"The U.S. Food and Drug Administration today approved Coagadex, Coagulation Factor X (Human), for hereditary Factor X (10) deficiency. Until today’s orphan drug approval, no specific coagulation factor replacement therapy was available for p"...
Mechanism Of Action
ALPROLIX™ is a fully recombinant, fusion protein that temporarily replaces the missing coagulation Factor IX needed for effective hemostasis. ALPROLIX™ contains the Fc region of human IgG1, which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation, and prolonging their plasma half-life.
Hemophilia B is a bleeding disorder characterized by a deficiency of functional coagulation Factor IX (FIX), which leads to a prolonged clotting time in the activated partial thromboplastin time (aPTT) assay, an established in vitro test for the biological activity of Factor IX. Treatment with ALPROLIX™ shortens the aPTT over the effective dosing period.
The pharmacokinetics (PK) of ALPROLIX™ (rFIXFc) were evaluated in 22 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters (Table 4) were based on plasma FIX activity measured by the one-stage clotting assay. Blood samples for PK analysis were collected prior to dosing and at 11 time points up to 240 hours (10 days) after dosing. The PK data demonstrate that ALPROLIX™ has a prolonged circulating half-life. 12
Table 4: Pharmacokinetic Parameters (Arithmetic Mean,
|PK Parameters||rFIXFc (50 IU/kg)
(N = 22)
|Cmax (IU/dL)||46.04 (68.3%)|
|AUCinf (h*IU/dL)||1619.1 (26.1%)|
|CL (mL/kg/h)||3.304 (28.4%)|
|Vss (mL/kg)||327.0 (28.2%)|
|Terminal T½ (h)||86.52 (37.2%)|
|MRT (h)||101.96 (29.7%)|
|IR (IU/dL per IU/kg)||1.0154 (58.7%)|
|Time to 1% FIX activity (d)||11.489 (23.8%)|
|Abbreviations: IR = incremental recovery; AUCinf = area under the FIX activity time curve; T½ = elimination half-life; MRT = mean residence time; CL = bodyweight adjusted clearance; Vss = bodyweight adjusted volume of distribution at steady-state, Time to 1% FIX activity = estimated time in days after dose when FIX activity has declined to approximately 1 IU/dL above baseline|
The ALPROLIX™ PK profile was stable over repeated dosing as shown by comparable PK parameters at Week 26.
The PK parameters following a 100 IU/kg dose of ALPROLIX™ were evaluated in a subset of 27 subjects. For this subset, the mean drug clearance (CL) was 2.65 (21.7%) mL/kg/h, the maximum activity (Cmax) was 99.89 IU/dL (20.1%) and the time to 1% FIX activity was 15.8 days (21.3%).
Pediatric and Adolescent Pharmacokinetics
Pharmacokinetic (PK) parameters of ALPROLIX™ (rFIXFc) were determined for adolescents (12 to 17 years of age) and children (2 to 11 years of age) in open-label, multi-center studies of previously treated patients [see Use in Specific Populations].
Pharmacokinetic parameters were evaluated following a 10 minute intravenous infusion in 11 evaluable adolescents who received a single dose of ALPROLIX™. PK samples were collected prior to dosing and at multiple time points up to 336 hours (14 days) after dosing. In a separate study, PK parameters were evaluated following a 10 minute intravenous infusion in 18 evaluable children (2 to 11 years of age) who received a single dose of ALPROLIX™. PK samples were collected prior to dosing and at multiple time points up to 168 hours (7 days) after dosing. PK parameters for ALPROLIX™ were estimated based on the plasma FIX activity over time profile.
Table 5 presents the PK parameters calculated from the pediatric data of 29 subjects 2 to 17 years of age. Compared to adults, incremental recovery appeared to be lower and bodyweight- adjusted clearance appeared to be higher in children under 12 years of age. This may result in a need for per kg bodyweight dose adjustments in children under 12 years of age. [see Use In Specific Populations]
Table 5: Comparison of Pharmacokinetic Parameters of
rFIXFc by Age Category
|PK parameters1||2 to 5 years
(N = 5)
|6 to 11 years
(N = 13)
|12 to 17 years
(N = 11)
|IR (IU/dL per IU/kg)||0.5980 (15.7%)||0.7422 (29.2%)||0.8929 (36.4%)|
|AUC/Dose (IU•h/dL per IU/kg)||23.18 (15.9%)||29.38 (26.6%)||30.23 (22.2%)|
|T½ (h)||66.40 (32.1%)||72.23 (23.1%)||83.59 (19.1%)|
|MRT (h)||80.52 (22.3%)||84.06 (18.6%)||95.13 (19.4%)|
|CL (mL/h/kg)||4.406 (16.8%)||3.613 (25.1%)||3.483 (25.6%)|
|Vss (mL/kg)||349.0 (19.2%)||303.0 (28.5%)||326.0 (24.9%)|
|1PK parameters are presented in arithmetic
Abbreviations: IR = incremental recovery; AUC = area under the FIX activity time curve; T ½= elimination half-life; MRT = mean residence time; CL = bodyweight adjusted clearance; Vss = bodyweight adjusted volume of distribution at steady-state
The safety and efficacy of ALPROLIX™ was evaluated in a multi-center, prospective, open-label clinical trial that compared each of two prophylactic treatment regimens (fixed weekly and individualized interval) to episodic (on-demand) treatment; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management of subjects undergoing major surgical procedures. A total of 123 previously treated patients (PTPs) with severe hemophilia B ( ≤ 2% endogenous FIX activity), ages 12-71, were followed for up to 77 weeks.
Sixty three subjects in the fixed weekly interval arm received ALPROLIX™ for routine prophylaxis starting at an initial dose of 50 IU/kg. The dose was adjusted to maintain FIX trough level between 1% and 3% above baseline or higher, as clinically indicated to prevent bleeding. Fifty subjects required at least one dose adjustment and the median number of dose adjustments was one. The overall median dose on study was 45.2 IU/kg (interquartile range: 38.1, 53.7). The median weekly dose during the last 6 months on study in 58 subjects who were on study for at least 9 months was 40.7 IU/kg (interquartile range: 32.3, 54.1).
Twenty nine subjects in the individualized interval arm received ALPROLIX™ for routine prophylaxis at a dose of 100 IU/kg every 10 days, with the interval adjusted to maintain FIX trough level between 1% and 3% above baseline or higher, as clinically indicated to prevent bleeding. The overall median interval on study was 12.5 days (interquartile range: 10.4, 13.4). The median interval during the last 6 months in 26 subjects who were on study for at least 9 months was 13.8 days (interquartile range: 10.5, 14.0). 14
Twenty seven subjects received ALPROLIX™ as needed for the treatment of bleeding episodes in the episodic (on-demand) treatment arm.
Twelve subjects received ALPROLIX™ for perioperative management in 14 major surgical procedures. Major surgery was defined as any surgical procedures with or without general anesthesia in which a major body cavity was penetrated and exposed, or a substantial impairment of physical or physiological functions was produced. Four subjects in this arm did not participate in the other arms.
Control and Prevention of Bleeding Episodes
A total of 636 bleeding events were observed by 114 subjects in the fixed weekly interval prophylaxis, individualized interval prophylaxis, and the episodic (on-demand) arms. The median total dose to treat a bleeding episode was 46.99 IU/kg (interquartile range: 33.33, 62.50). Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. Efficacy in control of bleeding episodes is summarized in Table 6.
Table 6: Efficacy in Control of Bleeding
|New Bleeding Episodes||(n=636)|
|Number of injections to treat bleeding episodes|
|1 injection||575 (90.4%)|
|2 injections||44 (6.9%)|
|3 injections||17 (2.7%)|
|Response* to first injection||(n=613)|
|Excellent or good||513 (83.7%)|
|No response||10 (1.6%)|
|*Excellent: abrupt pain relief and/or improvement in signs of bleeding; Good: definite pain relief and/or improvement in signs of bleeding but possibly requiring another injection in 1-2 days; Moderate: probable or slight beneficial effect and requiring more than one injection; No response: no improvement, or worsening. Response evaluated at approximately 8 hours after treatment.|
Using a negative binomial model, a reduction in annualized bleeding rate (ABR) of 83% (76-89%) for subjects in the fixed weekly interval arm and a reduction of 87% (80-92%) for subjects in the individualized interval arm compared to the episodic (on-demand) treatment arm was observed.
The median duration of treatment on study was 51.4 weeks (range < 1-77). A comparison of the ABRs in subjects evaluable for efficacy is summarized in Table 7.
Table 7: Median Annualized Bleeding Rate (ABR) by
|Bleeding Episode Etiology||Prophylaxis Fixed Weekly Interval
|Prophylaxis Individualized Interval
|Episodic (On Demand)
|Overall ABR (IQR)*||2.95
|Spontaneous ABR (IQR)*||1.04
|* IQR=interquartile range
Five subjects (2 in prophylaxis fixed weekly interval arm, 3 in prophylaxis individualized interval arm) did not have sufficient data to be included in the efficacy analysis.
Fourteen major surgical procedures were performed in 12 subjects, including 5 knee replacements, abdominal surgery and a complex dental procedure. Perioperative Factor IX replacement with ALPROLIX™ was by bolus infusion only. The safety of continuous infusion was not evaluated. Hemostasis was assessed by the investigator at 24 hours after surgery using a 4-point scale of excellent, good, fair, and none. The hemostatic response was rated as excellent (n=13) or good (n=1) in 100% of major surgeries. There were an additional 15 minor surgical procedures in 13 subjects. There was no clinical evidence of thrombotic complications in any of the subjects.
Last reviewed on RxList: 4/10/2014
This monograph has been modified to include the generic and brand name in many instances.
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