Recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) could result in a “paradigm shift” in prophylaxis regimens for patients with hemophilia B, according to researchers reporting results from a phase III trial.
At dosing intervals of up to 14 days, rIX-FP was a safe and effective factor IX (FIX) replacement product for preventing and treating bleeding episodes in an open-label study of 63 previously treated adolescents and adults with severe hemophilia B.
Compared to standard FIX products, rIX-FP is more active, has a longer half-life, and has better clearance. A study is now underway to see whether a 21-day prophylaxis regimen provides even better results than the 14-day regimen, reported Dr. Elena Santagostino of Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Foundation, Maggiore Hospital Policlinico, Milan, and her associates in the PROLONG-9FP Investigators Study Group.
For prophylaxis, standard FIX products are administered two times per week. Patients are at increased risk of bleeding when their FIX activity is low, particularly just before their next scheduled dose. With the prolonged FIX activity of rIX-FP, the dosing is less frequent and that could potentially improve adherence, the researchers wrote (Blood. 2016;127[14]:1761-9).
In addition, rIX-FP was associated with a reduced risk of spontaneous and trauma-related bleeding episodes.
The findings came from a study of patients who had FIX activity levels of 2% or less and were assigned to one of two groups. The first group received routine prophylaxis once every 7 days for 26 weeks; they were then placed on either a 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively. The second group received on-demand treatment of bleeding episodes for 26 weeks and were then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. Only patients who were previously receiving on-demand treatment were eligible for group 2 assignment.
Patients self-administered rIX-FP for routine prophylaxis and on-demand treatment of bleeding episodes; all home administrations were recorded in an electronic diary. A second dose of rIX-FP was administered at least 24 hours after the first injection, if needed, to achieve hemostasis. Efficacy and safety assessments were performed at study sites on a monthly basis.
The study design controlled for the variability of bleeding frequency within the hemophilia B patient population, as group 2 patients started rIX-FP treatment on-demand and continued on 7-day prophylaxis. During the on-demand phase, rIX-FP controlled 98.6% of bleeding episodes, and 93.6% of bleeds were controlled with one infusion.
Once the group was switched to 7-day prophylaxis, the median annualized spontaneous bleeding rate dropped to 0.0 and all target joints resolved.(P less than .0001). No patient developed an inhibitor, and no safety concerns were identified.
The annualized bleeding rate decreased slightly in group 2 patients during on-demand treatment with rIX-FP, compared with the rate in the 12-month period before they entered the study. The researchers speculated that on-demand treatment with rIX-FP “might provide, to a certain extent, some protection against a subsequent bleeding episode. Therefore, patients with a severe bleeding phenotype treated on-demand might experience fewer bleeding episodes if switched to rIX-FP. Furthermore, such on-demand patients who require more than one infusion per month may have the benefit of a reduction of ABR by administering a similar number of infusions according to a 14-day prophylaxis regimen with rIX-FP.”
The sample size was small, however, and differences of care in the clinical study could have affected the results.
Compared to other FIX products, rIX-FP had an extended terminal half-life of 102 hours, 4.3-fold longer than seen with the patients’ previous FIX treatment. Other pharmacokinetic measures such as area under the curve (7176 h × IU/dL), clearance (0.77 mL/h per kg), and incremental recovery (1.27 IU/dL per IU/kg) also were improved. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg every 7 days and 75 IU/kg every 14 days, respectively. Rather than half-life alone, a slower clearance may be a factor in the success of prophylaxis regimens, the researchers said.
The principal investigators received research support from CSL Behring, which sponsored the study and was responsible for trial operations and data analysis.
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