Current Drug Discovery Technologies (v.9, #2)

Heparin and vitamin K antagonists (VKA) have been the mainstay of anticoagulant therapy for more than 60 years, thus representing true milestones in the improvement of patients care. Nevertheless, these drugs have several limitations, such as the need for parenteral administration (i.e. heparins), slow onset of action, a narrow therapeutic window, multiple drug interactions, genetic polymorphisms and need for anticoagulant monitoring (i.e. VKA). In recent years, new anticoagulant drugs have been developed with the aim of overcoming the limitations of traditional anticoagulants. New oral anticoagulants, like dabigatran, rivaroxaban and apixaban, have been recently licensed for the prophylaxis of venous thromboembolism (VTE) after hip or knee replacement in Europe and other countries. These new drugs also have the potential to replace warfarin for long-term anticoagulation. This special issue of Current Drug Discovery Technologies, for which I have the honour to be Guest Editor, includes seven review articles highlighting in detail some of important points relating to development of new anticoagulants from a historical, biopharmaceutical, methodological, clinical and future perspective....

The history of the traditional anticoagulants is marked by both perseverance and serendipity. The anticoagulant effect of heparin was discovered by McLean in 1915, while he was searching for a procoagulant in dog liver. Link identified dicumarol from spoiled sweet clover hay in 1939 as the causal agent of the sweet clover disease, a hemorrhagic disorder in cattle. Hirudin extracts from the medicinal leech were first used for parenteral anticoagulation in the clinic in 1909, but their use was limited due to adverse effects and difficulties in achieving highly purified extracts. Heparins and coumarins (i.e.: warfarin, phenprocoumon, acenocoumarol) have been the mainstay of anticoagulant therapy for more than 60 years. Over the past decades, the drug discovery paradigm has shifted toward rational design following a target-based approach, in which specific proteins, or “targets”, are chosen on current understandings of pathophysiology, small molecules that inhibit the target's activity may be identified by high-throughput screening and, in selected cases, these new molecules can be developed further as drugs. Despite the application of rational design, serendipity has still played a significant role in some of the new discoveries. This review will focus on the discovery of the main anticoagulant drugs in current clinical use, like unfractionated heparin, low-molecular-weight heparins, fondaparinux, coumarins (i.e.: warfarin, acenocoumarol, phenprocoumon), parenteral direct thrombin inhibitors (DTIs) (i.e.: argatroban, recombinant hirudins, bivalirudin), oral DTIs (i.e.: dabigatran) and oral direct factor Xa inhibitors (i.e.: rivaroxaban, apixaban).

Coinciding in time with the expiration of the patent of enoxaparin and clopidogrel, a number of new antithrombotics (anticoagulants and antiplatelets with new mechanisms of action) have been developed or are still under development for both venous and arterial thromboembolic complications. The effect of antithrombotic drugs is a continuum where a fine tune assessment of the ischemic events that are intended to be prevented and bleeding complications derived naturally from the own mechanism of action of the administered agent is essential. This paper discusses relevant aspects of pivotal studies aimed to support the marketing authorisation application of new antithrombotics for the prophylaxis or treatment of venous thromboembolism on one hand, and arterial thromboembolism on the other hand (acute coronary syndromes and stroke and systemic embolic events in patients with atrial fibrillation). General methodological issues and tools to assess efficacy and safety parameters and problems encountered in the way they are measured and classified are discussed.

Several oral direct anti-Xa agents and one antithrombin agent are currently under clinical development for the prevention and treatment of venous thromboembolism (VTE). The anti-Xa inhibitors rivaroxaban (10 mg once daily) and apixaban (2.5 mg twice daily) as well as the thrombin inhibitor dabigatran (150 or 220 mg once daily) have been recently licensed for the prevention of VTE in total hip or knee replacement. The publication of the results of studies with rivaroxaban and apixaban in the prevention of VTE in medical patients are awaited. Phase III studies on the treatment of VTE showed the non inferiority of rivaroxaban (15 mg twice daily in the first three weeks and 20 mg once daily thereafter) and dabigatran (150 mg twice daily) to standard treatment. The incidence of major or clinically relevant non-major bleeding was similar in patients receiving standard treatment and rivaroxaban or dabigatran. Clinical trials on VTE treatment are currently ongoing with apixaban and edoxaban. A number of phase II clinical trials are currently ongoing with several other antiXa agents in the prophylaxis and treatment of VTE.

For decades, unfractionated heparin (UFH) was the most widely used parenteral anticoagulant in a variety of clinical scenarios requiring rapid and reversible anticoagulation. The shortcomings of UFH include a high inter-individual variability and the occurrence of heparin induced thrombocytopenia with the potential for serious thromboembolic complications. These shortcomings prompted the successful clinical development of low molecular weight heparins (LMWH) and indirect factor Xa inhibitors such as fondaparinux. LMWH and fondaparinux demonstrated superiority in many clinical scenarios including acute coronary syndromes (ACS). However the long half-life and the lack of a specific antidote still require the usage of UFH in clinical situations where a rapid reversibility of the anticoagulation is required. Especially in ACS patients undergoing PCI, a direct parenteral inhibition of thrombin with the direct thrombin inhibitor (DTI) bivalirudin proved to be an alternative anticoagulant strategy. This has set the stage for the clinical development of other parenteral DTIs. The reduction in clinical ischemic events that were achieved with indirect factor Xa inhibitors in patients with ACS facilitated the clinical development of the first parenteral direct factor Xa inhibitor, otamixaban which is currently investigated in a phase III clinical trial in patients with ACS undergoing PCI. This article discusses novel parenteral factor Xa and thrombin inhibitors currently under clinical investigation including aptamers, a new class of drugs that allows the parallel development of the combination of active drug and reversal agent, which is facilitated by the DNA or RNA structure of which aptamers are composed of.

The aim of the present paper is to address the legal aspects, technical requirements and possible conditions of use associated to low molecular weight heparin generics and biosimilars that are arriving to the market in United States and the European Union, respectively. To this end the concept of “similar biological medicinal product” that was coined in 2003 by the pharmaceutical legislation of the European Union is compared to the concept of generic in the United States and the concept of generic in the European Union. This different legal basis determines directly the technical requirements to obtain a marketing authorisation. Therefore, the chemical/biological, non-clinical and clinical requirements to demonstrate therapeutic equivalence are different in these two Regulatory Authorities, FDA and EMA. Consequently, the possible conditions of use are different. In the United States the products approved as generics by the FDA are considered interchangeable to the Reference Listed Drug. In contrast, the EMA legislation only deals with the approvability or prescribability of the medicines and it is a national / regional decision of the member States to consider these biosimilar products as interchangeable or not.

Reversing Anticoagulant Therapy by Shari Ghanny (143-149).
For more than 50 years, heparin(s) and warfarin have been the most important anticoagulant agents, and clinicians are accustomed to their specific antidotes (protamine sulfate and vitamin K/plasma [or factor concentrates], respectively). Recently, there has been an explosion of novel anticoagulant development: ideally, these newer agents should have advantages over traditional anticoagulants, such as fewer side effects, a more predictable pharmacokinetic profile (and potentially no need for monitoring), minimal drug-drug interactions, and so forth. But, unlike the older agents, the newer anticoagulants do not have specific antidotes. There is increasing focus on the use of nonspecific procoagulants, such as non-activated and activated prothrombin complex concentrates (PCCs) and recombinant factor VIIa (rFVIIa), to manage major bleeding or need for emergency invasive procedures. This paper reviews several of the novel anticoagulants and presents the available evidence for their “reversal”. Based on extrapolation from animal models, clinical anecdote, and an understanding of their mechanism of action, we recommend treating major bleeding complications of DTIs, as follows (in descending order of preference): activated PCCs; rFVIIa; and (non-activated) PCCs. For management of fondaparinux-associated bleeding, rFVIIa has some rationale (for which we provide an illustrative case). The increasing use of novel anticoagulants will require physicians to have an understanding of rational approaches to “reverse” their anticoagulant effects when true antidotes do not exist.

Unfractionated heparin (UFH) and the vitamin K antagonists (VKA), have been standard anticoagulants for the last 70 years. They have a widespread effect on many coagulation factors, the serine proteases for UFH and the vitamin K dependent factors for the VKAs. Refinements in the heparin molecule have occurred with the development of low molecular weight heparins and eventually, fondaparinux, the latter of which, has only indirect anti-Xa activity. In the last two decades, more target-specific drugs such as the parenteral direct thrombin inhibitors have been introduced into clinical practice (lepirudin, bivalirudin, argatroban, and desirudin) and are widely used for selected indications in hospitalized patients. More recently, the trend in anticoagulant development continues to target a specific factor either directly or indirectly. Of great interest is the recent development of many oral direct factor inhibitors, the first new agents poised to replace the VKAs. Of these, the oral direct Xa and IIa inhibitors are most promising and are far along in development. However, other coagulation factors have been considered suitable targets for drug development. The following paper discusses these agents and their selected targets, heparin