Bristol-Myers Squibb Company (BMS) and Pfizer Inc. announced results of the first human study evaluating the reversal of the anticoagulant effect of Eliquis (apixaban) by 4-factor prothrombin complex concentrates (PCCs) in healthy subjects.
The study results demonstrated that both PCCs, Sanquin’s Cofact (a heparin-free formulation) and CSL Behring’s Beriplex P/N (a formulation containing heparin) reversed the steady-state pharmacodynamic effects of Eliquis in several coagulation assessments, including endogenous thrombin potential (ETP). The full data presented during the Antithrombotic Therapy: Anticoagulant Therapy session at the 56th annual meeting of the American Society of Hematology (ASH) in San Francisco, CA.
“The Bristol-Myers Squibb and Pfizer alliance remains committed to delivering important treatment options to patients and physicians and is pleased with the positive results of this study investigating the potential use of these PCCs to reverse the anticoagulant effect of Eliquis,” said Steven Romano, MD, senior vice president and head, Medicines Development Group, Pfizer Global Innovative Pharmaceutical Business. “These results support further evaluation of the use of PCCs in Eliquis-treated subjects.”
“Throughout our collaboration with Pfizer, the alliance has been dedicated to further investigating the use and application of Eliquis,” said Douglas Manion, MD, head of specialty development, Bristol-Myers Squibb. “We are pleased with the positive results of this study and look forward to further exploration of prothrombin complex concentrates.”
Eliquis is a novel oral anticoagulant that specifically inhibits Factor Xa. This study evaluated the effect of two non-activated 4-factor PCCs, Cofact and Beriplex P/N, on Eliquis pharmacodynamics and pharmacokinetics in healthy subjects. Cofact and Beriplex P/N are used to stop severe bleeding in patients taking vitamin K antagonists, such as warfarin, or with a blood clotting factor deficiency. Currently there are no approved reversal agents for Eliquis or other direct Factor Xa inhibitors.
The study was an open label, randomized, placebo-controlled, three-period crossover study in 15 healthy, adult subjects (mean age 33±7 years). Within each period, subjects received Eliquis 10 mg twice daily. On day four (after steady-state was achieved), three hours after Eliquis administration, subjects received a 30-minute infusion of 4-factor PCCs, either 50 IU/kg Cofact or Beriplex P/N, or an equivalent volume of saline solution. The effect of Cofact and Beriplex P/N on the pharmacodynamics of Eliquis was based upon changes in endogenous thrombin potential, a measure of thrombin-mediated coagulation. Treatment periods were separated by an 11-day washout, after which the alternate treatment was administered.
The mean Eliquis pharmacokinetic profiles were consistent across all treatment groups and were not affected by PCC administration. Following completion of the 30-minute Cofact infusion, the effect of Eliquis on ETP was significantly reduced compared to placebo (p <0.001). Following completion of the 30-minute Beriplex P/N infusion, the effect of Eliquis on ETP was reduced; however, this did not achieve statistical significance (p >0.05). Mean ETP was comparable to the day four Eliquis pre-dose value (steady-state trough Eliquis concentration) at the end of the Cofact infusion and 30 minutes after completing the Beriplex P/N infusion. Mean ETP was within the baseline value (Eliquis naïve) within 5.5 hours after completing the infusion for both PCCs.
In this study, no serious adverse events, bleeding-related events or signs of thrombosis were reported with Eliquis administration with or without PCC treatment.
Overall, these data demonstrate that Cofact and Beriplex P/N reversed the steady-state pharmacodynamic effects of Eliquis as measured by ETP and support further evaluation of PCCs in the management of patients treated with Eliquis who require reversal of its anticoagulant effect.
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis decreases thrombin generation and blood clot formation. Eliquis is approved for multiple indications in the US based on efficacy and safety data, including results from seven phase 3 clinical trials. Eliquis is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE following initial therapy.