The recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) is a safe and effective treatment for patients with hemophilia B, according to results from a recent phase III trial published in Blood. Also, given its longer circulating half-life, rIX-FP may be a more convenient option for patients, resulting in less frequent injections.
Current prophylaxis treatment calls for frequent intravenous (IV) injections of FIX replacement product, with the standard half-life of these products often necessitating IV injections twice weekly. The need for frequent injections can put a burden on both patients with hemophilia B and their caregivers and may affect long-term treatment compliance.
In this prospective, non-randomized, international, open-label trial, Elena Santagostino, MD, from Maggiore Hospital Policlinico and University in Milan, Italy, and colleagues evaluated the safety and efficacy of rIX-FP in 63 men (age range = 12-61 years) with severe hemophilia B who were previously treated. Mean age was 33 years, with seven patients age 18 years or younger.
The authors reported the results of a crossover study that compared the efficacy of two different regimens:
- Group one: Patients received routine prophylaxis once every seven days for 26 weeks, followed by either a seven-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively. Starting doses were 35-50 IU/kg.
- Group two: Patients received on-demand treatment for bleeding episodes for 26 weeks, then switched to a seven-day prophylaxis regimen for a mean of 45 weeks with a fixed dose of 35-50 IU/kg.
Patients who had at least 150 exposure days with previous FIX replacement therapy and no detectable inhibitor to FIX or inhibitor history were eligible for study enrollment. Patients involved in the on-demand treatment cohort were required to have had a minimum of two non-trauma-induced bleeding episodes treated per month in the three to six months prior to study inclusion.
The study’s primary endpoints included prevention of bleeding episodes (determined by a reduction in median annualized spontaneous bleeding rate [AsBR]) and safety of rIX-FP.
“rIX-FP demonstrated improved pharmacokinetic parameters over all marketed FIX products,” the authors reported. The terminal half-life was 102 hours – 4.3-fold longer than previous FIX treatment. Patients maintained mean trough levels of 20 IU/dL and 12.4 IU/dL FIX activity on prophylaxis with, respectively, rIX-FP 40 IU/kg every seven days and 75 IU.kg every 14 days.
Patients in the 14-day treatment group used a median of 162.3 IU/kg of rIX-FP40 per month, while patients in the seven-day treatment group used a median of 194.7 IU/kg per month.
“Prior to study entry, the median consumption on prophylaxis with standard FIX products was 256.6 IU/kg per month,” Dr. Santagostino and colleagues noted.
Compared with on-demand treatment, prophylaxis rIX-FP led to significantly lower AsBR: 0 vs. 15.43, respectively (p<0.0001). There was also a 100 percent resolution of target joints where bleeding occurred when switching from on-demand to prophylaxis rIX-FP (p<0.0001).
A total of 358 bleeding episodes occurred and were treated with rIX-FP; 93.6 percent and 98.6 percent of these episodes were treated successfully with one or ≤2 rIX-FP infusions, respectively. Efficacy was similar between prophylaxis and on-demand groups, regardless of the bleeding cause (spontaneous, trauma-induced, or unknown) and the bleeding location (joint, muscle, or other). The majority of total and spontaneous bleeding episodes (58.7% and 66.2%, respectively) occurred in the elbow, knee, and ankle joints, and there were also no life-threatening bleeding episodes during the study.
A total of 347 treatment-related adverse events (AEs) were recorded in 54 patients (85.7%); most were mild or moderate in severity. The most common AEs included nasopharyngitis, headache, arthralgia, and influenza. In addition, 28 injection site reactions (0.7%) were reported by 12 patients.
There were 3,907 injections of rIX-FP during the study, for a mean of 64.8 exposure days per patient (72.4 in Group 1 and 51.5 in Group 2). No inhibitors against FIX were detected in any patient receiving rIX-FP, thus, the authors wrote, “the primary safety objective was successfully achieved.” No patients developed an inhibitor and no additional safety concerns were raised, they added.
“rIX-FP is safe and effective in preventing and treating bleeding episodes in previously treated adolescents and adults with hemophilia B, [which] allows for a paradigm shift of routine prophylaxis regimen at dosing intervals of up to 14 days,” concluded Dr. Santagostino and co-authors.
An ongoing study is currently underway to assess the efficacy of a 21-day prophylaxis regimen with a dose of 100 IU/kg rIX-FP.
Limitations of the study include its small sample size and non-randomized design.
Santagostino E, Martinowitz U, Lissitchkov T, et al. Long acting recombinant fusion protein linking coagulation factor IX with albumin (rIXFP) in hemophilia B: Results of a phase 3 trial. Blood. 2016 January 11. [Epub ahead of print]