Recombinant coagulation Factor IX albumin fusion protein shows promise for hemophilia B

A long-acting recombinant fusion protein that links coagulation Factor IX with albumin appeared safe and effective for the prevention and treatment of bleeding episodes in patients with hemophilia B, according to the results of a global phase 3 study.

"Hemophilia B — particularly moderate and severe forms ( 5% Factor IX [FIX] activity) — is associated with spontaneous bleeding into joints, muscles and soft tissues that may lead to crippling arthropathy, while bleeding in the intracranial, neck/throat or gastrointestinal spaces may be life-threatening,” Elena Santagostino, MD, PhD, clinical assistant at Maggiore Hospital’s Hemophilia and Thrombosis Center and contract professor of clinical and experimental hematology at University of Milan, and colleagues wrote. “Current prophylaxis therapy requires frequent IV injections of FIX replacement product, maintaining appropriate FIX trough levels to effectively reduce the incidence of hemarthroses and other bleeding episodes.”

The recombinant fusion protein that links coagulation Factor IX with recombinant albumin (rIX-FP; CSL Behring) has an increased circulating half-life compared with recombinant FIX because albumin is protected from degradation by pH-dependent binding to the neonatal Fc receptor, according to the researchers. This characteristic — in combination with the improved pharmacokinetics and prolonged pharmacodynamic activity demonstrated in preclinical and early studies — suggests patients may need less frequent injections to maintain a circulating FIX level high enough to minimize the occurrence of spontaneous bleeding episodes.

Thus, Santagostino and colleagues sought to determine whether rIX-FP could serve as a safe and effective option for the management and prevention of bleeding episodes in adolescent and adult patients with moderate-to-severe previously treated hemophilia B (defined by FIX activity 2 IU/dL).

The study included data from 63 male patients (mean age, 33 years; range, 12-61).

Santagostino and colleagues divided patients into two treatment groups, which included a prophylaxis group (group 1; n = 40) or on-demand treatment group (group 2; n = 23).

Patients in group 1 received routine prophylaxis once every 7 days for 26 weeks, after which they could reduce their intervals to 10 or 14 days if they did not experience spontaneous bleeds for at least 4 weeks.

Patients in group 2 were assigned to on-demand treatment for bleeding episodes for 26 weeks, followed by 7-day prophylaxis for at least 26 weeks (mean, 45 weeks).

Patients assigned to the on-demand group reported a higher median non-trauma induced bleeding rate than patients in the prophylaxis group in the 12 months immediately preceding study entry (median, 21 vs. 1).

The efficacy of rIX-FP for the prevention of bleeding episodes served as the primary endpoint. Safety and pharmacokinetics served as secondary endpoints.

The researchers observed a mean terminal half-life of rIX-FP of 102 hours, representing a 4.3-fold increase over previous FIX treatment.

Patients maintained a mean trough of 20 IU/dL FIX activity on prophylaxis with weekly rIX-FP dosed at 40 IU/kg. For patients dosed with 75 IU/kg every 2 weeks, mean trough activity was 12 IU/dL.

Patients who switched from on-demand treatment to prophylaxis with rIX-FP experienced a 100% reduction in median annualized spontaneous bleeding rate (AsBR), as well as a 100% resolution of target joints (P < .0001).

All prophylaxis regimens had a median AsBR of 0, with 98.6% of 358 reported bleeding episodes treated successfully. Of these, 96.3% were treated with a single injection of rIX-FP.

The researchers did not detect the development of inhibitors against FIX in any patient, thus meeting the study’s safety objective.

Fifty-four patients (85.7%) experienced a treatment-emergent adverse event, the most frequent of which included nasopharyngitis (n = 16), headache (n = 15), arthralgia (n = 9) and influenza (n = 7).

Two patients discontinued treatment due to adverse events.

“In conclusion, rIX-FP is safe and effective in preventing and treating bleeding episodes in previously treated adolescents and adults with hemophilia B,” Santagostino and colleagues wrote. “The enriched pharmacokinetic profile allows for a paradigm shift of routine prophylaxis regimen at dosing intervals of up to 14 days. With a half-life of over 100 hours, 5- to 7-fold better clearance and area under the curve, and higher incremental recovery than standard FIX products, rIX-FP will provide prolonged hemostatic coverage. A study is currently underway to evaluate the efficacy of a 21-day prophylaxis regimen with a dose of 100 IU/kg rIX-FP.” – by Cameron Kelsall

Disclosure: CSL Behring funding this study. Santagostino reports research funding from CSL Behring during the conduct of this study, as well as honoraria from and consultant roles with Baxter/Baxalta, Bayer, Biotest, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Pfizer, Roche and Sobi/Biogen Idec. She further reports unrestricted research grants from Novo Nordisk and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.