rFIXFc as Prophylaxis and Treatment in Pediatric Hemophilia B

Results from the phase III B-LONG study published in Blood Advances found that recombinant factor IX Fc fusion protein (rFIXFc) was an effective prophylactic agent and treatment for bleeding episodes in previously untreated children with hemophilia B.

rFIXFc, the first extended half-life FIX therapy approved for hemophilia B, is indicated as a prophylactic therapy to reduce bleeding episode frequency, manage bleeding episodes, and control bleeding in perioperative settings. The treatment comprises a single rFIX molecule covalently fused to the dimeric Fc domain of immunoglobulin G1.

The open-label, multicenter study, led by Beatrice Nolan, MD, of National Children’s Research Centre in Dublin, Ireland, included 33 previously untreated patients younger than age 18 with hemophilia B. Across the 24 sites, investigators were given the option to treat patients with rFIXFc on-demand prior to starting prophylaxis according to the local standard of care. In an effort to keep practice aligned with global standards of care, it was expected that investigators start the prophylactic regimen either before or after a third hemarthrosis episode.

“These findings confirm the ability of rFIXFc to achieve low ABRs with extended dosing intervals in this very young patient population.”

—Beatrice Nolan, MD

Prophylaxis comprised an initial 50 IU/kg weekly dose of rFIXFc, but adjustments were made to this recommended dose and the dosing interval based on evaluation of pharmacokinetic data, physical activity, and bleeding.

During the treatment period, patients were exposed to rFIXFc for 50 days or more, unless the end of study or study withdrawal occurred. The end of the study occurred after 20 or more patients reached 50 or more exposure days to the therapy. A single exposure day was defined as a full 24-hour period of receiving one or more doses of rFIXFc.

Researchers looked for the occurrence of inhibitor development during treatment. A positive inhibitor was defined as a 0.60 BU/mL or greater inhibitor test result, which was confirmed by an additional test result of 0.60 BU/mL or greater from a different sample taken two to four weeks later.

The majority of patients were younger than age 1 (79%). The median age of the cohort was 7.2 months at baseline. Additionally, most patients (67%) were white. Out of 33 patients, 29 demonstrated FIX activity less than one IU/dL at time of screening, while the remaining patients had FIX activity of one to two IU/DL at screening.

Approximately 15% of patients had spontaneous bleeding episodes within a three-month period prior to screening. A total of six patients (18%) reported a family history of inhibitors, but most patients and their families were unsure of their family history regarding inhibitors (82%).

A total of 22 patients (67%) initiated on-demand treatment, with 77% of these patients (n=22) switching to prophylaxis. Approximately 33% of patients (n=11) started with a prophylactic regimen.

The median duration of treatment was 22.9 weeks for the on-demand treatment and 77.5 weeks for the prophylactic strategy. Overall, the median duration of therapy was 83 weeks. The median number of exposure days was 76. The median dosing interval across patients who received the prophylactic regimen was seven days and the median weekly dose among these patients was 58 IU/kg.

Out of the 33 patients who received rFIXFc, one (3.03%; 95% CI 0.08-15.76) developed a low-titer inhibitor following 11 exposure days. A patient with severe hemophilia experienced hypersensitivity during the 11th rFIXFc infusion.

Over the 57.5 patient-years of follow-up and during 2,233 exposure days, approximately 70% of patients (n=23) experienced a total of 58 treatment-emergent serious adverse events. Only two of these events were considered related to the treatment regimen.

The overall median annualized bleed rate (ABR), the study’s secondary endpoint, was 1.24. The ABR in patients who had 50 or more exposure days with a prophylactic regimen had an overall median ABR of 1.32. Most bleeding events required one infusion for the purposes of resolving bleeding.

“These findings are consistent with previously published data on the use of rFIXFc in previously treated patients, confirming the ability of rFIXFc to achieve low ABRs with extended dosing intervals in this very young patient population,” the researchers concluded.

The study authors report relationships with Sanofi and Sobi, which funded the study.

Reference

Nolan B, Klukowska A, Shapiro A, et al. Final results of the PUPs B-LONG study: evaluating safety and efficacy of rFIXFc in previously untreated patients with hemophilia B. Blood Adv. 2021;5(13):2732-2739.