Bristol-Myers Squibb Company and Pfizer Inc. announced that the European Commission has approved Eliquis for the treatment of DVT and PE, and the prevention of recurrent DVT and PE in adults.
The European Commission approval applies to all European Union (EU) member states as well as Iceland and Norway. Eliquis is also approved in the EU for the prevention of venous thromboembolism (VTE) in adults who have undergone elective total hip or knee replacement surgery, and for the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors.
“Every year, approximately one million patients in the EU are diagnosed with VTE,” said Dr. Elliott Levy, senior vice president, head of Specialty Development, Bristol-Myers Squibb. “Once a VTE has occurred, approximately 33 per cent of patients may experience a recurrence within 10 years.”
The marketing authorization for Eliquis follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, and is supported by two pivotal Phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT. AMPLIFY (Apixaban for the initial Management of PuLmonary embolIsm and deep vein thrombosis as First-line therapY) was designed to demonstrate the efficacy and safety of Eliquis for the treatment of DVT and PE versus enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR= 2) and warfarin (target INR range 2.0-3.0) orally for six months. AMPLIFY-EXT (Apixaban after the initial Management of Pulmonary embolism and deep vein thrombosis with First-line therapy-Extended treatment) was designed to demonstrate the efficacy and safety of Eliquis compared to placebo for the prevention of recurrent DVT and PE following six to 12 months of anticoagulant treatment for DVT and/or PE.
“The European Commission’s approval of Eliquis for the treatment of DVT and PE and the prevention of recurrence is an important milestone and demonstrates Bristol-Myers Squibb and Pfizer’s ongoing commitment to bringing innovative medicines to patients who need them,” said Steve Romano, senior vice president, head of Medicines Development Group for Global Innovative Pharmaceuticals, Pfizer Inc.
As described in the SmPC, in the AMPLIFY study a total of 5,395 patients were randomized to treatment with Eliquis 10 mg twice daily orally for seven days followed by Eliquis 5 mg twice daily orally for six months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least five days (until INR= 2) and warfarin (target INR range 2.0-3.0) orally for six months.
The mean age was 56.9 years and 89.8 percent of randomized patients had unprovoked VTE events.In the study, Eliquis was shown to be non-inferior to enoxaparin/warfarin in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death.
Eliquis efficacy in initial treatment of VTE was consistent between patients who were treated for a PE [Relative Risk 0.9; 95 percent CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95 percent CI (0.5, 1.3)]. Efficacy across subgroups, including age, gender, body mass index (BMI), renal function, extent of index PE, location of DVT thrombus, and prior parenteral heparin use was generally consistent.
For patients randomized to warfarin, the mean percentage of time in therapeutic range (TTR) (INR 2.0-3.0) was 60.9. The effect of Eliquis on recurrent symptomatic VTE or VTE- related death was consistent across the different levels of center TTR; within the highest quartile of TTR according to center, the relative risk for Eliquis vs enoxaparin/warfarin was 0.79 (95 per cent CI, 0.39, 1.61).
The primary safety endpoint was major bleeding. In the study, Eliquis was statistically superior to enoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95 per cent confidence interval (0.17, 0.55), P-value <0.0001].
The adjudicated major bleeding and clinically relevant non-major (CRNM) bleeding at any anatomical site were generally lower in the Eliquis group as compared to the enoxaparin/warfarin group. Adjudicated International Society on Thrombosis and Haemostasis (ISTH) major gastrointestinal bleeding occurred in 6 (0.2 percent) Eliquis-treated patients and 17 (0.6 percent) enoxaparin/warfarin-treated patients.
As described in the SmPC, in the AMPLIFY-EXT study a total of 2,482 patients were randomized to treatment with Eliquis 2.5 mg twice daily orally,Eliquis 5 mg twice daily orally, or placebo for 12 months after completing six to 12 months of initial anticoagulant treatment. Of these, 836 patients (33.7 percent) participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.
The mean age was 56.7 years and 91.7 percent of randomised patients had unprovoked VTE events.
In the study, both doses of Eliquis were statistically superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death.
Eliquis efficacy for prevention of a recurrence of a VTE was maintained across subgroups, including age, gender, BMI, and renal function.
The primary safety endpoint was major bleeding during the treatment period. In the study, the incidence in major bleeding for both Eliquis doses was not statistically different from placebo. There was no statistically significant difference in the incidence of major, clinically relevant non-major, minor, and all bleeding between the Eliquis 2.5 mg twice daily and placebo treatment groups. The recommended dose of Eliquis for the prevention of recurrent DVT and PE is 2.5 mg taken orally twice daily.
Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1 per cent) Eliquis-treated patient at the 5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1 per cent) placebo-treated patient.