Hemophilia

Rebinyn^® (Nonacog beta pegol), also known as Refixia^® in Europe, is a glycopegylated recombinant factor IX protein, with an extended terminal half-life. Conjugation of the protein to a 40-kDa polyethylene glycol (PEG) group slows its removal from the circulation and extends its terminal half-life. The drug is administered intravenously. Refixia is approved in Europe for the treatment and prophylaxis of bleeding in patients with hemophilia B who are younger than 12 years.^1,2 

On May 31, 2017, the US Food and Drug Administration (FDA) approved Rebinyn, manufactured by Novo Nordisk, for the on-demand treatment and management of episodes of bleeding, as well as the perioperative management of bleeding, in adults and children with hemophilia B.^2,3 It is not indicated for the induction of immune tolerance in patients with hemophilia B.⁴ Rebinyn was approved by the European Medicines Agency (EMA) on June 2, 2017. The EMA authorized the marketing of nonacog beta pegol under the trade name Refixia, and the EMA approval included more indications than the FDA approval, allowing the drug to be used for both prophylaxis and treatment. However, the EMA restricted Rebinyn use to children age 12 and older because neurodevelopmental issues due to an accumulation of PEG were observed in animal studies.² 

Congenital hemophilia B is an X-linked disease characterized by a deficiency or absence of clotting factor IX. Depending on the level of residual factor IX activity, the disease is classified as severe (<1%), moderate (1%-5%), or mild (>5%-40%). In the vast majority of patients, the hemophilia is mild to moderate, with bleeding generally precipitated by trauma or surgery. For those with severe disease or repeated episodes of bleeding, routine factor replacement (prophylaxis) is indicated.⁵ 

Mechanism of Action

Patients with hemophilia B lack coagulation factor IX, which is necessary for efficient hemostasis. Rebinyn temporarily replaces deficient clotting factor IX. Factor XIa and the factor VII/tissue factor complex activate factor IX. Cleavage of the activation peptide, which includes the 40-kDa PEG moiety, occurs when Rebinyn is activated, leaving the native factor IX molecule. Activated factor IX, in combination with activated factor VIII, activates factor X. Prothrombin is converted to thrombin by activated factor X. Thrombin subsequently converts fibrinogen to fibrin, causing a clot to form. Rebinyn boosts factor IX levels in the plasma and can temporarily resolve the coagulation factor deficiency in patients with hemophilia B, as evidenced by a reduction in the activated partial thromboplastin time (aPTT). In comparison with unmodified factor IX, Rebinyn has a longer half-life.⁶ 

Efficacy in Trials and Trial Results

The safety and pharmacokinetics of Rebinyn/Refixia were assessed in male patients 18 to 65 years of age with nonbleeding hemophilia B in a phase 1 clinical trial (NCT00956345). Participants were administered a single dose (25, 50, or 100 U/kg) intravenously. The drug was found to be effective in treating bleeding in a dose-dependent manner.⁷

The prophylactic and on-demand efficacy and tolerability of Rebinym/Refixia in the prevention and management of episodes of bleeding in patients with hemophilia B have been verified in phase 3 clinical trials: Paradigm2 (NCT01333111), Paradigm3 (NCT01386528), Paradigm4 (NCT01395810), and Paradigm5 (NCT01467427).^8-12

Warnings, Precautions, and Adverse Reactions

Rebinyn/Refixia can cause allergic hypersensitivity responses.The product contains traces of hamster proteins. Patients should be encouraged to stop using the drug and notify their doctor if hypersensitivity symptoms develop.¹³ 

Rebinyn use may cause neutralizing antibodies (inhibitors) to develop. If bleeding is not managed with the appropriate dose or the expected plasma factor IX activity levels are not achieved, an assay is done to determine the factor IX inhibitor concentration.⁴

Clinical surveillance for possible signs of thrombotic and consumptive coagulopathy should be started with proper biological testing when this product is administered to patients with liver disease, postoperative patients, newborn infants, or patients at risk for thrombotic events or disseminated intravascular coagulation (DIC), given the potential risk for thrombotic complications.¹³

Rebinyn/Refixia can increase cardiovascular risk in persons who already have risk factors for cardiovascular disease. If a central venous access device (CVAD) is required, the risk for CVAD-related problems, such as local site infections, bacteremia, and catheter site thrombosis, should be taken into account.¹³ The most common adverse effects, experienced by 1% or more of patients in clinical trials, include itching and injection site reactions.³ Rebinyn has not been studied for drug-drug interactions, and no interactions with other medical treatments have been reported.⁶

References

1. ​​Syed YY. Nonacog beta pegol: a review in haemophilia B. Drugs. 2017;77(18):2003-2012. doi: 10.1007/s40265-017-0836-8. Erratum in: Drugs. 2018;78(11):1169.
2. REBINYN safety and utilization review. US Food and Drug Administration. April 2020. Accessed December 24, 2021.
3. ​​REBINYN (coagulation factor IX [recombinant], glycoPEGylated). Prescribing information. Novo Nordisk. Revised June 2020. Accessed December 24, 2021.
4. REBINYN (coagulation factor IX [recombinant], glycoPEGylated). Prescribing information. Revised June 2017. Accessed December 24, 2021.
5. Simpson ML, Kulkarni R, Escuriola Ettingshausen C, Medom Meldgaard R, Cooper DL, Klamroth R. 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. J Blood Med. 2019;10:391-398. doi:10.2147/JBM.S217539
6. REBINYN product monograph. November 29, 2017. Accessed December 24, 2021.
7. Rebinyn/Refixia. Hemophilia News Today. Accessed December 24, 2021.
8. Negrier C, Young G, Abdul Karim F, et al. Recombinant long‐acting glycoPEGylated factor IX (nonacog beta pegol) in hemophilia B: assessment of target joints in multinational phase 3 clinical trials. Haemophilia. 2016;22(4):507‐513. doi:10.1111/hae.12902
9. Young G, Collins PW, Colberg T, et al. Nonacog beta pegol (N9‐GP) in hemophilia B: a multinational phase III safety and efficacy extension trial (paradigm 4). Thromb Res. 2016;141:69‐76. doi:10.1016/j.thromres.2016.02.030
10. Cacao 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. doi:10.1111/jth.13360 
11. Collins PW, Young G, Knobe K, et al. Recombinant long‐acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014;124(26):3880‐3886. doi:10.1182/blood-2014-05-573055
12. Ezban M, Hermit MB, Persson E. FIXing postinfusion monitoring: assay experiences with N9-GP (nonacog beta pegol; Refixia®; Rebinyn®). Haemophilia. 2019;25(1):154-161. doi:10.1111/hae.13671
13. Refixia, INN-nonacog beta pegol (europa.eu). Summary of product characteristics. Accessed December 24, 2021.

Reviewed by Debjyoti Talukdar, MD, on 12/27/2021.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.