Refixia or Rebinyn (nonacog beta pegol, or N9-GP), an approved replacement therapy for hemophilia B, is effective and has a good safety profile in previously untreated boys younger than 6 with severe to moderately severe disease, an early analysis of a Phase 3 trial indicates.
In the European Union, Refixia is approved to treat and prevent bleeding in patients ages 12 and older. In the U.S., where it approved under the brand name Rebinyn, it can treat patients of all ages, with dosing by weight. Both are marketed by Novo Nordisk.
The study, “Nonacog beta pegol (N9‐GP) in hemophilia B: First report on safety and efficacy in previously untreated and minimally treated patients,” was published in the journal Research and Practice in Thrombosis and Haemostasis.
Hemophilia B is caused by missing or defective factor IX (FIX), a blood clotting protein. A common way of treating the disease is replacement therapy, which consists in providing a working version of FIX.
Refixia/Rebinyn is an extended half-life product, meaning it contains a version of FIX that has been modified to last longer in the body. Its efficacy has been validated in clinical trials, but so far only in participants who were previously been given hemophilia treatments.
Having data in previously untreated patients is of interest, because such patients are at high risk of developing inhibitors, an immune response that makes the therapy ineffective and increases the likelihood of allergic reactions.
An international team that included two researchers at Novo Nordisk analyzed data from the ongoing paradigm 6 Phase 3 trial (NCT02141074), which is evaluating Refixia/Rebinyn in boys younger than 6 with FIX activity ≤ 2%, meaning moderately severe to severe disease. It defines untreated patients as those never treated at all, as well as those previously treated for no more than three days in total.
This trial is still recruiting eligible boys at multiple locations around the world. Additional information can be found here.
The analysis included 37 children (median age 1 year). Prophylactic (preventive) administration of Refixia/Rebinyn was done by weekly infusions at a dose of 40 international units (IU) per kg of body weight. Mild or moderate bleeds were treated with Refixia/Rebinyn at the same dose; severe bleeds were treated with a double dose.
Boys younger than 2 — for whom regular injections can be challenging — were allowed “preprophylaxis” treatment, in which they received either Refixia/Rebinyn only for bleeds, or infusions were done on a custom schedule with additional doses given as needed.
Of these 37 children, 13 started directly on prophylaxis, and 24 on preprophylaxis; 15 transitioned to prophylactic treatment as of the analysis cut-off date. Thirty-one boys have been treated for at least 10 days, and 21 have been treated for at least 50 days.
Two (6.1%) boys in the preprophylaxis group developed an immune response against Refixia, and were withdrawn from the study. The prevalence of inhibitory antibodies was “within the expected range for this patient population,” the researchers wrote.
Ten other participants tested positive for antibodies that bound either to the treatment itself (though not inhibitory) or to proteins used in its manufacturing.
A total of 380 adverse events were reported in 36 boys. Most (87.1%) were mild, and 96.6% were deemed unlikely to be related to treatment with Refixia/Rebinyn.
Thirteen adverse events, reported in seven patients, were considered possibly or probably related to treatment. Four of these adverse events — including three deemed serious — occurred in the two boys who developed inhibitory antibodies. The remaining adverse events included rash, conjunctivitis, and hearing loss.
Among boys treated with weekly prophylaxis, about two-thirds (67.9%) had no reported bleeds, and 24 (85.7%) had no spontaneous bleeds. The estimated mean annual bleeding rate was 0.31 bleeds/year; the rate of spontaneous bleeds was 0.08.
Of the total 48 bleeds, bleeding control were rated “good” or “excellent” in 45 (93.8%).
Most (42, 87.5%) bleeds were controlled with a single injection of Refixia/Rebinyn, including all 15 bleeds that occurred in boys treated with weekly prophylaxis. All spontaneous bleeds and 90.3% of traumatic bleeds were successfully treated.
Additional analyses also indicated that FIX activity was markedly elevated with Refixia/Rebinyn use.
These results indicate that Refixia/Rebinyn was well-tolerated and “provided effective hemostatic [bleeding control] coverage,” the scientists wrote.
The study’s primary limitation is the low number of participants, the investigators said, adding the final analysis for this still recruiting trial will include more patients.
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