CSL Behring presents rIX-FP for hemophilia B Phase III data evaluating efficacy, safety and improved dosing at ISTH 2015

CSL Behring has presented data from Phase III studies evaluating the efficacy and long-term safety of its investigational long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP). The data, shared in three separate oral presentations at the 2015 International Society on Thrombosis and Haemostasis (ISTH) Congress in Toronto, support the use of rIX-FP for routine prophylaxis, dosed once up to every 14 days, and for on-demand treatment of bleeding episodes in previously-treated adults and children with hemophilia B. The findings also

 include efficacy and safety results supporting the use of rIX-FP in patients undergoing surgical procedures. "The pivotal data for rIX-FP are exciting because they suggest the potential for prolonged dosing intervals of up to two weeks for routine prophylaxis," said Elena Santagostino, M.D., Ph.D., Professor in the Medical School of Clinical and Experimental Hematology at the University of Milan/IRCCS Maggiore Hospital, and lead investigator. "The trials also showed that this less frequent dosing was possible without compromising therapeutic benefit. This suggests rIX-FP, if approved, could be an important new treatment option, especially, for patients who lead active lifestyles and require a prophylactic regimen."

Key Study Findings

• rIX-FP in previously-treated adults and adolescents (abstract #OR347): The first Phase III study was a global safety and efficacy trial assessing rIX-FP for prophylaxis treatment once every 7, 10 and 14 days and on-demand treatment of bleeding episodes in 63 previously-treated patients (12-61 years of age) with hemophilia B (FIX activity ≤2% of normal). In one arm, 23 previously on-demand patients received only on-demand treatment for 6 months and then switched to 7-day prophylaxis treatment. In the other arm, 40 patients received 7-day prophylaxis treatment for 6 months and then, if eligible, switched to a 10- or 14-day prophylaxis treatment interval for 12 to 18 months.
  
  In patients who started on-demand treatment then switched to prophylaxis treatment, annualized spontaneous bleeding rates (AsBR) decreased by 100 percent from a median 15.43 during the on-demand treatment phase to 0.00 in the prophylaxis treatment phase (p<0.0001). Among patients who started on 7-day prophylaxis treatment then switched to 10- or 14-day prophylaxis treatment, the median AsBR rate was 0.00. In total, 99 percent of bleeding events were successfully managed with one or two infusions, with 94 percent of bleeds controlled with only one infusion regardless of the cause or location. Patients on 14-day prophylaxis treatment used a median dose of 75 IU/kg, which was 50 percent less therapy compared with their previously used FIX products. None of the patients developed inhibitors to factor IX or antibodies to rIX-FP. Related adverse events were reported in five patients (7.9 percent). The most common adverse reaction in clinical trials was headache. Overall, rIX-FP was well tolerated and no safety concerns were identified.

"These data provide additional evidence of the benefits of CSL Behring's recombinant albumin fusion technology, which was designed to significantly reduce clearance and provide longer-lasting hemostatic efficacy of factor IX to allow for less frequent dosing," said Dr. Andrew Cuthbertson, Chief Scientific Officer and Director of R&D, CSL Limited. "CSL Behring has long been committed to protecting the health of people living with a range of serious medical conditions and rIX-FP exemplifies our promise to developing and delivering innovative products that have the potential to improve the care of patients around the world."

• rIX-FP in previously-treated children (abstract #OR346): A second Phase III global study evaluated the safety and efficacy of rIX-FP for prophylaxis treatment once every 7 days and treatment of bleeding episodes in 27 children, age 1-11 years, with hemophilia B (FIX activity ≤2% of normal). Patients were treated for 12 months and/or 50 exposure days.
  
  The median AsBR was 0.00, and similar for patients under age 6 and those between 6 and 11 years. In total, 97 percent of bleeding episodes were successfully managed by one or two infusions, with 89 percent treated with only one infusion. Overall, the pharmacokinetic profile demonstrated a greater than 5-fold longer half-life, reduced clearance for rIX-FP versus other FIX products, supporting prophylaxis treatment intervals every 7 to 14 days. Investigators rated 96 percent of the treatments as effective (excellent or good). A total of 25 patients achieved 50 or more exposure days. None of the patients developed inhibitors to factor IX or antibodies to rIX-FP, and there were no related adverse events or withdrawals from the study.
• rIX-FP in previously-treated patients undergoing surgery (abstract #PO253): The third study was a surgical sub-group analysis included in the phase III studies as part of the global PROLONG-9FP clinical program. This abstract evaluated the use of rIX-FP to prevent bleeding during and post-surgery in 10 patients with hemophilia B (ages 8 to 51 years). The results showed that a single dose of rIX-FP was sufficient to maintain hemostasis during surgery. Over the 14-day post-surgical study period, patients needed anywhere from two to seven infusions. Both the consumption and dosing frequency of rIX-FP were considered remarkably low based on the type of surgery performed. The response was rated by investigators as excellent or good during all procedures. None of the patients developed inhibitors to factor FIX or antibodies to rIX-FP, and there were no related adverse events or withdrawals from the study.

About rIX-FP

CSL Behring engineered rIX-FP to provide longer lasting hemostatic efficacy of recombinant factor IX through genetic fusion with recombinant albumin. CSL Behring selected albumin as its recombinant genetic fusion partner for its coagulation factor proteins due to its long physiological half-life. In addition, recombinant albumin has been shown to have a good tolerability profile, low potential for immunogenic reactions and a well-known mechanism of clearance. The cleavable linker connecting recombinant factor IX and recombinant albumin has been specifically designed to preserve the native function of the coagulation factor in the fusion protein, while benefiting from recombinant albumin's long physiological half-life.

In February 2015, the U.S. Food and Drug Administration accepted for review CSL Behring's Biologics License Application (BLA) for rIX-FP. In March 2015, the European Medicines Agency (EMA) started the Centralized Procedure for reviewing CSL Behring's Marketing Authorization Application (MAA) for rIX-FP.

The PROLONG-9FP clinical development program for rIX-FP covers patients from the age of 1 to 61 years. Studies in the program were conducted as open-label, multicenter, PK, safety and efficacy studies of rIX-FP in previously treated patients with hemophilia B (FIX ≤ 2%).

Study design details for rIX-FP (CSL654) are available at clinicaltrials.gov.

About Hemophilia B

Hemophilia B (congenital factor IX deficiency) is characterized by deficient or defective factor IX and affects approximately 1 in 25,000 to 50,000 people. Hemophilia B is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. Nearly all hemophilia B patients are male.