For use in adults and children with hemophilia B for on demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes. Not for immune tolerance induction.
aA single 40 IU/kg dose should be enough for minor and moderate bleeds. Major bleeds can be increased to 80 IU/kg. Additional doses of 40 IU/kg may be recommended.3
bBased on PK modeling to World Federation of Hemophilia (WFH) recommended FIX levels needed to treat bleeds.
Fewer doses for surgery and severe bleeds1,2
Based on pharmacokinetic (PK) modeling to WFH-recommended FIX levels needed to treat bleeds.
See study designs
Collins et al (2012) and Simpson et al (2019)
Rebinyn®1
rFIX1
pdFIX1
rFIXFc2
Estimated total infusions
for severe bleeds
Rebinyn®1
80 IU/kg total
rFIX1
350 IU/kg total
pdFIX1
310 IU/kg total
rFIXFc2
230 IU/kg total
Estimated total infusions
for surgery
Rebinyn®1
160 IU/kg total
rFIX1
790 IU/kg total
pdFIX1
750 IU/kg total
rFIXFc2
480 IU/kg total
WFH=World Federation of Hemophilia; FIX=Factor IX; rFIX=Recombinant Factor IX; pdFIX=Plasma-derived Factor IX; rFIXFc=Recombinant Factor IX-Fc fusion protein.
Rebinyn® offers effective bleed control across age groups
98% of bleeds treated with 1-2 infusions in adults and adolescents in paradigm 2 clinical trial3,6,c
N=143 bleeding episodes
95% of bleeds were rated as successful (defined as excellent or good) in adults and adolescents in paradigm 2 clinical trial3,6,d
N=142 bleeding episodes
93% of bleeds were rated as successful (defined as excellent or good) in children in paradigm 5 clinical trial5,e
N=42 bleeding episodes
cResults shown are from the on-demand arm of the adolescent/adult trial paradigm 2, in which 15 previously treated adolescent/adult subjects were treated for on-demand bleeds. In 14 subjects, there were a total of 143 bleeding episodes. In 1 subject, no bleeding episode data were recorded.
dResults shown are based on a bleed assessment by either the patient (for home treatment) or the study investigator (for treatment under medical supervision). Bleeds were assessed using a 4-point scale of excellent, good, moderate, or poor.
eThe 42 bleeding episodes occurred in 15 patients receiving 40 IU/kg of Rebinyn® once weekly for prophylaxis.5
Rebinyn® could be right for Karla.
With high factor activity that lasts longer than Alprolix®7,f and 4-minute infusions,3 Rebinyn® could fit Karla’s busy lifestyle.
For illustrative purposes.
fBased upon a phase 1 study (paradigm 7) of 15 patients administered a single dose of Rebinyn® 50 IU/kg compared with a single dose of Alprolix® 50 IU/kg. See study design.
Study designs
Collins et al (2012)
Pharmacokinetic modeling for Rebinyn® dose setting
Patients: 15 previously treated male patients aged 21 to 55 years with hemophilia B. Patients had FIX activity ≤2 IU/dL and at least 150 exposure days to any FIX product.8
Study design: Data from the above patients, who participated in the first human-dose (FHD) trial for Rebinyn® (Negrier 2011), were used to generate population pharmacokinetic models for Rebinyn® (n=15), pdFIX (n=8), and rFIX (n=7). The model was validated by simulating data from the FHD trial 1000 times and comparing the model’s output to the observed data from the trial.1,8
Primary endpoint: To simulate different dose levels and dosing frequencies for Rebinyn® and inform the design of phase 3 pivotal and surgical trials investigating Rebinyn® dosing regimens.1
Simpson et al (2019)
Pharmacokinetic modeling of on-demand and surgical use of Rebinyn® and rFIXc
Patients: 15 previously treated male patients aged 18 to 70 years with hemophilia B who had participated in the paradigm 7 clinical trial. Patients had FIX activity ≤2 IU/dL and at least 150 exposure days to any FIX product. During paradigm 7, patients received single 50 IU/kg doses of Rebinyn® and rFIXc at least 21 days apart, with blood samples collected at 14 time-points across 10 days following each dose.7
Study design: Population pharmacokinetic models were built using data from paradigm 7 and validated against data from paradigm 2 (n=59). Model selection was guided by visual inspection of goodness-of-fit plots, plausibility of parameter estimates, and changes in –2 Log Likelihood. A P-value of 0.001 was used in model extension/reduction criteria throughout the analysis.2
Primary endpoint: Simulate plasma FIX activity following dosing with Rebinyn® and rFIXc for surgery and on-demand treatment of bleeds.2
Collins et al (2014)6
paradigm 2: pivotal phase 3 trial in adults and adolescents
Patients: 74 male patients aged 13 to 70 years with hemophilia B. Patients had FIX activity ≤2 IU/dL, no history of inhibitors to FIX, and at least 150 exposure days to any FIX product.
Study design: Patients were selected for prophylaxis or on-demand treatment at screening. On-demand patients participated in the trial for 28 weeks and received a single dose of 40 IU/kg for bleeding episodes (80 IU/kg for severe bleeding episodes). Prophylaxis patients participated for 52 weeks. Prophylaxis patients were randomly divided into groups of 10 IU/kg once weekly and 40 IU/kg once weekly. Patients were blinded to the prophylaxis dose. The investigator was blinded but could become unblinded if it became necessary to measure a patient’s FIX activity. A pharmacokinetic assessment of the two prophylactic doses was conducted using a subset of these patients. Pharmacokinetic assessments were based on a 1-stage clotting assay and performed at trial initiation (single dose assessments) and after 12 to 44 weeks of prophylaxis (steady state assessments) with both trial doses. The assessments included 7 sampling points up to 168 hours post injection.
Primary endpoint: Safety of Rebinyn®, measured by factors including development of FIX inhibitors (per Nijmegan modified Bethesda assay), adverse events, noninhibitory binding antibodies against Rebinyn®, and antibodies against host cell proteins.
Secondary endpoints: Efficacy of Rebinyn® for bleed prophylaxis and when treating spontaneous or traumatic bleeding episodes. Assessment included number of doses, amount of product used, duration of bleed, and annual bleed rate.
Carcao et al (2016)5
paradigm 5: phase 3 clinical trial in children
Patients: 25 previously treated children with severe or moderately severe hemophilia B. Children were ≤12 years old, had an FIX activity level of ≤2%, had a history of ≥ 50 exposure days to other FIX products, and weighed ≥10 kg.
Study design: International, multicenter, open-label, non-controlled, single-arm trial designed following EMA guidelines. Patients were stratified into two age groups: 0–6 years and 7–12 years. The trial consisted of a main phase of 52 weeks, and an extension phase. All patients received a fixed dose of 40 IU/kg of Rebinyn® intravenously once weekly for prophylaxis. A pharmacokinetic (PK) assessment was conducted after the first dose of Rebinyn®, with the last PK sample collected 1 week after that dose and just prior to administration of the second dose. Breakthrough bleeds were treated with a single dose of 40 IU/kg of Rebinyn® (mild-to-moderate bleeds) or 80 IU/kg of Rebinyn® (severe bleeds).
Primary endpoint: Immunogenicity of Rebinyn® as measured by the occurrence of FIX inhibitors (≥0.6 BU) over at least 50 exposure days.
Secondary endpoint: Efficacy of Rebinyn® in long-term prophylaxis as assessed by the estimated number of bleeds per year, success in treating breakthrough bleeds, and safety other than immunogenicity. FIX activity was also a secondary endpoint, measured after the first single-dose exposure and again at steady state.
Ettinghausen et al (2019)7
paradigm 7: open-label crossover trial comparing Rebinyn® and recombinant Factor IX-Fc fusion protein (rFIXFc)
Patients: 15 previously treated male patients aged 18 to 70 years with hemophilia B. Patients had FIX activity ≤2 IU/dL and at least 150 exposure days to any FIX product.
Study design: Patients were randomly assigned a single 50 IU/kg dose of either Rebinyn® or rFIXFc, followed by a 50 IU/kg dose of the other product at least 21 days later. Pharmacokinetic (PK) assessment was performed on blood samples drawn over 10 days postdose for each product, using both 1-stage and chromogenic assays.
Primary endpoint: Area under the FIX activity-time curve for each product.
Secondary endpoints: PK endpoints including maximum FIX activity dose-normalized to 50 IU/kg, terminal half-life, and incremental recovery at 30 minutes.
Powerful bleed protection
Studies show Rebinyn® prophylaxis helps prevent spontaneous and traumatic bleeds.3
Simple prophylaxis dosing
Convenient, once-weekly dosing for all patients.
Important Safety Information for Rebinyn®
Contraindications
- Rebinyn® is contraindicated in patients with a known hypersensitivity to Rebinyn® or its components, including hamster proteins.
Warnings and Precautions
- Hypersensitivity Reactions: Allergic-type hypersensitivity reactions, including anaphylaxis, have occurred with Rebinyn®. Signs may include angioedema, chest tightness, difficulty breathing, wheezing, urticaria, and itching. Discontinue Rebinyn® if allergic- or anaphylactic-type reactions occur and initiate appropriate treatment.
- Inhibitors: The formation of inhibitors (neutralizing antibodies) to Factor IX has occurred following Rebinyn®. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled as expected with the administered dose, perform an assay that measures Factor IX inhibitor concentration. Monitor all patients using clinical observations and laboratory tests for the development of inhibitors. Factor IX activity assay results may vary with the type of activated partial thromboplastin time reagent used.
- Thrombotic Events: The use of Factor IX-containing products has been associated with thromboembolic complications. Monitor for thrombotic and consumptive coagulopathy when administering Rebinyn® to patients with liver disease, post-operatively, to newborn infants, or to patients at risk of thrombosis or disseminated intravascular coagulation (DIC).
- Nephrotic Syndrome: Nephrotic syndrome has been reported following immune tolerance induction therapy with Factor IX products in hemophilia B patients with Factor IX inhibitors, often with a history of allergic reactions to Factor IX. The safety and efficacy of using Rebinyn® for immune tolerance induction have not been established.
Adverse Reactions
- The most common adverse reactions reported in previously treated patients in clinical trials (≥1%) were itching and injection site reactions. The most common adverse reactions (≥1%) in previously untreated patients reported in clinical trials were rash, FIX inhibitors, hypersensitivity, itching, injection site reaction, and anaphylactic reaction.
- Animals administered Rebinyn® showed accumulation of PEG in the choroid plexus, pituitary, circumventricular organs, and cranial motor neurons. The potential clinical implications of these animal findings are unknown. Consider whether the patient is vulnerable to cognitive impairment, such as infants and children who have developing brains, and patients who are cognitively impaired.
Please click here for Rebinyn® Prescribing Information.
Indications and Usage
Rebinyn®, Coagulation Factor IX (Recombinant), GlycoPEGylated, is a recombinant DNA derived coagulation Factor IX concentrate indicated for use in adults and children with hemophilia B (congenital Factor IX deficiency) for on demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes.
Limitations of Use: Rebinyn® is not indicated for immune tolerance induction in patients with hemophilia B.
Important Safety Information for Rebinyn®
Contraindications
- Rebinyn® is contraindicated in patients with a known hypersensitivity to Rebinyn® or its components, including hamster proteins.
Warnings and Precautions
- Hypersensitivity Reactions: Allergic-type hypersensitivity reactions, including anaphylaxis, have occurred with Rebinyn®. Signs may include angioedema, chest tightness, difficulty breathing, wheezing, urticaria, and itching. Discontinue Rebinyn® if allergic- or anaphylactic-type reactions occur and initiate appropriate treatment.
- Inhibitors: The formation of inhibitors (neutralizing antibodies) to Factor IX has occurred following Rebinyn®. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled as expected with the administered dose, perform an assay that measures Factor IX inhibitor concentration. Monitor all patients using clinical observations and laboratory tests for the development of inhibitors. Factor IX activity assay results may vary with the type of activated partial thromboplastin time reagent used.
- Thrombotic Events: The use of Factor IX-containing products has been associated with thromboembolic complications. Monitor for thrombotic and consumptive coagulopathy when administering Rebinyn® to patients with liver disease, post-operatively, to newborn infants, or to patients at risk of thrombosis or disseminated intravascular coagulation (DIC).
- Nephrotic Syndrome: Nephrotic syndrome has been reported following immune tolerance induction therapy with Factor IX products in hemophilia B patients with Factor IX inhibitors, often with a history of allergic reactions to Factor IX. The safety and efficacy of using Rebinyn® for immune tolerance induction have not been established.
Adverse Reactions
- The most common adverse reactions reported in previously treated patients in clinical trials (≥1%) were itching and injection site reactions. The most common adverse reactions (≥1%) in previously untreated patients reported in clinical trials were rash, FIX inhibitors, hypersensitivity, itching, injection site reaction, and anaphylactic reaction.
- Animals administered Rebinyn® showed accumulation of PEG in the choroid plexus, pituitary, circumventricular organs, and cranial motor neurons. The potential clinical implications of these animal findings are unknown. Consider whether the patient is vulnerable to cognitive impairment, such as infants and children who have developing brains, and patients who are cognitively impaired.
Please click here for Rebinyn® Prescribing Information.
Indications and Usage
Rebinyn®, Coagulation Factor IX (Recombinant), GlycoPEGylated, is a recombinant DNA derived coagulation Factor IX concentrate indicated for use in adults and children with hemophilia B (congenital Factor IX deficiency) for on demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes.
Limitations of Use: Rebinyn® is not indicated for immune tolerance induction in patients with hemophilia B.
References:
- Collins PW, Moss J, Knobe K, et al. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. Thromb Haemost. 2012;10(11):2305-2312.
- Simpson M, Kulkarni R, Ettingshausen C, et al. Population pharmacokinetic modeling of on-demand and surgical use of nonacog beta pegol (N9-GP) and rFIXFc based upon the paradigm 7 comparative pharmacokinetic study.) Blood Med. 2019;10:391-398.
- Rebinyn [package insert]. Plainsboro, NJ: Novo Nordisk Inc.
- Young G, Collins PW, Colberg T, et al. Nonacog beta pegol (N9-GP) in haemophilia B: a multinational phase III safety and efficacy extension trial (paradigm 4). Thromb Res. 2016;141:69-76.
- Carcao M, Zak M, Abdul Karim F, et al. Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial. J Thromb Haemost. 2016;14(8):1521-1529.
- Collins PW, Young G, Knobe K, et al; paradigm 2 Investigators. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014;124(26):3880-3886.
- Ettingshausen CE, Hegemann I, Simpson ML, et al. Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: a randomized trial. Res Pract Thromb Haemost. 2019;3(2):268-276.
- Negrier C, Knobe K, Tiede A, et al. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood. 2011;118(10):2695-2701.