Rebinyn/Refixia for hemophilia

Last updated Nov. 11, 2022, by Marta Figueiredo, PhD

Fact-checked by Joana Carvalho, PhD


What is Rebinyn/Refixia for hemophilia?

Rebinyn or Refixia (nonacog beta pegol, or N9-GP) is a replacement therapy developed by Novo Nordisk to treat and prevent bleeds in people with hemophilia B.

How does Rebinyn/Refixia work?

Hemophilia B, an inherited disease characterized by prolonged and excessive bleeding, is caused by a missing or defective blood clotting protein, called factor IX (FIX), due to mutations in the F9 gene.

As a replacement therapy, Rebinyn/Refixia delivers a modified, working version of the missing FIX directly into patients’ bloodstream to control and treat bleeds. The therapy is an extended half-life product, meaning the delivered FIX was modified to last longer in the body and to reduce dosing frequency. Specifically, FIX was attached to a polyethylene glycol (PEG) molecule, in a process called PEGylation, which is known to prevent the premature breakdown of the clotting factor in the body.

Who can take Rebinyn/Refixia?

Rebinyn was approved by the U.S. Food and Drug Administration in May 2017 to control and treat bleeds — and to prevent bleeds in the time around surgery (perioperative period) — in both children and adults with hemophilia B. The FDA extended Rebinyn’s approval in 2022 so it could also be used as a routine preventive treatment, or prophylaxis, to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia B.

The European Commission also approved the therapy — under the brand name Refixia — in mid-2017 as a prophylactic and on-demand treatment for bleeds in hemophilia B patients ages 12 and older.

Rebinyn also has been available in Canada since late 2017 for on-demand use and to prevent bleeds in the perioperative period in all hemophilia B patients, and for routine prophylaxis in adults. That approval was extended by Health Canada in 2022, allowing it to be given as a routine prophylactic treatment for bleeding episodes in hemophilia B patients under age 18.

Who should not take Rebinyn/Refixia?

Rebinyn/Refixia should not be taken by patients with known allergic reactions to FIX or any of the therapy’s components, which include hamster proteins.

How is Rebinyn/Refixia administered?

Rebinyn/Refixia is given as an infusion directly into the bloodstream. It is available as a dry powder that must be diluted in an appropriate liquid solution, which is provided in a 4 mL prefilled syringe.

Single-use vials are available in four strengths:

  • 500 international units (IU), that after dilution provide about 125 IU per mL
  • 1,000 IU, that after dilution provide about 250 IU per mL
  • 2,000 IU, that after dilution provide about 500 IU per mL
  • 3,000 IU, that after dilution provide about 750 IU per mL

The recommended dose for on-demand treatment to control bleeding episodes is a single infusion of 40 IU per kilogram of body weight (IU/kg) for minor and moderate bleeds, and 80 IU/kg for major bleeds. When needed, additional infusions of 40 IU/kg can be given.

For minor surgeries, a single 40 IU/kg dose before surgery may be sufficient to prevent bleeds. For major surgeries, it is recommended patients receive an 80 IU/kg infusion before surgery, and additional 40 IU/kg infusions post-surgery, as clinically needed.

The recommended dose for prophylaxis is 40 IU/kg once weekly. Adjustments of doses and administration intervals may be considered for each case, based on the achieved FIX levels and bleeding tendencies.

The therapy may be administered at a hemophilia treatment center, at a healthcare provider’s office, or at home. Patients should learn how to administer the therapy with the help of their hemophilia treatment center or healthcare provider.

Rebinyn/Refixia in clinical trials

After showing promise in animal models of hemophilia B, three ascending doses of Rebinyn/Refixia were initially tested in a first-in-human Phase 1 clinical trial (NCT00956345) involving 16 men with hemophilia B who previously had received FIX products.

Results showed the therapy was generally safe across all doses and that it remained in the body for longer periods than replacement therapies previously used by the patients, in a dose-dependent manner.

Rebinyn/Refixia’s approvals were mainly based on data from four global Phase 3 trials: PARADIGM 2, PARADIGM 3, PARADIGM 4, and PARADIGM 5. These studies evaluated the therapy’s safety and effectiveness in routine prophylaxis, on-demand treatment, and perioperative management in more than 100 previously treated boys and men with hemophilia B.

PARADIGM 2 trial

In the PARADIGM 2 study (NCT01333111), 74 male patients, ages 13–70, received either preventive treatment with Rebinyn/Refixia  — 10 or 40 IU/kg once weekly — for 52 weeks, or on-demand treatment for 28 weeks.

Data showed the therapy was well-tolerated and effective both at preventing and treating bleeding episodes.

PARADIGM 3 trial

The PARADIGM 3 trial (NCT01386528) enrolled 13 adolescent and adult patients, ages 15–56 years, who were undergoing major surgery. Participants received a single 80 IU/kg-dose of the therapy four hours before surgery and additional infusions of 40 IU/kg after the procedure, at the investigator’s discretion.

Rebinyn/Refixia safely and effectively prevented and treated bleeds in the perioperative setting.

PARADIGM 4 extension study

A total of 71 participants of PARADIGM 2 and 3 trials chose to enroll in the PARADIGM 4 extension study (NCT01395810), in which they received preventive or on-demand treatment regimens of Rebinyn/Refixia for up to two years.

Long-term treatment was shown to be associated with a favorable safety profile and a good protection against bleeds in a preventive modality, as well as in an on-demand basis.

Ongoing trials

The ongoing PARADIGM 5 trial (NCT01467427) is assessing the 11-year safety and effectiveness of the therapy — given once a week at 40 IU/kg, and at 40 or 80 IU/kg to treat bleeds — in 25 boys, ages 1–12 years.

Top-line data showed one year of treatment was well-tolerated and effective at preventing and treating bleeds in this younger patient population. Similar results were observed in the 17 boys who were treated for at least five years in the study, with 64% of them having experienced no bleeding episodes. Spontaneous bleeds were all mild to moderate in severity, and 93% were rapidly controlled with one or two infusions of the therapy.

Consistent with previous trials, no participant developed neutralizing antibodies against the delivered FIX, which could have rendered the therapy useless.

PARADIGM 6 trial

Another global Phase 3 study, called PARADIGM 6 (NCT02141074), is testing the therapy in up to 60 previously untreated boys, up to 6 years of age, with hemophilia B. Participants are receiving 40 IU/kg of Rebinyn/Refixia once a week, and 40 or 80 IU/kg to treat bleeds for up to about eight years.

Interim data from 37 boys demonstrated that 67.9% of those given weekly preventive treatment had no reported bleeds and 85.7% had no spontaneous bleeds. Also, all spontaneous bleeds and 90.3% of traumatic bleeds were successfully treated.

While the therapy was generally safe, two boys developed neutralizing antibodies against FIX and were withdrawn from the study.

Common side effects of Rebinyn/Refixia

The most common side effects associated with Rebinyn/Refixia are:

  • itching
  • swelling, pain, rash, or redness at the location of the infusion

Allergic reactions

Allergic reactions, including severe and potentially life-threatening reactions (anaphylaxis), may occur during treatment with Rebinyn/Refixia, since the medication contains traces of hamster proteins that some patients may be allergic to. Patients or their caregivers should immediately call their healthcare provider or get emergency treatment if they experience signs of an allergic reaction, such as hives, chest tightness, wheezing, difficulty breathing, and/or swelling of the face.

Development of neutralizing antibodies

Development of neutralizing antibodies against the therapy may occur during treatment. These neutralizing antibodies have also been reported to be associated with allergic reactions. It has been suggested that patients who develop neutralizing antibodies may be at an increased risk of experiencing severe allergic reactions following additional exposure to the supplied FIX. For this reason, it is recommended that all patients given Rebinyn/Refixia be monitored for the presence of neutralizing antibodies, including those experiencing allergic reactions.

Blood clots

Thrombotic, or blood clotting, events may occur in patients treated with FIX-containing products, such as Rebinyn/Refixia. The medication can also interfere with certain blood clotting tests. Given that the use of FIX-containing products has been associated with the development of blood clot-related events, patients with liver disease, newborns, and those at higher risk of blood clots should be closely monitored for early signs of blood clot-related events. In each case, the treatment’s benefit should be weighed against the risk of these potential complications.

Use in pregnancy and breastfeeding

It is unknown if Rebinyn/Refixia can affect the developing fetus, compromise female fertility, pass to breast milk, or have harmful effects on breastfed infants. Patients who plan to become pregnant or breastfeed should talk with their healthcare team and only continue treatment during these periods if the potential benefit justifies the potential risks to the fetus or infant.

 


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