BeneFIX: For once-weekly prophylaxis (patients ≥16 years old) and on-demand use​​​​​​​2

Once-Weekly Prophylaxis

Efficacy

Proven bleed protection for patients on prophylaxis

Patients receiving BeneFIX at 100 IU/kg once weekly had a lower median total annualized bleeding rate (ABR) than patients treated on demand3,4

ABR, annualized bleeding rate; IQR, interquartile range.
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In joints (IQR, 0.0-2.9) and soft tissue/muscle (IQR, 0.0-0.0), median ABR with BeneFIX once-weekly prophylaxis was zero3,4

In 13 of 25 patients, FIX trough activity was measured 6 to 8 days after dosing with BeneFIX3:

  • 8 of 13 patients measured >2 IU/dL (min-max, 2.13-10.39 IU/dL)
  • 3 patients had a factor IX concentration (FIX:C) of 0.0 and an ABR on prophylaxis of 0.0 
    • 2 patients also had trough levels of 0.0 and ABRs of 12.5 and 13.3, respectively4

   †For each study visit, the recovery value for 1 individual, different in each case, could not be determined for logistical reasons (lack of collection of predose FIX activity, unscheduled visit, or missing information about the dose administered). Of the 17 FIX:C levels observed in 13 patients approximately 1 week after dosing, 8 were >2 IU/dL (min-max, 2.13-10.39 IU/dL). 

FIX distribution ​​​​​​​

Pharmacokinetics in hemophilia B—there may be more to the story

Preclinical studies suggest that FIX moves into the extravascular space, eventually redistributing into the plasma for elimination5-8

  • Due to its low molecular weight, FIX is thought to migrate out of the plasma and into the interstitial fluid
  • In the extravascular space, FIX appears to bind reversibly to type IV collagen, where it is not measured by pharmacokinetics

** This is an optional area where footnotes can live.

PK, pharmacokinetics.
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Plasma trough levels may not reflect all the BeneFIX activity in the body, as preclinical studies suggest potential distribution into the extravascular space5

  • In an animal model, hemostasis following injury was observed 7 days after an infusion of BeneFIX, despite undetectable FIX in the plasma

Extravascular binding may contribute to the hemostatic potential of BeneFIX5

  • Interpatient variability may apply. Due to the lack of validated assays, the potential contribution of collagen type IV–bound FIX to hemostatic potential in an individual patient cannot be measured at this time
  • Data from animal studies do not indicate clinical efficacy
  • Preclinical data may not necessarily correlate with clinical outcomes

Safety

Once-weekly prophylaxis with BeneFIX is available in the same formulation and tolerability you’ve come to expect2

In a clinical study of 25 PTPs, zero patients developed an inhibitor while taking BeneFIX once weekly

  • No thrombotic events or allergic reactions were observed
  • No patients were withdrawn due to an adverse reaction
    • Common adverse reactions were headache (36%), fever (20%), and cough (8%)

Adverse reactions reported in ≥10% of patients during the prophylaxis treatment period of the study3,‡

Adverse reaction

Number of patients

Inappropriate schedule of drug administration

6 (24%)

Arthralgia

5 (20%)

Toothache

5 (20%)

Upper respiratory tract infection

5 (20%)

Drug dose omission

4 (16%)

Headache

4 (16%)

Fever

4 (16%)

Back pain

3 (12%)

Local swelling

3 (12%)

Medication error

3 (12%)

Pharyngitis

3 (12%)

Underdose

3 (12%)

Wrong dose administered

3 (12%)

​​​​​​​‡Excludes adverse reaction data from the on-demand treatment period.3

Study description:
 A multicenter, prospective, open-label clinical trial of 25 patients (age range: 12-54 years) assessed the efficacy and safety of 12 months of BeneFIX 100 IU/kg once-weekly prophylaxis regimen compared with 6 months of on-demand treatment. When administered at a dose of 100 IU/kg once weekly, the ABR for the prophylaxis period was significantly lower (P<0.0001) than the ABR for the on-demand period (mean ± standard deviation [SD]: 3.6 ± 4.6, median: 2.0, min-max: 0-13.8 versus mean: 32.9 ± 17.4, median: 33.6, min-max: 6.1-69.0, respectively). The primary efficacy end point was the ABR, defined as the number of bleeding events per year and calculated as the number of bleeding events/(days on treatment/365.25).2,3


Eligible patients were males aged 12 to 65 years, with moderately severe to severe hemophilia B (FIX:C ≤2%), ≥12 bleeding episodes in the 12-month period before screening (6 of which must have been joint bleeding events), and ≥100 exposure days to FIX products. Patients were excluded if they had a history of or current FIX inhibitors, received FIX as a prophylaxis regimen within 12 months of screening, underwent major surgery or orthopedic surgery in the previous 3 months or if such surgery was planned during study participation, a prothrombin time >1.5x the upper limit of normal (ULN) or an international normalized ratio >1.5, or a platelet count <100,000 µL.3
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Common (≥5%) adverse reactions were headache (36%), fever (20%), and cough (8%). No subject was withdrawn from the trial due to an adverse reaction. In the trial, no inhibitors were detected and no thrombotic events or anaphylactic reactions were reported.2


References:
  1. Center for Biologics Evaluation and Research, US Food and Drug Administration, US Department of Health and Human Services. CBER Approval Letter, Coagulation Factor IX (Recombinant), Genetics Institute, Inc. February 11, 1997. Accessed May 12, 2021. wayback.archive-it.org/7993/20170723024338/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm057039.htm
  2. ​​​​​​​BeneFIX. Prescribing information. Pfizer Inc.; 2021.
  3. Kavakli K, Smith L, Kuliczkowski K, et al. Once-weekly prophylactic treatment vs. on-demand treatment with nonacog alfa in patients with moderately severe to severe haemophilia B. Haemophilia. 2016;22(3):381-388. doi:10.1111/hae.12878
  4. Data on file. Pfizer Inc., New York, NY.
  5. Feng D, Stafford KA, Broze GJ, Stafford DW. Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost. 2013;11(12):2176-2178. doi:10.1111/jth.12421
  6. Shapiro AD, Korth-Bradley J, Poon M-C. Use of pharmacokinetics in the coagulation factor treatment of patients with haemophilia. Haemophilia. 2005;11(6):571-582. doi.10.1111/j.1365-2516.2005.01149.x
  7. Cooley B, Funkhouser W, Monroe D, et al. Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice. Blood. 2016;128(2):286-292. doi:10.1182/blood-2016-01-696104
  8. Björkman S, Carlsson M, Berntorp E. Pharmacokinetics of factor IX in patients with haemophilia B. Methodological aspects and physiological interpretation. Eur J Clin Pharmacol. 1994;46(4):325-332. doi:10.1007/BF00194400​​​​​​​
  9. Nazeef M, Sheehan JP. New developments in the management of moderate-to-severe hemophilia B. J Blood Med. 2016;7:27-38. doi:10.2147/JBM.S81520

Efficacy & Safety

  • Once-Weekly Prophylaxis
  • On-Demand Bleed Control
  • Surgical Efficacy
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  • BeneFIX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein (CHO).
  • Hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX. Closely monitor patients for signs and symptoms of acute anaphylaxis, particularly during the early phases of initial exposure to the product. Immediately discontinue the administration of the product and initiate appropriate treatment if symptoms occur.
  • Patients may develop hypersensitivity to hamster protein as BeneFIX contains trace amounts.
  • BeneFIX has been associated with the development of thromboembolic complications, including in patients receiving continuous infusion through a central venous catheter. The safety and efficacy of BeneFIX  administration by continuous infusion have not been established.
  • Neutralizing antibodies (inhibitors) have been reported following the administration of BeneFIX. If expected plasma factor IX activity levels are not attained, or if the patient presents with an allergic reaction, or if bleeding is not controlled following an expected dose of BeneFIX, perform an assay that measures factor IX inhibitor concentration.
  • The most common adverse reactions (>5%) from clinical trials were fever, cough, nausea, injection site reaction, injection site pain, headache, dizziness, and rash.

BeneFIX, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated for the treatment of:

  • Adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
    • On-demand treatment and control of bleeding episodes.
    • Perioperative management of bleeding.
  • Patients 16 years of age and older with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
    • Routine prophylaxis to reduce the frequency of bleeding episodes.

Limitation of use:

BeneFIX is not indicated for induction of immune tolerance in patients with hemophilia B.

Please see full Prescribing Information for BeneFIX.

Indication

BeneFIX, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated for the treatment of:

  • Adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
    • On-demand treatment and control of bleeding episodes.
    • Perioperative management of bleeding.
  • Patients 16 years of age and older with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
    • Routine prophylaxis to reduce the frequency of bleeding episodes.

Limitation of use:
BeneFIX is not indicated for induction of immune tolerance in patients with hemophilia B.

Please see full Prescribing Information for BeneFIX.