CSL Behring advances therapeutics for hemophilia

Novel recombinant factor VIII single chain aimed at adolescents and adults

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TORONTO—CSL Behring presented data from a Phase 1/3 study on the efficacy and safety of its novel investigational recombinant factor VIII single chain (rVIII-SingleChain) in adolescents and adults with hemophilia A during a late-breaking abstract session at the 2015 International Society on Thrombosis and Haemostasis (ISTH) Congress. Overall, patients using rVIII-SingleChain to prevent bleeding (prophylaxis) were well controlled with two to three infusions per week and developed no inhibitors.
Debra Bensen-Kennedy, therapeutic area head for coagulation and oncology at CSL Behring, notes that next-generation molecules give patients a new and significant advantage with improved acceptance of prophylaxis based on home infusions.
Citing similar game-changers for both hemophilia A and the more rare hemophilia B, Bensen-Kennedy ventures that both molecules are significant. “The two are phenotypically similar but factors VIII [hemophilia A] and IX [hemophilia B] are different.”
Patients using rVIII-SingleChain to prevent bleeding had low annualized bleeding rates (median of 1.14) and an annualized spontaneous bleeding rate of zero. rVIII-SingleChain had improved pharmacokinetic parameters compared with octocog alfa, the comparator. Of 848 bleeds treated in the study, 94 percent were successfully controlled with no more than two infusions of rVIII-SingleChain, with 81 percent controlled by only one infusion.
The majority of bleeding events treated with rVIII-SingleChain and assessed by investigators (94 percent of 835 assessed bleeding events) were rated as excellent or good. The data are part of the AFFINITY Phase 1/3 study, an open-label, multicenter trial examining the safety, efficacy and pharmacokinetics of rVIII-SingleChain compared with recombinant human antihemophilic factor VIII (octocog alfa).
“In this large-scale study, we observed relatively low annualized bleeding rates and a median of zero spontaneous bleeding events with rVIII-SingleChain for routine prophylaxis for patients with hemophilia A,” said Dr. Ingrid Pabinger-Fasching of the Medical University of Vienna in Austria, lead investigator of the pivotal trial. “As the first and only single-chain recombinant factor product, rVIII-SingleChain has the potential to offer improved protection from bleeding with less frequent dosing, and an excellent safety profile thus far.”
Results presented in the late-breaking session included data on more than 14,000 exposure days in 146 patients on prophylaxis and 27 patients treated on demand for a bleeding event. In total, 120 patients were treated for more than 50 days of exposure; 52 had more than 100 days of exposure. Among patients in the prophylaxis group, 32 percent were dosed twice weekly and 54 percent received treatment three times per week. The most common adverse events were naso-pharyngitis, arthralgia and headache. Overall, rVIII-SingleChain was well tolerated and no inhibitors have been reported, Bensen-Kennedy notes.
“Our novel rVIII-SingleChain was specifically designed to improve the stability and provide longer-lasting hemostatic efficacy of factor VIII, thereby addressing the need to provide hemophilia A patients with a treatment that may require fewer infusions while maintaining its therapeutic effect,” said Dr. Andrew Cuthbertson, chief scientific officer and director of research and development at CSL Ltd. “These pivotal data are promising and are supportive of CSL Behring’s commitment to bringing this therapy to the market and to helping improve the care of people living with hemophilia A.”
Specifically designed for greater molecular stability, rVIII-SingleChain is a novel recombinant single-chain factor VIII (FVIII) construct that uses a covalent bond that forms one structural entity, a single chain, to improve the stability of FVIII and provide longer-lasting FVIII activity.
Hemophilia A (congenital factor VIII deficiency) is caused by deficient or defective factor VIII. The condition is characterized by prolonged or spontaneous bleeding, especially into the muscles, joints or internal organs. Affecting approximately one in 5,000 to 10,000 people, hemophilia A is the most common form of hemophilia. Nearly all hemophilia A patients are male.
Also at the 2015 ISTH Congress in Toronto, CSL Behring shared three oral presentations from Phase 3 stuides to support the use of its long-acting fusion protein 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 included 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 Dr. Elena Santagostino, 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.”
“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 Cuthbertson. “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.”
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 started the centralized procedure for reviewing CSL Behring’s Marketing Authorization Application (MAA) for rIX-FP.
Hemophilia B (congenital factor IX deficiency) is characterized by deficient or defective factor IX and affects approximately one in 25,000 to 50,000 people. It is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints or internal organs. Almost all individuals with this disease are male.
CSL Behring therapies are used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic disease of the newborn. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a global biopharmaceutical company and a member of the CSL Group of companies. The parent company, CSL Ltd., is headquartered in Melbourne, Australia.

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