The US Food and Drug Administration (FDA) has accepted for standard review CSL Behring's Biologics License Application (BLA) for a human 4-factor prothrombin complex concentrate (PCC) for the urgent reversal of vitamin K-antagonist therapy (i.e., warfarin) in patients with acute major bleeding. If approved by the FDA, the CSL Behring 4-factor PCC would be the first agent of its kind available in the United States.

If approved by the FDA, the CSL Behring 4-factor PCC would be the first agent of its kind available in the United States.

“The acceptance by FDA of this 4-factor PCC BLA marks an important step toward addressing the urgent unmet need for a rapid and simple way to reverse the effects of warfarin during bleeding emergencies,” said Val Romberg, senior vice president, Research and Development at CSL Behring. “This 4-factor PCC has the potential to be a significant new tool in stopping excessive bleeding in patients on warfarin, where fresh frozen plasma is the current standard of care.”

The CSL Behring BLA submission is based on results from three prospective phase III clinical trials that evaluated the safety and efficacy of PCC in patients who required urgent reversal of warfarin therapy. The pivotal, acute major bleeding trial demonstrated that PCC was comparable to plasma at 24 hours in patients who required urgent reversal of warfarin therapy (72.4 per cent and 65.4 per cent, respectively). Additionally, the co-primary efficacy endpoint analysis showed that the 4-factor PCC was superior in achieving target INR correction within 30 minutes at the end of infusion as compared to plasma (62.2 per cent and 9.6 per cent, respectively). Four-factor PCC was also superior to plasma in rapidly and safely raising the levels of clotting factors II, VII, IX, X, and anticoagulant Proteins C and S at the same 30 minutes post-treatment time point (p values<0.0001).

Prothrombin complex concentrates (PCC) are derived from human plasma. SL Behring’s investigational PCC contains four important pro-coagulant factors in significant quantities: Factor II (prothrombin), Factor VII, Factor IX and Factor X, as well as anticoagulant Proteins C and S. CSL Behring currently markets this PCC in 24 countries throughout the world.

Guidelines from the American College of Chest Physicians recommend 4-factor PCC, rather than plasma, for rapid reversal of anticoagulation in patients with vitamin K antagonist associated major bleeding. The guidelines also recommend the use of vitamin K (5 to10 mg) administered by slow intravenous (IV) infusion rather than reversal with coagulation factors alone.

This was an open-label, randomized, multicentre phase III b study to assess the efficacy, safety and tolerance of human 4-factor prothrombin complex concentrate (PCC) to plasma for rapid reversal of acute major bleeding in patients receiving warfarin therapy. The study enrolled 212 patients. The primary endpoint was hemostatic efficacy with respect to the adequacy of stopping an ongoing major bleed within 24 hours from the start of infusion. The secondary endpoints evaluated plasma levels of major clotting factors (Factors II, VII, IX, X, proteins C and S); time to INR correction; number of transfusions, amount of blood products used, and hemostatic agents; and safety and tolerability (including all-cause mortality).

CSL Behring is a leader in the plasma protein therapeutics industry and is committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide.