The development and introduction of biosimilar anticoagulants – focus on enoxaparin

Jeffrey S Ginsberg

Department of Medicine, McMaster University, Hamilton, Ontario, Canada


Abstract: The aims of this paper are to discuss the: (1) pharmacology of low-molecular-weight heparins (LMWHs) emphasizing their synthesis, mechanism of action, and comparison with the parent compound, unfractionated heparin (UFH); and (2) recent controversial approval by the Food and Drug Administration (FDA) of a generic enoxaparin. Enoxaparin is one of several LMWHs that are currently available worldwide for clinical use. LMWHs are derived by chemical or enzymatic depolymerization of the “parent” molecule, UFH. Both UFH and LMWHs exert their primary antithrombotic effect by binding to and catalyzing the naturally-occurring anticoagulant, antithrombin. LMWHs are more effective at inhibiting factor Xa than factor IIa (thrombin). They also produce less heparin-induced thrombocytopenia and osteoporosis than UFH and are at least as effective and safe as UFH for each approved indication. They are safe and effective when given subcutaneously once or twice daily, without the need for anticoagulant monitoring, and are suitable for out-of-hospital treatment. The FDA first approved enoxaparin (Lovenox^®) in March 1993. Despite its cost effectiveness, individual patients without drug insurance are often left paying for the cost of the drug. Uninsured pregnant subjects are particularly disadvantaged because they often require several months of therapy, costing several thousand dollars. To evaluate a less expensive, generic enoxaparin, the FDA chose to use the “abbreviated new drug application” because it considered enoxaparin to be a drug rather than a biologic medicine. This requires that the generic enoxaparin meets the following five criteria for “sameness”: equivalence of (1) UFH source material and method of depolymerization; (2) physicochemical properties; (3) disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) biological and biochemical assays; and (5) in vivo pharmacokinetic profile. Based upon meeting these criteria, and despite protests from several outside expert groups, the generic enoxaparin was approved by the FDA in July 2010.

Keywords: antithrombotic therapy, enoxaparin, unfractionated heparin, low molecular weight heparin