Abstract
BACKGROUND:
In the United States, rIX-FP, rFIXFc, and rFIX are approved as treatment options for people with hemophilia B (PwHB). Although clinical trials have demonstrated the efficacy and safety of each product, real-world data can help to understand their use and treatment outcomes in the absence of direct head-to-head trials.
OBJECTIVE:
To assess real-world factor IX (FIX) consumption and bleeding outcomes for PwHB receiving rIX-FP, rFIXFc, or rFIX prophylaxis.
METHODS:
Retrospective, deidentified medical record information for PwHB with moderate or severe hemophilia B (FIX activity ≤5%) treated with rIX-FP, rFIXFc, or rFIX prophylaxis for at least 12 months was obtained from Hemophilia Treatment Centers in the United States between 2020 and 2023. FIX consumption was calculated using the most recently prescribed dosing frequency and dosage. Annualized bleeding rate (ABR), annualized spontaneous bleeding rate, and annualized joint bleeding rate were calculated based on the number of bleeding events over the observation period. Generalized linear models adjusting for covariates were used to test the statistical significance of the differences of consumption and ABR among the products.
RESULTS:
Overall, 213 PwHB (53% with severe disease) aged 12 years and older were included for main analysis, with a mean age (range) of 32.7 (12-84) years. PwHB treated with rIX-FP prophylaxis had significantly lower mean FIX consumption compared with those receiving rFIXFc (45.8 vs 65.4 IU/kg/week; P = 0.0003) and rFIX (95.7 IU/kg/week; P < 0.0001). The mean dosing interval was 10.2, 7.3, and 5.2 days for rIX-FP, rFIXFc, and rFIX, respectively. Mean ABR was significantly lower in PwHB receiving rIX-FP compared with the other 2 products (rIX-FP vs rFIXFc: 1.2 vs 2.1; P = 0.0119; rIX-FP vs rFIX: 1.2 vs 2.3; P = 0.004). Mean annualized spontaneous bleeding rate was 0.4, 1.0, and 0.7 for rIX-FP, rFIXFc, and rFIX, respectively. Mean annualized joint bleeding rate was 0.7, 1.1, and 1.2 for rIX-FP, rFIXFc, and rFIX, respectively. The pattern of results for PwHB of all ages (including those aged <12 years, N = 50) were similar to those reported for PwHB aged 12 years and older. In a subgroup of 16 PwHB who switched to rIX-FP from a previous FIX product, mean FIX consumption was significantly reduced after switching to rIX-FP (49.0 vs 94.2 IU/kg/week; P = 0.0004). Mean ABR was also significantly reduced after switching to rIX-FP (3.2 vs 1.7; P = 0.0009).
CONCLUSIONS:
In this retrospective study, rIX-FP prophylaxis was associated with lower FIX consumption and potentially improved protection against bleeds compared with prophylactic treatment with rFIXFc and rFIX.
Plain language summary
This retrospective study collected data on factor consumption and bleeding outcomes in people with hemophilia B receiving prophylaxis with one of 3 commonly prescribed factor IX (FIX) products from real-world clinical practice. Results showed that compared with prophylactic treatment with rFIXFc and rFIX, rIX-FP prophylaxis was associated with reduced FIX consumption and potentially improved protection against bleeds.
Implications for managed care pharmacy
This retrospective study found that people with hemophilia B who received prophylaxis with rIX-FP demonstrated lower FIX consumption compared with rFIXFc and rFIX and may achieve better outcomes. Health systems may take into account these findings in their considerations of treatments for hemophilia B, in order to improve patient health and to manage costs.
Hemophilia B is a rare inherited bleeding disorder caused by a mutation in the F9 gene, leading to deficiency of coagulation factor IX (FIX). 1 People with hemophilia B (PwHB) may experience excessive trauma-related bleeding, as well as spontaneous hemorrhage; disease severity is generally correlated with the clotting FIX level. 1 For people with severe hemophilia B (FIX levels <1%) and some people with moderate disease (FIX levels 1%-5%), the current standard of care for treatment is prophylactic infusions with FIX concentrates. 1 , 2 Standard half-life (SHL) FIX concentrates may be associated with a high number of infusions in order to maintain higher trough FIX levels and therefore place a high treatment burden on PwHB and their caregivers. 1 , 2 Owing to their prolonged half-life, extended half-life (EHL) FIX concentrates can allow PwHB to reduce the frequency of their infusions while maintaining higher FIX levels. 1 , 2
Three products are commonly prescribed in the United States for prophylaxis: an EHL product linking recombinant FIX (rFIX) with albumin (rIX-FP; albutrepenonacog alfa, IDELVION, CSL Behring), an EHL fusion protein in which the Fc fragment of immunoglobulin G is fused to rFIX (rFIXFc; eftrenonacog alfa, ALPROLIX, Sobi), and the SHL FIX concentrate, rFIX (nonacog alfa, BeneFIX, Pfizer). 3 – 11 The efficacy and safety of rIX-FP in previously treated adults/adolescents and children with hemophilia B has been demonstrated in clinical trials. 12 – 15 Clinical trials have also demonstrated the efficacy and safety of rFIXFc and rFIX, 5 – 11 although there have been no direct head-to-head comparisons with rIX-FP. Another product, nonacog beta pegol (N9-GP), was approved for prophylaxis in the United States in August 2022 and was not included, because no PwHB received on-label prophylaxis treatment with it for the duration of data collection of this study, as described in Methods. Real-world data can provide insights into the use and effectiveness of rIX-FP, rFIXFc, and rFIX in clinical practice. 16 A patient medical record review of 145 patients who were treated with rIX-FP for at least 8 weeks, of whom 84 were on prophylaxis and also treated with prior FIX prophylaxis, was conducted in the United States to assess factor consumption and bleeding events in PwHB treated with rIX-FP prophylaxis, compared with prior prophylactic treatment with rFIXFc or rFIX. 17 Annualized bleeding rate (ABR) was reduced with rIX-FP compared with rFIXFc and rFIX. Additionally, median factor consumption was 1.6 and 2.5 times lower with rIX-FP compared with rFIXFc and rFIX, respectively.
More recent real-world data comparing prophylaxis with rIX-FP with other commonly used FIX concentrates in a larger sample size across the United States are needed. This patient medical record analysis aimed to assess real-world factor consumption and bleeding outcomes for people with moderate or severe hemophilia B prescribed prophylaxis with rIX-FP, rFIXFc, or rFIX, in the United States. The design of this study was based on parallel comparisons of the 3 different products, which differed from the switch design of the previous study that compared rIX-FP vs prior products for the same patients.
Methods
A retrospective, anonymized patient medical record review was conducted across hemophilia treatment centers in the United States between January 1, 2020, and January 31, 2023. Following institutional review board evaluation, the study was determined to be exempt from institutional review board oversight under category 4, for which informed consent is not required.
STUDY POPULATION
Male patients with moderate or severe hemophilia B (1%-5% and <1% FIX activity, respectively) aged 12 years or older who had been receiving prophylactic treatment for a minimum of 12 months with rIX-FP, rFIXFc, or rFIX were included in the primary analyses. Supplemental analyses including PwHB of all ages are also examined. The main reason for this age cutoff was because of different dosing in the product labels as a result of clinical trials conducted separately for those aged 12 years and older and those younger than 12 years. Those aged 12 years and older constituted the majority of PwHB in this study. PwHB were excluded if they were positive for FIX inhibitors, had an unknown number of bleeds, or had any known congenital or acquired coagulation disorder other than hemophilia B. For a subanalysis comparing rIX-FP and prior FIX products, the medical records of PwHB who switched to rIX-FP from January 2020 onward were reviewed from January 2019, to ensure that at least 12 months of data associated with their previous treatment were collected.
Measures were taken to minimize center bias and to obtain reliable and generalizable results. Participation by specialized treatment centers across the entirety of the United States (covering the West, South, Northeast, and Midwest regions) was encouraged, and in total, 39 hemophilia treatment centers participated. A data collection protocol was established across all centers to reduce data entry variations and to enable comparability of results. Health care professionals (HCPs) were instructed to select and submit medical records from all eligible PwHB, but medical record selection was made at the discretion of the participating HCPs. The study sponsor was anonymous to the participating HCPs in order to reduce the potential influence on medical record selection. Center distribution was regularly reviewed, and recruitment strategies were refined to encourage participation from hemophilia treatment centers in underrepresented geographic regions, without reference to any specific product, thereby supporting a balanced geographic representation of centers.
STUDY OUTCOMES
The primary outcomes compared were FIX consumption (IU/kg/week) and ABR between PwHB prescribed rIX-FP, rFIXFc, or rFIX for prophylaxis. FIX consumption was calculated based on the most recently prescribed dosing regimen (ie, dose and dosing frequency) during the observation period. ABR was calculated by annualizing the number of total bleeding episodes over the observation period.
The following secondary outcomes were compared among PwHB prescribed rIX-FP, rFIXFc, or rFIX for prophylaxis:
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•
Dosing frequency
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Annualized spontaneous bleeding rate (AsBR) and annualized joint bleeding rate (AjBR); calculated by annualizing the number of spontaneous/joint bleeding episodes over the observation period
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The percentage of PwHB with zero total bleeds, zero spontaneous bleeds, and zero joint bleeds
The exploratory outcomes included the following:
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Comparison of FIX consumption, ABR, AsBR, AjBR, zero total bleeds, zero spontaneous bleeds, and zero joint bleeds, for people with moderate disease and severe disease separately, who were prescribed rIX-FP, rFIXFc, or rFIX prophylaxis, as subgroup analyses
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Switch analysis evaluating FIX consumption, dosing frequency, ABR, AsBR, AjBR, and zero total bleeds, for rIX-FP prophylaxis compared with a minimum of 12 months of previous FIX treatment
STATISTICAL ANALYSES
Generalized linear model (GLM) regressions with covariates were used to test for statistically significant differences in FIX consumption and ABR among the products. When analyzing FIX consumption, the GLM incorporated age, weight, and disease severity as covariates, and the Gaussian family with an identity link function was used. When analyzing ABR, the GLM incorporated age, weight, disease severity, and FIX consumption as covariates, and a negative binomial family was chosen with a log link function. Adjusted P values from the GLMs were obtained to compare the products. A logistic regression model was used to assess the statistical significance in percentages of PwHB with zero total bleeds, zero spontaneous bleeds, and zero joint bleeds among the FIX products.
Wilcoxon signed-rank tests were used for the switch analysis, to assess the statistical significance of differences in mean FIX consumption, ABR, AsBR, and AjBR before and after switching to rIX-FP prophylaxis from prior FIX products. Dosing frequency was assessed with descriptive statistics without formal statistical test. Stata (version 17.0 or later) was used to perform statistical analyses.
Results
STUDY POPULATION
Overall, 253 PwHB were included in the study from 39 centers across the United States, of whom 213 PwHB were aged 12 years or older (Table 1). Characteristics for PwHB of all ages are presented in Supplementary Table 1 (177.7KB, pdf) (available in online article). Of the PwHB aged 12 years and older receiving FIX prophylaxis, 88 were treated with rIX-FP, 70 were treated with rFIXFc, and 55 were treated with rFIX. The proportion of those with severe disease was 53.4% (47/88), 54.3% (38/70), and 50.9% (28/55) for those treated with rIX-FP, rFIXFc, and rFIX, respectively. The mean (SD) observation period was 32 (7.8), 31.4 (8.2), and 29.3 (9.0) months for PwHB treated with rIX-FP, rFIXFc, and rFIX prophylaxis, respectively.
TABLE 1.
Study Population Characteristics for PwHB Aged 12 Years and Older
| FIX product | rIX-FP (N = 88) | rFIXFc (N = 70) | rFIX (N = 55) |
|---|---|---|---|
| Age, mean (SD), years | 30.9 (15.0) | 36.2 (16.2) | 31.3 (17.3) |
| Weight, mean (SD), kg | 77.4 (18.3) | 79.2 (15.5) | 76.4 (18.4) |
| Hemophilia B severity, n (%) | |||
| Severe (FIX <1%) | 47 (53.4) | 38 (54.3) | 28 (50.9) |
| Moderate (FIX 1%-5%) | 41 (46.6) | 32 (45.7) | 27 (49.1) |
| Observation period, mean (SD), months | 32 (7.8) | 31.4 (8.2) | 29.3 (9.0) |
FIX = factor IX; PwHB = people with hemophilia B; rFIX = recombinant FIX; rFIXFc = recombinant FIX Fc fusion protein; rIX-FP = recombinant FIX albumin fusion protein.
FIX CONSUMPTION (PRIMARY OUTCOME) AND DOSING INTERVALS
FIX consumption for PwHB aged 12 years and older is presented in Table 2. Mean (SD) FIX consumption was significantly lower for PwHB receiving rIX-FP (45.8 [22.9] IU/kg/week) compared with rFIXFc (65.4 [31.4] IU/kg/week; P = 0.0003) and rFIX (95.7 [46.2] IU/kg/week; P < 0.0001). In those with severe disease, mean (SD) FIX consumption was significantly lower for those receiving rIX-FP (47.1 [16.5] IU/kg/week) compared with rFIXFc (66.1 [26.9] IU/kg/week; P = 0.0083) and rFIX (109.0 [47.7] IU/kg/week; P < 0.0001). In people with moderate disease, mean (SD) FIX consumption was significantly lower for those receiving rIX-FP (44.3 [28.8] IU/kg/week) vs rFIXFc (64.6 [36.5] IU/kg/week; P = 0.0212) and rFIX (81.9 [41.1] IU/kg/week; P < 0.0001). Results for FIX consumption across PwHB of all ages were similar to those reported for those aged 12 years and older (Supplementary Table 2 (177.7KB, pdf) ).
TABLE 2.
Summary of FIX Consumption for PwHB Aged 12 Years and Older
| FIX product | rIX-FP | rFIXFc | rFIX |
|---|---|---|---|
| PwHB (aged ≥12 years) | |||
| FIX consumption, IU/kg/week | |||
| n | 88 | 70 | 55 |
| Mean (SD) | 45.8 (22.9) | 65.4 (31.4) | 95.7 (46.2) |
| Median (min, max) | 40.3 (6.7, 125.0) | 57.4 (13.6, 200.0) | 100.0 (25.0, 259.3) |
| P value for consumption comparison a | NA | 0.0003 b | <0.0001 b |
| People with severe hemophilia B (aged ≥12 years) | |||
| FIX consumption, IU/kg/week | |||
| n | 47 | 38 | 28 |
| Mean (SD) | 47.1 (16.5) | 66.1 (26.9) | 109.0 (47.7) |
| Median (min, max) | 45.3 (25.0, 86.5) | 61.9 (13.6, 185.4) | 100.0 (46.2, 259.3) |
| P value for consumption comparison a | NA | 0.0083 b | <0.0001 b |
| People with moderate hemophilia B (aged ≥12 years) | |||
| FIX consumption, IU/kg/week | |||
| n | 41 | 32 | 27 |
| Mean (SD) | 44.3 (28.8) | 64.6 (36.5) | 81.9 (41.1) |
| Median (min, max) | 35.7 (6.7, 125.0) | 50.0 (38.0, 200.0) | 84.0 (25.0, 240.0) |
| P value for consumption comparison a | NA | 0.0212 b | <0.0001 b |
The generalized linear model for FIX consumption incorporated age, weight, and hemophilia severity as covariates.
Represents a statistical significance (P < 0.05).
FIX = factor IX; IU = international units; max = maximum; min = minimum; NA = not applicable; PwHB = people with hemophilia B; rFIX = recombinant FIX; rFIXFc = recombinant FIX Fc fusion protein; rIX-FP = recombinant FIX albumin fusion protein.
The mean (SD) dosing interval for PwHB aged 12 years and older was 10.2 (4.6), 7.3 (2.3), and 5.2 (2.1) days for rIX-FP, rFIXFc, and rFIX, respectively (Figure 1A). The percentage of PwHB dosed more frequently than once a week was 9.0%, 14.3%, and 47.2% for those treated with rIX-FP, rFIXFc, and rFIX, respectively. The percentage dosed weekly was 43.2%, 61.4%, and 50.9%, respectively. The percentage dosed at an interval between 9 and 11 days was 8.0%, 21.4%, and 1.8%, respectively. The percentage dosed every 14 days was 33.0%, 2.9%, and 0%, respectively. No PwHB were dosed every 21 days with rFIXFc or rFIX, while 6.8% (6/88) of PwHB receiving rIX-FP were dosed every 21 days.
FIGURE 1.
Mean Dosing Interval by Brand for PwHB Aged 12 Years and Older
(A) All PwHB (aged ≥12 years). (B) People with severe hemophilia B (aged ≥12 years). (C) People with moderate hemophilia B (aged ≥12 years).
PwHB = people with hemophilia B; rFIX = recombinant FIX; rFIXFc = recombinant FIX Fc fusion protein; rIX-FP = recombinant FIX albumin fusion protein.
The trend of mean dosing interval comparing rIX-FP, rFIXFc, and rFIX was similar for people with severe and moderate disease (Figures 1B and 1C). Results for dosing intervals across PwHB of all ages were also similar to those reported for PwHB aged 12 years and older (Supplementary Figure 1 (177.7KB, pdf) ).
ABR (PRIMARY OUTCOME), AsBR, AjBR, AND PERCENTAGES OF PwHB WITH ZERO TOTAL BLEEDS, ZERO SPONTANEOUS BLEEDS, AND ZERO JOINT BLEEDS
Bleeding rates for PwHB aged 12 years and older are presented in Table 3. Mean (SD) ABR was significantly lower for PwHB aged 12 years and older receiving rIX-FP prophylaxis compared with the other 2 products (rIX-FP vs rFIXFc: 1.2 [1.5] vs 2.1 [1.9]; P = 0.0119; rIX-FP vs rFIX: 1.2 [1.5] vs 2.3 [2.8]; P = 0.004). Overall, statistical differences between products were not observed for the percentage of patients achieving an ABR of zero. Of PwHB treated with rIX-FP, 28.4% achieved an ABR of zero, compared with 17.1% treated with rFIXFc (P = 0.2188) and 20.0% treated with rFIX (P = 0.4822). In those with severe disease aged 12 years and older, mean (SD) ABR was not significantly different for those treated with rIX-FP (1.6 [1.6]) compared with rFIXFc (2.3 [1.8]; P = 0.4708) and rFIX (2.4 [3.4]; P = 0.2419). In those with moderate disease, mean (SD) ABR was significantly lower for PwHB receiving rIX-FP (0.8 [1.3]) compared with rFIXFc (1.9 [2.0]; P = 0.0068) and rFIX (2.2 [1.8]; P = 0.0031). Mean (SD) AsBR was significantly lower for PwHB aged 12 years and older receiving rIX-FP prophylaxis (0.4 [0.8]) compared with rFIXFc (1.0 [1.3]; P = 0.0173). There was no significant difference between those receiving rIX-FP and rFIX (0.4 [0.8] vs 0.7 [1.1]; P = 0.0853). Significantly more PwHB treated with rIX-FP achieved an AsBR of zero compared with those receiving rFIXFc (67.7% vs 43.1%; P = 0.0134). There was no significant difference between the percentage of PwHB treated with rIX-FP and rFIX who achieved an AsBR of zero (67.7% vs 54.3%; P = 0.1160). In people with severe disease aged 12 years and older, mean (SD) AsBR was significantly lower for those treated with rIX-FP (0.4 [0.8]) compared with rFIXFc (1.4 [1.5]; P = 0.0263). There was no significant difference between those receiving rIX-FP and rFIX (0.4 [0.8] vs 0.4 [0.8]; P = 0.6553). In people with moderate disease aged 12 years and older, mean (SD) AsBR was not significantly different for PwHB receiving rIX-FP (0.4 [0.9]) compared with rFIXFc (0.6 [1.0]; P = 0.2844) and rFIX (1.1 [1.2]; P = 0.0749).
TABLE 3.
Summary of Bleeding Rates (ABR, AsBR, and AjBR) for All PwHB Aged 12 Years and Older
| FIX product | rIX-FP | rFIXFc | rFIX |
|---|---|---|---|
| All PwHB (aged ≥12 years) | |||
| ABR | |||
| n | 88 | 70 | 55 |
| Mean (SD) | 1.2 (1.5) | 2.1 (1.9) | 2.3 (2.8) |
| Median (min, max) | 0.6 (0.0, 7.8) | 1.3 (0.0, 6.7) | 1.6 (0.0, 17.4) |
| P value for ABR comparison a | NA | 0.0119 b | 0.004 b |
| PwHB with zero ABR, n (%) | 25 (28.4) | 12 (17.1) | 11 (20.0) |
| P value for zero ABR comparison | NA | 0.2188 | 0.4822 |
| AsBR | |||
| n | 62 | 51 | 46 |
| Mean (SD) | 0.4 (0.8) | 1.0 (1.3) | 0.7 (1.1) |
| Median (min, max) | 0.0 (0.0, 3.4) | 0.3 (0.0, 5.5) | 0.0 (0.0, 3.8) |
| P value for AsBR comparison a | NA | 0.0173 b | 0.0853 |
| PwHB with zero AsBR, n (%) | 42 (67.7) | 22 (43.1) | 25 (54.3) |
| P value for zero AsBR comparison | NA | 0.0134 b | 0.1160 |
| AjBR | |||
| n | 63 | 55 | 46 |
| Mean (SD) | 0.7 (0.9) | 1.1 (1.3) | 1.2 (1.3) |
| Median (min, max) | 0.3 (0.0, 4.3) | 0.6 (0.0, 4.8) | 1.0 (0.0, 4.3) |
| P value for AjBR comparison a | NA | 0.0882 | 0.0861 |
| PwHB with zero AjBR, n (%) | 28 (44.4) | 14 (25.5) | 14 (30.4) |
| P value for zero AjBR comparison | NA | 0.1141 | 0.2611 |
| People with severe hemophilia B (aged ≥12 years) | |||
| ABR | |||
| n | 47 | 38 | 28 |
| Mean (SD) | 1.6 (1.6) | 2.3 (1.8) | 2.4 (3.4) |
| Median (min, max) | 1.0 (0.0, 7.8) | 2.1 (0.0, 5.7) | 1.6 (0.0, 17.4) |
| P value for ABR comparison a | NA | 0.4708 | 0.2419 |
| PwHB with zero ABR, n (%) | 5 (10.6) | 4 (10.5) | 5 (17.9) |
| P value for zero ABR comparison | NA | 0.5132 | 0.2721 |
| AsBR | |||
| n | 29 | 25 | 22 |
| Mean (SD) | 0.4 (0.8) | 1.4 (1.5) | 0.4 (0.8) |
| Median (min, max) | 0.0 (0.0, 3.0) | 1.3 (0.0, 5.5) | 0.0 (0.0, 2.9) |
| P value for AsBR comparison a | NA | 0.0263 b | 0.6553 |
| PwHB with zero AsBR, n (%) | 19 (65.5) | 10 (40.0) | 13 (59.1) |
| P value for zero AsBR comparison | NA | 0.0650 | 0.4380 |
| AjBR | |||
| n | 31 | 27 | 22 |
| Mean (SD) | 0.8 (0.8) | 1.3 (1.3) | 1.3 (1.2) |
| Median (min, max) | 0.8 (0.0, 3.1) | 0.7 (0.0, 4.5) | 1.0 (0.0, 4.3) |
| P value for AjBR comparison a | NA | 0.6023 | 0.8543 |
| PwHB with zero AjBR, n (%) | 6 (19.4) | 6 (22.2) | 5 (22.7) |
| P value for zero AjBR comparison | NA | 0.2529 | 0.4731 |
| People with moderate hemophilia B (aged ≥12 years) | |||
| ABR | |||
| n | 41 | 32 | 27 |
| Mean (SD) | 0.8 (1.3) | 1.9 (2.0) | 2.2 (1.8) |
| Median (min, max) | 0.3 (0.0, 5.2) | 0.8 (0.0, 6.7) | 1.9 (0.0, 6.4) |
| P value for ABR comparison a | NA | 0.0068 b | 0.0031 b |
| PwHB with zero ABR, n (%) | 20 (48.8) | 8 (25.0) | 6 (22.2) |
| P value for zero ABR comparison | NA | 0.0774 | 0.1082 |
| AsBR | |||
| n | 33 | 26 | 24 |
| Mean (SD) | 0.4 (0.9) | 0.6 (1.0) | 1.1 (1.2) |
| Median (min, max) | 0.0 (0.0, 3.4) | 0.3 (0.0, 4.0) | 0.3 (0.0, 3.8) |
| P value for AsBR comparison a | NA | 0.2844 | 0.0749 |
| PwHB with zero AsBR, n (%) | 23 (69.7) | 12 (46.2) | 12 (50.0) |
| P value for zero AsBR comparison | NA | 0.0662 | 0.2213 |
| AjBR | |||
| n | 32 | 28 | 24 |
| Mean (SD) | 0.5 (1.1) | 1.0 (1.2) | 1.2 (1.4) |
| Median (min, max) | 0.0 (0.0, 4.3) | 0.4 (0.0, 4.8) | 0.6 (0.0, 4.3) |
| P value for AjBR comparison a | NA | 0.1310 | 0.0507 |
| PwHB with zero AjBR, n (%) | 22 (68.8) | 8 (28.6) | 9 (37.5) |
| P value for zero AjBR comparison | NA | 0.0070 b | 0.0494 b |
The generalized linear model for ABR incorporated age, weight, hemophilia severity, and factor consumption as covariates.
Represents a statistical significance (P < 0.05).
ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; AsBR = annualized spontaneous bleeding rate; FIX = factor IX; max = maximum; min = minimum; NA = not applicable; PwHB = people with hemophilia B; rFIX = recombinant FIX; rFIXFc = recombinant FIX Fc fusion protein; rIX-FP = recombinant FIX albumin fusion protein.
Mean (SD) AjBR for PwHB aged 12 years and older was not significantly different for those treated with rIX-FP (0.7 [0.9]) compared with rFIXFc (1.1 [1.3]; P = 0.0882) and rFIX (1.2 [1.3]; P = 0.0861). There was no significant difference observed between PwHB treated with rIX-FP and rFIXFc or rFIX who achieved an AjBR of zero (44.4% vs 25.5%, P = 0.1141 or 44.4% vs 30.4%, P = 0.2611, respectively). In people with severe disease aged 12 years and older, mean (SD) AjBR was not significantly different for those treated with rIX-FP (0.8 [0.8]) compared with rFIXFc (1.3 [1.3]; P = 0.6023) and rFIX (1.3 [1.2]; P = 0.8543). In people with moderate disease aged 12 years and older, mean (SD) AjBR was not significantly different for PwHB receiving rIX-FP (0.5 [1.1]) compared with rFIXFc (1.0 [1.2]; P = 0.1310) and rFIX (1.2 [1.4]; P = 0.0507).
The pattern of results for bleeding outcomes across PwHB of all ages were similar to those reported for PwHB aged 12 years and older (Supplementary Table 3 (177.7KB, pdf) ).
SWITCH ANALYSIS
Overall, data were collected for 16 PwHB of all ages who switched to rIX-FP prophylaxis from a prior FIX product. In total, 10 PwHB switched from rFIX, 4 switched from rFIXFc, 1 switched from N9-GP (Rebinyn, Novo Nordisk), and 1 switched from nonacog gamma (RIXUBIS, Takeda). Five PwHB had moderate disease and 11 had severe disease. Mean (SD) age at the time of switching to rIX-FP was 26.1 (13.0) years; 2 PwHB were younger than 12 years. The mean (SD) observation period was 25.6 (7.5) months before and 23.4 (7.5) months after the switch.
Mean (SD) FIX consumption was significantly reduced after switching to rIX-FP prophylaxis from a previous product (49.0 [16.2] vs 94.2 [23.7] IU/kg/week; P = 0.0004) (Table 4). After switching to rIX-FP, all 16 PwHB were dosed once weekly or less frequently, compared with 7/16 (43.8%) prior to switching. Overall, 6/16 (37.5%) were dosed at intervals longer than every 10 days after switching, compared with none prior to switching.
TABLE 4.
Consumption, Dosing, and Bleeding Outcomes in PwHB of All Ages Switching to rIX-FP
| Before switch (n = 16) | After switch (n = 16) | P value | |
|---|---|---|---|
| FIX consumption, mean (SD), IU/kg/week | 94.2 (23.7) | 49.0 (16.2) | 0.0004 a |
| PwHB dosed at weekly interval or longer, n (%) | 7 (43.8) | 16 (100.0) | — |
| PwHB dosed at intervals longer than every 10 d, n (%) | 0 (0.0) | 6 (37.5) | — |
| ABR, mean (SD) | 3.2 (2.1) | 1.7 (1.5) | 0.0009 a |
| PwHB with zero bleeds, n (%) | 0 (0.0) | 0 (0.0) | — |
| Before switch (n = 12) | After switch (n = 12) | P value | |
| AsBR, mean (SD) | 0.2 (0.4) | 0.0 (0.0) | 0.0467 a |
| AjBR, mean (SD) | 1.7 (1.3) | 0.8 (0.5) | 0.0253 a |
Represents a statistical significance (P < 0.05).
ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; AsBR = annualized spontaneous bleeding rate; d = day; FIX = factor IX; IU = international units; PwHB = people with hemophilia B; rIX-FP = recombinant FIX albumin fusion protein.
Mean (SD) ABR was significantly reduced from 3.2 (2.1) before switching to 1.7 (1.5) after switching to rIX-FP (P = 0.0009) (Table 4). The data required for calculating AsBR and AjBR were available for 12/16 (75.0%) PwHB who switched to rIX-FP (Table 4). Mean (SD) AsBR was significantly reduced from 0.2 (0.4) before switching to 0.0 (0.0) after switching to rIX-FP (P = 0.0467). Mean (SD) AjBR was significantly reduced from 1.7 (1.3) before switching to 0.8 (0.5) after switching to rIX-FP (P = 0.0253).
Discussion
This real-world study assessed factor consumption and bleeding outcomes of prophylaxis with 3 FIX replacement products, rIX-FP, rFIXFc, and rFIX, in people with moderate or severe hemophilia B in the United States. In this retrospective patient medical record analysis, PwHB receiving prophylaxis with rIX-FP had significantly lower FIX consumption and showed improved bleed control as measured by a statistically significant difference in the overall ABR, when compared with rFIXFc and rFIX in those aged 12 years and older. The same pattern of results was shown in people with moderate disease. In those with severe disease, prophylactic use of rIX-FP also showed significantly lower FIX consumption when compared with rFIXFc and rFIX; ABR was numerically lower with rIX-FP but not statistically significant. Prophylactic use of rIX-FP was also associated with the highest proportion of PwHB experiencing zero total bleeds compared with rFIXFc and rFIX, although no statistical differences were observed. Mean AsBR was significantly lower for patients treated with rIX-FP compared with rFIXFc, but no significant difference was seen when compared with rFIX. Mean AjBR for patients treated with rIX-FP was numerically but not significantly lower than that of patients treated with rFIXFc and rFIX. An increased proportion of PwHB receiving rIX-FP were dosed at intervals longer than once weekly compared with those prescribed rFIXFc and rFIX. In the subanalysis of PwHB (n = 16) who switched from prophylaxis with a prior FIX product to rIX-FP, FIX consumption and ABR were significantly reduced in PwHB of all ages. Of those who switched to rIX-FP and had data available, AsBR and AjBR were also significantly reduced after switching to rIX-FP from a previous FIX product.
Compared with SHL FIX products, the improved pharmacokinetics of EHL FIX products allow for extended dosing intervals, ultimately reducing the treatment burden for PwHB. 1 , 2 In the present study, prophylactic use of rIX-FP in people with severe/moderate hemophilia B aged 12 years and older was associated with decreased FIX consumption and lower bleeding rates, compared with another EHL FIX product and an SHL FIX product, both commonly used in the United States. Mean FIX consumption for all 3 FIX products in this study was in line with the recommended prophylaxis dosing guidelines in the US Food and Drug Administration-approved labels. 18 – 20 This supports the findings of the adult/adolescent phase 3 clinical trial and extension study that demonstrated that the dosing frequency of rIX-FP prophylaxis can be extended to every 14 days (or every 21 days in selected adult PwHB) while maintaining excellent bleed protection. 12 , 13 The extended dosing options with rIX-FP allows PwHB the opportunity to tailor their treatment to suit their specific needs.
These results, which directly compare rIX-FP and other FIX products in 213 participants, also align with a previous patient medical record review in the United States, in which a switch analysis demonstrated prophylactic use of rIX-FP was associated with lower ABR and factor consumption, compared with prior prophylactic treatment with rFIXFc and rFIX. 17 The subset analysis of patients switching to rIX-FP from prior FIX therapy also supported these findings. Real-world studies in clinical practice are important to confirm the results from clinical trials, but with a population that is more similar to the general hemophilia population.
Direct head-to-head comparison data from clinical trials of hemophilia B products are lacking. However, recently, a matching-adjusted indirect comparison of data from the phase 3 clinical trials of rIX-FP (PROLONG-9FP) and rFIXFc (B-LONG) demonstrated that prophylactic treatment with rIX-FP was associated with a significantly lower AsBR and a significantly higher proportion of PwHB experiencing zero bleeds, compared with rFIXFc. 21 As more PwHB switch to EHL FIX products, it is essential that outcomes from further real-world settings, including pediatric and female patients and participants from different countries and regions, are compared with the findings from clinical trials to provide data that are more aligned with the patient population in clinical practice.
LIMITATIONS
The findings of this retrospective patient medical record review may not be an overall representation of the whole hemophilia B population in the United States, owing to potential selection bias that may exist because of center distribution and voluntary participation and a lack of both randomization and blinding. Although the number of PwHB sampled in this study is low, because of the rarity of hemophilia B, we believe this study provides a good representation of the population of PwHB in the United States, which was recorded by the World Federation of Hemophilia as 4,195 in 2023. 22 Another general limitation of patient medical record studies is the risk of incomplete or inaccurate documentation; however, the design of the current study aligns with previously published medical record reviews. 23 – 26 Patients were also not randomized and observers were not blinded. Individual centers, who were blind to the study sponsor, were responsible for the selection of eligible patient medical records, independently from the authors of this study; therefore, there may also be potential selection bias owing to variation in patient management across involved centers. To mitigate this, regionally diverse centers were selected for inclusion and regularly assessed, thus increasing the portrayal of varying treatment regimens. No patterns of systemic product specific bias were observed throughout the study. Although not all participating centers used all 3 products, the majority (21 out of 36) did provide data for more than 1 product. Because of the requirement of at least 12 months of prophylaxis, it was likely that dosing regimens and frequencies were stabilized at the end of the data period. In the subset of cases where complete dosing histories during the study period were collected, only a small number of dosing changes were reported. These changes showed no evidence of brand bias and had minimal impact on the results, regardless of whether they were included in the analysis. There are no prior reports of one product being more likely to have dosing changes compared with any other; therefore, there is limited risk of systemic bias in the factor consumption comparison. Analyzing the impact of confounding variables is limited because of the difficulty in collecting true baseline joint health and bleeding rate data owing to the multiple-year history that patients have with these products, compounded by the often poorly recorded data on physical activity. FIX consumption was also calculated based on the prescribed dosing regimen and therefore may not accurately reflect the actual consumption of FIX by PwHB. Finally, N9-GP (Rebinyn) prophylaxis was not included in this study because of the low numbers of PwHB on this therapy and insufficient sample size that can be collected for a meaningful comparative analysis.
Conclusions
This retrospective patient medical record analysis in the United States demonstrated that rIX-FP prophylaxis was associated with reduced FIX consumption and potentially improved protection against bleeds compared with prophylactic treatment with rFIXFc and rFIX. It also showed that switching to rIX-FP from a prior FIX product is associated with a significant reduction in FIX consumption and ABR.
Disclosures
Dr Escobar reports consultancy for Novo Nordisk, CSL Behring, Genentech/Roche, Sanofi, Takeda, Bayer, Hemabiologics, LFB, Regeneron, and NHF. Drs Yan, Drelich, Zhang, and Kayode are employees of CSL Behring. Dr Yang and Ms Jabati are employees of Adivo Associates. Dr Simpson reports consultancy for Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sanofi.
This research was funded by CSL Behring LLC.
Acknowledgments
This study was conducted by Adivo Associates and funded by CSL Behring LLC. Medical writing support was provided by Meridian HealthComms (part of the BioScript group), Macclesfield, UK in accordance with Good Publication Practice (GPP2022), and was funded by CSL Behring LLC.
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