 100% in the weekly and 90% in every 2 weeks groups. No patients developed inhibitors or discontinued treatment. Among those on prophylaxis, no bleeding events occurred in patients ≥2 years, while 88% (15/17) of those <2 years experienced superficial perioral, or subcutaneous bleeding, with 2/15 requiring treatment. Every 2 weeks regimen had lower FIX trough levels than the weekly regimen (median: 4% vs. 10%) and a higher annualized bleeding rate (ABR: 8.2 vs. 4.9). The most common bleeding type was traumatic (ABR: 4.8), followed by spontaneous (1.6) and undetermined (0.7). All treated bleeds resolved successfully. In vivo recovery (IVR) positively correlated with body weight in patients <10 kg.

Conclusion

This study provides real‐world insights into rIX‐FP use in paediatric PUPs, demonstrating its favourable safety, effective prophylaxis, and lower IVR in infants.

1. Introduction

Haemophilia B is a rare X‐linked bleeding disorder caused by a deficiency or dysfunction of coagulation factor IX (FIX). Its incidence is approximately 1/25,000–30,000 live male births, with haemophilia B accounting for 15.8% of all haemophilia cases [1, 2]. In Japan, as of 31 May, 2023, 6506 haemophilia patients were reported, including 1252 with haemophilia B [3]. These patients experience recurrent spontaneous bleeding in joints, soft tissues, and muscles, leading to musculoskeletal complications, as well as excessive bleeding after trauma or surgery [2, 4]. The standard treatment is prophylactic replacement therapy with coagulation factor products to prevent bleeding events [2].

Recombinant fusion protein linking coagulation FIX with albumin (rIX‐FP; IDELVION) is an extended half‐life FIX replacement product indicated for haemophilia B [5]. Previous studies have demonstrated its favourable safety profile and efficacy in treating bleeds in both adults and paediatric patients [6, 7, 8]. In Japan, rIX‐FP was approved in 2016 for long‐term prophylaxis at a weekly dose of 35–50 IU/kg [9]. Depending on the patient's condition, up to 75 IU/kg every 14 days is acceptable, but it must not exceed 75 IU/kg per 14 days. Well‐controlled adolescents and adults (≥12 years) on 75 IU/kg every 14 days for over 6 months may receive up to 100 IU/kg every 21 days [9]. These regimens are supported by population pharmacokinetics (PK) modelling data [10, 11].

Inhibitor development is a serious adverse reaction in haemophilia patients receiving factor replacement therapy, with previously untreated patients (PUPs) being particularly susceptible [12]. PUPs are at increased risk of developing inhibitors to FIX, which can trigger allergic or anaphylactic reactions and compromise treatment outcomes [12, 13, 14, 15]. Immune tolerance induction is generally less effective in haemophilia B than in haemophilia A [16]. Although the pivotal Phase 3 trial of rIX‐FP reported no inhibitors in paediatric previously treated patients (PTPs) aged <12 years [6], a subsequent PUP sub‐study identified one inhibitor case [17]. The pivotal trial did not include patients aged <2 years. In the PUP sub‐study, the single inhibitor occurred in an 11‐year‐old; no inhibitors were observed in those aged <2 years, but small sample size limits conclusions. Moreover, real‐world data on rIX‐FP use in paediatric PUPs are limited, creating uncertainty regarding its clinical use.

Given the limited evidence supporting rFIX‐FP treatment in infants and paediatric patients, particularly within the PUP population, current management approaches by paediatricians and specialists remain unclear. To address this gap, we conducted a retrospective chart review to evaluate the management of paediatric PUPs treated with rFIX‐FP.

2. Methods

2.1. Study Conduct

This study was conducted in accordance with the Declaration of Helsinki and the “Ethical Guidelines for Medical and Biological Research Involving Human Subjects” in Japan. It was approved by the MINS Research Ethics Committee and registered at UMIN (UMIN000053718). The informed consent form and assent document were also approved. Investigators ensured that patients or their legal representatives received full written information about this observational study. According to the child's capacity, investigators also provided age‐appropriate information using the assent document.

2.2. Study Design and Patients

This multicentre, retrospective, non‐interventional chart review aimed to provide real‐world data on paediatric PUPs with haemophilia B initiating rIX‐FP in Japan. A total of 21 patients were enrolled from 17 sites across Japan (Appendix), all of whom initiated rIX‐FP during the study period. Eligible patients were <12 years old, diagnosed with haemophilia B, and started rIX‐FP between 1 May, 2017, and 30 September, 2023. Eligible patients received rIX‐FP for prophylaxis, on‐demand, or perioperative treatment according to the approved label. They were also required to have either (1) continued therapy for >6 months, or (2) ≥6 months of documented follow‐up (i.e., clinic visits, treatment records, or laboratory results available over at least 6 months after rIX‐FP initiation, even if treatment was discontinued earlier). Of the 21 enrolled patients, one was excluded from all analyses except for safety evaluation due to deviation from the treatment regimen. Therefore, efficacy and other endpoints were evaluated in 20 patients, while safety analyses included all 21 patients. Patients must have had no prior exposure to FIX products, adhered to protocols, and not participated in interventional trials or rIX‐FP Post‐Marketing Surveillance during the study. Clinical data were retrospectively collected from patient medical records, covering the period from rIX‐FP initiation through 31 October, 2024. An exposure day (ED) was defined as any calendar day on which the patient received at least one infusion of rIX‐FP, regardless of the number of infusions administered on that day.

2.3. Study Objectives

Primary endpoints included treatment patterns. Baseline characteristics were summarized as descriptive parameters to provide clinical context for the interpretation of outcomes. Secondary endpoints were safety and efficacy. Safety assessments included inhibitor development and allergic reactions; efficacy included annualized bleeding rate (ABR). All bleeding and response to treatment were evaluated by treating physicians based on clinical judgment.

Data from patients on off‐label rIX‐FP regimens were excluded from efficacy analyses but included in safety assessments to ensure comprehensive safety evaluation.

2.4. Statistical Analysis

Continuous variables were summarized using the mean and standard deviation (SD) or the median and interquartile range (IQR), depending on the data distribution. Categorical variables were presented as counts and percentages. All statistical analyses were descriptive. Analyses were stratified by age group, regimen group, and included all eligible patients.

3. Results

3.1. Patient Characteristics

Of the 21 enrolled patients, one was excluded from all analyses except for safety evaluation due to deviation from the treatment regimen. A total of 20 paediatric patients with haemophilia B who initiated rIX‐FP treatment were included, of whom 19 were <2 years old and 1 was aged 2–11 years (Table 1). The mean (SD) age at treatment initiation was 0.8 (0.8) years, and at diagnosis was 0.5 (0.6) years. All patients were male. Median (IQR) body weight was 7.7 kg (6.8–9.5), and median FIX activity at diagnosis was 1.0% (0.0–1.5). The severity at diagnosis was severe in 50% (10/20), moderate in 35% (7/20), and mild in 15% (3/20) of patients. A family history of haemophilia was present in 65% (13/20), and none had a family history of FIX inhibitors. The <2‐year‐old group showed a wide distribution in FIX activity at diagnosis (mean 2.9.%, SD 8.4), although the median remained low at 0.9%, reflecting the skewed distribution caused by outliers. The most common reason for the initial visit was family history (40%, 8/20), followed by bleeding events (30%, 6/20), prolonged APTT (15%, 3/20) and other reasons.

TABLE 1.

Baseline demographics and patient characteristics.

Characteristics	<2 years (N = 19)	2–11 years (N = 1)	Total (N = 20)
Age at treatment initiation, years
Mean (SD)	0.6 (0.4)	3.7	0.8 (0.8)
Median (IQR)	0.6 (0.4, 0.8)	3.7	0.6 (0.5, 0.9)
Age at diagnosis, years
Mean (SD)	0.4 (0.5)	1.7	0.5 (0.6)
Median (IQR)	0.1 (0.0, 0.8)	1.7	0.2 (0.0, 0.8)
Sex, male, n (%)	19 (100)	1 (100)	20 (100)
Body weight (kg)
Mean (SD)	7.7 (2.3)	15.0	8.1 (2.8)
Median (IQR)	7.7 (6.8, 9.4)	15.0	7.7 (6.8, 9.5)
FIX activity at diagnosis, %
Mean (SD)	2.9 (8.4)	7.0	3.1 (8.3)
Median (IQR)	0.9 (0.0, 1.0)	7.0	1.0 (0.0, 1.5)
Severity a at diagnosis, n (%)
Mild	2 (11)	1 (100)	3 (15)
Moderate	7 (37)	0 (0)	7 (35)
Severe	10 (53)	0 (0)	10 (50)
Family history of haemophilia, n (%)
Yes	12 (63)	1 (100)	13 (65)
No	7 (37)	0 (0)	7 (35)
Family history of FIX inhibitors, n (%)
Yes	0 (0)	0 (0)	0 (0)
No	13 (68)	1 (100)	14 (70)
Unknown	6 (32)	0 (0)	6 (30)
Reason for the initial visit, n (%)
Bleeding event	6 (32)	0 (0)	6 (30)
Family history	8 (42)	0 (0)	8 (40)
Prolonged APTT	3 (16)	0 (0)	3 (15)
Diagnosed at another hospital	1 (5)	0 (0)	1 (5)
Other	2 (11)	1 (100)	3 (15)

Abbreviations: APTT, activated partial thromboplastin time; FIX, factor IX; IQR, interquartile range; SD, standard deviation.

^a Severity: Mild, FIX activity 5% to <40%; Moderate, 1% to <5%; Severe, <1%.

Among the included patients, one notable case (patient No. 5, Figure S1) involved diagnosis during the neonatal period following cardiovascular surgery. The patient was found to have coarctation of the aorta and a ventricular septal defect on Day 2 of life, and subsequently underwent aortic arch reconstruction and ventricular septal defect closure on Day 7. The diagnosis of mild haemophilia B was made in the context of this surgical intervention.

3.2. Treatment Patterns and Dosing

Eighteen of 20 patients (90%) received regular prophylaxis with rIX‐FP (Table 2). Age distributions at diagnosis and treatment start are shown in Figure 1A,B. The median (IQR) treatment duration was 23.9 (17.8–36.9) months, and the median number of exposure days (EDs) was 67.5 (33.5–109.0); 85% (17/20) of patients had ≥25 EDs. Among patients aged <2 years, 13 (68%) had ≥50 EDs. The mean (SD) monthly injection frequency was 2.7 (1.3), corresponding to a mean weekly frequency of 0.63 (0.30). The mean (SD) dose per injection was 67.6 (27.1) IU/kg, which corresponds to a mean weekly dose of approximately 42.4 (17.1) IU/kg/week. Injection frequency varied between 1.4 and 6.1 times/month based on individual patient‐level data (Figure S1), with a median of 2.4 (IQR: 2.2–4.0) times/month (Table 2). The highest number of EDs was 214, observed in a patient with severe haemophilia B who initiated early continuous prophylaxis (patient No. 2, Figure S1). Two patients in the <2‐year group did not receive regular prophylaxis, mostly due to delayed diagnosis. Dose adjustments occurred in 15 patients (75%), most commonly due to weight gain (80%, 12/15). Other reasons included increased activity level (20%, 3/15), treatment interval modification (13%, 2/15), and FIX trough level adjustment (7%, 1/15). Intravenous route was used for all, with no central venous access ports required. The mean IVR (incremental recovery) based on nine evaluable patients was 0.9 (0.4), with a median (IQR) of 1.0 (0.7–1.2), and it correlated positively with body weight (p < 0.001; Figure 2).

TABLE 2.

Summary of treatment and dosing conditions.

Treatment condition	<2 years (N = 19)	2–11 years (N = 1)	Total (N = 20)
Regular prophylaxis, n (%)
Yes	17 (90)	1 (100)	18 (90)
No	2 (11)	0 (0)	2 (10)
Treatment period, month
Mean (SD)	28.3 (12.0)	10.4	27.4 (12.4)
Median (IQR)	24.3 (18.8, 38.1)	10.4	23.9 (17.8, 36.9)
rIX‐FP exposure day, EDs
Mean (SD)	77.8 (52.6)	24.0	75.2 (52.6)
Median (IQR)	71.0 (38.0, 112.0)	24.0	67.5 (33.5, 109.0)
≧25EDs, n (%)	17 (90)	0 (0)	17 (85)
Injection per patient per month
Mean (SD)	2.7 (1.3)	2.3	2.7 (1.3)
Median (IQR)	2.5 (2.2, 4.4)	2.3	2.4 (2.2, 4.0)
Dose, IU/kg
Mean (SD)	67.7 (27.9)	66.4	67.6 (27.1)
Median (IQR)	61.2 (55.4, 69.6)	66.4	63.0 (56.1, 69.0)
IVR, [IU/dL]/[IU/kg], N	9	0	9
Mean (SD)	0.9 (0.4)	—	0.9 (0.4)
Median (IQR)	1.0 (0.7, 1.2)	—	1.0 (0.7, 1.2)
CV port use, n (%)	0 (0)	0 (0)	0 (0)
Changes in dosing conditions, n	15	0	15
Reasons for changes in dosing conditions, n (%)
Weight gain	12 (80)	0 (0)	—
Adjustment based on FIX trough levels	1 (7)	0 (0)	—
Increased bleeding frequency	1 (7)	0 (0)	—
Changes in the treatment interval	2 (13)	0 (0)	—
Inventory of specific vial quantities	1 (7)	0 (0)	—
Increased activity level	3 (20)	0 (0)	—

Abbreviations: CV, central venous; EDs, exposure days; FIX, factor IX; IQR, interquartile range; IVR, in vivo recovery; SD, standard deviation.

FIGURE 1.

Age distribution of patients. (A) Age at diagnosis. (B) Age at treatment initiation.

FIGURE 2.

Correlation between body weight and IVR (in vivo recovery).

3.3. Safety Profile

No patients developed anti‐FIX antibodies or FIX inhibitors. One allergic event was reported but did not require dose modification. The event was a mild, localized rash that resolved spontaneously (patient No. 10, Figure S1). No serious adverse reactions were observed during the study period (Table 3).

TABLE 3.

Adverse reactions of rIX‐FP.

Events	<2 years (N = 19)	2–11 years (N = 2)	Total (N = 21)
Regular prophylaxis, n (%)
Yes	17 (90)	2 (100)	19 (91)
No	2 (11)	0 (0)	2 (10)
Number of events, n
Allergy	1	0	1
Allergy requiring changes in dosing conditions	0	0	0
Anti‐FIX antibody positive	0	0	0

Abbreviation: FIX, factor IX.

3.4. Bleeding Events and Haemostatic Effectiveness

Among the 18 patients receiving prophylaxis (17 aged <2 years and one aged 2–11 years), 15 (83%) experienced at least one bleeding episode (Table 4 summarizes the number and percentage of patients who experienced each bleeding type), most commonly traumatic (75%), followed by spontaneous (35%), undetermined (25%), joint (30%), and surgery‐related (5%). All bleeding episodes occurred in the <2‐year‐old group; the 2–11‐year‐old patient, treated every 2 weeks, experienced no bleeds. Therefore, Table 4 presents data without age stratification.

TABLE 4.

Patient‐level summary of bleeding episodes and haemostatic response to rIX‐FP among paediatric patients (N = 20).

Treatment condition	Total (N = 20)
Patients with ≧1 bleeding episodes, n (%)	15 (75)
Type of bleeding episode, n (%)
Spontaneous	7 (35)
Traumatic	15 (75)
Surgery	1 (5)
Undetermined	5 (25)
Joint	6 (30)
Patients with treated bleeding by type, n (%)	13 (65)
Spontaneous	5 (25)
Traumatic	12 (60)
Surgery	0 (0)
Undetermined	0 (0)
Joint	6 (30)
Treatment during the perioperative period, n (%)	3 (15)

Notes: All bleeding events occurred in patients aged <2 years (N = 19). “Surgery” refers to bleeding events associated with a surgical procedure, whereas “treatment during the perioperative period” indicates prophylactic or post‐operative replacement therapy administered for surgical management.

Abbreviation: SD, standard deviation.

A total of 48 bleeding episodes were recorded in the <2‐year‐old group, of which 44 (92%) required treatment. These were observed in 13 patients (65% of the <2‐year‐old group), including all six patients with joint bleeds. Among treated episodes, 89% (39/44) were managed with a single injection of rIX‐FP and 9% (4/44) with two injections; one traumatic episode required five injections. Thus, 98% (43/44) were controlled with one or two doses. Detailed data on dose/kg and timing of second injections were inconsistently recorded and thus not analysed. The haemostatic success rate was 100% for all treated bleeds and perioperative cases (n = 3).

Perioperative cases included: (1) inguinal hernia repair managed with 36.6 IU/kg pre‐op and 61 IU/kg post‐op; (2) bilateral laparoscopic hernia repair managed with 78.7 IU/kg on two occasions; and (3) non‐operative intussusception reduction managed with 58.8 IU/kg once. All were considered minor surgeries with favourable outcomes. Figure S1 illustrates individual treatment patterns and bleeding episodes, most of which were isolated and occurred during prophylaxis.

3.5. Annualized Bleeding Rates (ABR)

Among the 18 patients receiving prophylaxis, 15 (83%) experienced at least one bleeding episode (Table 5). The median (IQR) total ABR was 5.0 (0.6–10.5), and the treatment‐requiring ABR was 0.5 (0.2–1.2). By bleed type, traumatic bleeds had the highest ABR (mean 4.5, SD 5.4), followed by spontaneous (mean 1.5, SD 3.4), joint (mean 0.3, SD 0.5), and undetermined (mean 0.7, SD 1.7) bleeds. These ABRs by bleed type reflect total episodes regardless of whether treatment was administered. Treatment‐requiring ABRs were low across all categories, including joint bleeds (mean 0.2, SD 0.4), with medians ≤0.7, indicating effective prophylaxis (Figure S2). Median time to first bleed was 70.0 days (IQR 12.0–142.0), and median FIX trough activity was 5.6% (4.0–9.5). When stratified by dosing interval, the median total ABR was lower in the weekly group (3.1 [IQR 0.6–5.2]) than in the every‐2‐weeks group (5.9 [2.9–14.0]). The corresponding treatment‐requiring ABRs were 0.4 [0.2–0.7] and 0.8 [0.1–1.5], respectively. The median FIX trough activity was also higher in the weekly group (10.0% [7.6–11.0]) than in the every‐2‐weeks group (4.0% [0–16.0]), while the proportion of patients with FIX trough ≤1% at any time was 0% versus 30%. These findings support the potential benefit of weekly dosing in maintaining higher FIX levels and reducing bleeding frequency in infants.

TABLE 5.

Annualized bleeding rates among paediatric patients receiving regular prophylaxis with rIX‐FP (N = 18 ^a ).

Treatment condition	Total (N = 18)
Time to first bleeding b , days
Mean (SD)	88.1 (82.5)
Median (IQR)	70.0 (12.0, 142.0)
Total ABR
Mean (SD)	6.8 (7.2)
Median (IQR)	5.0 (0.6, 10.5)
Treatment‐requiring total ABR
Mean (SD)	1.0 (1.2)
Median (IQR)	0.5 (0.0, 1.2)
Type of bleeding episode
Spontaneous ABR
Mean (SD)	1.5 (3.4)
Median (IQR)	0.0 (0.0, 1.6)
Treatment‐requiring spontaneous ABR
Mean (SD)	0.3 (0.7)
Median (min, max)	0.0 (0.0, 0.3)
Traumatic ABR
Mean (SD)	4.5 (5.4)
Median (IQR)	3.7 (0.4, 5.2)
Treatment‐requiring traumatic ABR
Mean (SD)	0.6 (0.9)
Median (IQR)	0.4 (0.0, 0.6)
Undetermined ABR
Mean (SD)	0.7 (1.7)
Median (IQR)	0.0 (0.0, 1.0)
Treatment‐requiring undetermined ABR
Mean (SD)	0.0 (0.0)
Median (IQR)	0.0 (0.0, 0.0)
Joint ABR
Mean (SD)	0.3 (0.5)
Median (IQR)	0.0 (0.0, 0.3)
Treatment‐requiring joint ABR
Mean (SD)	0.2 (0.4)
Median (IQR)	0.0 (0.0, 0.3)

Notes: Data in Table 5 are based on the 17 patients aged <2 years who received prophylaxis. The single patient aged 2–11 years was on every‐2‐weeks prophylaxis and experienced no bleeding events; therefore, this patient is not included in the ABR calculations.

Abbreviations: ABR, annualized bleeding rate; FIX, factor IX; IQR, interquartile range; SD, standard deviation.

^a Among the 18 patients receiving regular prophylaxis, 17 were aged <2 years. The only patient aged 2–11 years experienced no bleeding events and is included only in the FIX trough activity data.

^b (First bleeding date) – (treatment start date).

3.6. Trough Level and Growth

For patient No.18 (Figure S3), treatment began at 96 IU/kg every 2 weeks from birth (2.6 kg). FIX activity remained undetectable, even at 175 IU/kg. Activity rose gradually with growth, exceeding 5% by 6 months (∼6 kg). A positive correlation was observed between IVR and body weight (R ² = 0.8793; Figure 2), suggesting efficient FIX utilization in patients with higher body weight, particularly within the lower weight range (<10 kg).

4. Discussion

The data from this study in Japanese paediatric PUPs confirm the safety and efficacy of rIX‐FP in real‐world settings for both prophylaxis and on‐demand treatment of haemophilia B. To date, this study includes the largest cohort and longest exposure duration to date. Most patients had severe haemophilia B, with a median age of 0.6 years at treatment initiation, and 95% (19/20) weighed <10 kg. Overall, treatment was well tolerated and effective.

With a median of 67.5 EDs and nearly 90% of patients reaching ≥25 EDs, no patients developed FIX inhibitors or discontinued treatment. The highest number of EDs reached was 214, indicating sufficient exposure for inhibitor detection. None had a family history of FIX inhibitors, a known risk factor [2]. In a Phase 3 trial of paediatric PTPs [6], no inhibitors were reported. In contrast, a Phase 3 study of PUPs [17], with a median of 50 EDs and a maximum of 146 EDs, reported one case of inhibitor development in a patient with a large F9 gene deletion, a recognized risk factor [4]. The PedNet study [4], conducted before rIX‐FP became available for clinical use, previously reported a 9.3% incidence of inhibitor development. Although product‐specific and genetic factors may play roles, the absence of inhibitors here—even with extended exposure—suggests a favourable safety profile, though continued investigation is warranted.

The median age at diagnosis was approximately 1 month, with family history and bleeding episodes being the most common reasons for diagnosis in early infancy. Notably, over half of the patients had severe haemophilia B, a higher proportion than the 30%–40% typically reported [4]. By contrast, a Phase 3 study of PUPs [17] reported 91.7% mild cases. As inhibitors occur primarily in severe cases, the predominance of such patients in our cohort supports its relevance for long‐term safety evaluation. Treatment initiation was delayed by ∼5 months, likely due to venous access challenges in infants and institutional or caregiver considerations. Notably, no patient required central venous access. Venous access remains difficult in young children, especially with standard half‐life FIX products requiring two to three infusions per week [2]. Regular prophylaxis was initiated in 90% of patients, aligning with guideline recommendations for early initiation [2]. Nonetheless, bleeding still occurred in those <2 years, with total ABR higher than in adults [8], and ∼80% of episodes were trauma‐related. Subcutaneous bleeding was most common, likely reflecting age‐specific mobility. These findings offer valuable insights into bleeding patterns in this underrepresented age group.

Only 14% of bleeding episodes required rIX‐FP treatment. Moreover, 89% were controlled with one dose and 98% with two doses, indicating a rapid and effective haemostatic response. This is consistent with prior Phase 3 studies in adult and paediatric populations [6, 7, 8]. In patients <2 years old, median baseline FIX activity was <1% (severe), but improved to 6.6% with treatment—reaching moderate levels. This supports the real‐world effectiveness of rIX‐FP.

Most patients started with the every 2 weeks regimen, anticipating benefits from rIX‐FP's extended half‐life and convenience. According to the package insert [9], switching to every 2 weeks dosing is generally considered after stabilization with weekly dosing. However, many patients in this study began with every 2 weeks dosing and continued with it. Few patients adjusted their regimen based on trough levels, bleeding frequency, or activity level. Safety outcomes were similar between regimens, but median FIX trough levels were lower in the every 2 weeks group (4.0% vs. 10.0%), with three patients showing troughs ≤1%. Total ABR was also higher in the every 2 weeks group (median 5.9 vs. 3.1). Phase 3 studies in older patients found no efficacy differences between regimens [8], but since this study included mostly infants, weekly dosing may offer better protection in this population.

The PK profile of rIX‐FP differs between infants, children and adults [10, 11]. In this study, the IVR was 0.9—lower than the 1.23–1.38 range reported in prior Phase 3 studies [6, 7, 8], especially in those <10 kg. IVR positively correlated with body weight, suggesting faster clearance in younger, smaller patients. rIX‐FP, an albumin fusion protein, prolongs half‐life through the FcRn‐mediated metabolic pathway, essential for neonatal immune protection [18, 19]. However, FcRn expression may differ in infants, contributing to PK variability [19]. In the every 2 weeks group, one case started rIX‐FP on Day 14 of life with a FIX trough <1%, which gradually improved but remained <5% until about 6 months of age and 6 kg. Although extended intervals (1–3 weeks) are feasible in older patients [10, 11], a weekly regimen appears necessary to maintain therapeutic FIX levels in infants <10 kg.

Although no serious bleeds, including intracranial haemorrhage, occurred in this study, such events remain among the most severe complications in all age groups. In particular, intracranial haemorrhage in infants can result in significant long‐term morbidity and functional impairment [20]. Therefore, despite the favourable safety outcomes observed in our cohort, special attention should be given to maintaining adequate FIX levels in this vulnerable population. These considerations support the early initiation of weekly prophylaxis with rIX‐FP in infants, particularly those under 10 kg, to minimize the risk of potentially serious bleeding complications.

Several limitations should be considered in this study. Efficacy assessments were based on physician judgment, and the frequency of blood sampling varied, reflecting real‐world practice. This lack of standardization introduces potential variability. Although this is the largest and longest real‐world study of rIX‐FP in paediatric PUPs to date, sample size remains limited for definitive conclusions. However, all patients continued rIX‐FP treatment, enabling future accumulation of long‐term data.

In conclusion, this study provides robust real‐world evidence for the safety and efficacy of rIX‐FP in paediatric PUPs with haemophilia B. Although IVR variation was observed in patients <10 kg, the findings support rIX‐FP's use in this vulnerable population. These results enhance understanding of its role in infants and offer practical guidance for clinical decision‐making.

Author Contributions

K.N. was principal investigator for the study. C.N. supervised the study and will present the results of the study at the congress of the 67th annual meeting of the Japanese Society of Pediatric Hematology/Oncology. K.N., C.N., M.Y and N.T. contributed to the interpretation of results and preparation and review of the manuscripts. N.T. was responsible for the design of the study protocol and data analysis and contributed to writing the manuscript.

Funding

This research was supported by CSL Behring KK.

Ethics Statement

This study was conducted in accordance with the Declaration of Helsinki and the “Ethical Guidelines for Medical and Biological Research Involving Human Subjects” in Japan. It was approved by the MINS Research Ethics Committee and registered at UMIN (UMIN000053718). The informed consent form and assent document were also approved. Investigators ensured that patients or their legal representatives received full written information about this observational study. According to the child's capacity, investigators also provided age‐appropriate information using the assent document.

Conflicts of Interest

K.N. received the grant for basic research, and honoraria for speaking and consulting from CSL Behring K.K. and also received grants and personal fees (honoraria) from Chugai Pharmaceutical Co., Ltd., Sysmex Co., SEKISUI MEDICAL, Takeda Pharmaceutical Co., Sanofi S.A., KM Biologics Co., Novo Nordisk A/S, Bayer AG, Fujimoto Seiyaku, and Pfizer Inc. C.N. received honoraria for speaking and consulting from CSL Behring K.K. M.Y and N.T. are employees of CSL Behring K.K.

Supporting information

Supporting File 1: hae70161‐sup‐0001‐SuppMat.docx.

Supporting File2: hae70161‐sup‐0002‐FigureS1.tif.

Supporting File3: hae70161‐sup‐0003‐FigureS2.tif.

Supporting File4: hae70161‐sup‐0003‐FigureS2.tif.

Investigators contributing to patient data collection

(Listed in alphabetical order by institution)

• Beppu Medical Center, Department of Pediatrics – Hiroshi Koga

• Chiba University Hospital, Department of Pediatrics – Moeko Hino

• Gifu Prefectural General Medical Center, Department of Pediatrics – Kunihiro Matsunami

• Gunma Children's Medical Center, Department of Hematology/Oncology – Hirohide Kawasaki

• Hiroshima City Hiroshima Citizens Hospital, Department of Pediatrics – Shiho Nishimura

• Hokkaido Medical Center for Child Health and Rehabilitation, Department of Pediatric Hematology Oncology – Keita Igarashi

• Iwate Prefectural Kuji Hospital, Department of Pediatrics – Masahiro Endo

• Japanese Red Cross Narita Hospital, Department of Pediatrics – Hideaki Ueki

• Juntendo University Urayasu Hospital, Department of Pediatrics – Ken Takahashi

• Kanazawa University Hospital, Department of Pediatrics – Toshihiro Suzuki

• Kyorin University Hospital, Department of Pediatrics – Noritaka Miyazawa

• Nara Medical University, Department of Pediatrics – Keiji Nogami

• National Hospital Organization Hamada Medical Center, Department of Pediatrics – Chinatsu Ishimoto

• Okinawa Prefectural Nanbu Medical Center & Children's Medical Center, Department of Pediatric Hematology and Oncology – Takeshi Yagi

• Shiga University of Medical Science Hospital, Department of Pediatrics – Takashi Taga

• University of Fukui Hospital, Department of Pediatrics – Koji Suzuki

• Yamanashi Kosei Hospital, Department of Pediatrics – Kinuko Saito

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.