Description of the chemical and pharmacological characteristics of a new hemisynthetic ultra‐low‐molecular‐weight heparin, AVE5026

Background and objectives: AVE5026 is a novel, hemisynthetic, ultra‐low‐molecular‐weight heparin (ULMWH), which is in clinical development for prevention of venous thromboembolism. Its unique structural features result from the highly selective depolymerization of heparin by the phosphazene base that protects the antithrombin (AT)‐binding site from destruction. In the present paper, we describe the chemical and biological characteristics of AVE5026, as well as its effects on experimental thrombosis as compared to those of the low‐molecular‐weight heparin (LMWH) enoxaparin after a single subcutaneous (s.c.) administration in certain animal models. Method and results: AVE5026 has a higher anti‐factor Xa (anti‐FXa) activity (∼160 U mg−1) along with a catalytic anti‐thrombin (anti‐FIIa) activity (∼2 U mg−1) as a result of its structure being strongly enriched in specific AT‐binding oligosaccharides. In human plasma, potent inhibition of thrombin generation by AVE5026 was closely related to its anti‐FXa activity. In a rat venous thrombosis model, AVE5026 showed a dose‐dependent antithrombotic activity comparable to that of enoxaparin (ED50‐AVE5026 = 1.6 mg kg−1, ED50‐enoxaparin = 2.8 mg kg−1). Interestingly, non‐occlusive venous thrombosis in rabbits was inhibited by an ED50 of 0.1 mg kg−1 AVE5026, whereas 0.316 mg kg−1 enoxaparin was not active. In a canine model, similarly to enoxaparin (ED50 = 1.3 mg kg−1), AVE5026 dose‐dependently inhibited arterial thrombosis (ED50 = 2.0 mg kg−1). At equipotent doses, AVE5026 did not affect bleeding parameters, whereas enoxaparin showed increased hemorrhage in rats, rabbits and dogs. Conclusion: These unique structural attributes distinguish AVE5026 from the LMWH class. Based on these data in well‐established arterial and venous thrombosis models, AVE5026 could represent a valuable alternative in thrombosis prevention with an improved benefit‐risk profile as compared to that of enoxaparin.