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The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor

Key Points

  • In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first orally administered direct factor Xa inhibitor to be approved for clinical use in the prevention of venous thromboembolism (VTE) after elective hip- or knee-replacement surgery. This article reviews the rationale for its development, the chemical optimization programme that led to its synthesis, its pharmacological characterization and the completed and ongoing clinical studies that underlie its clinical promise.

  • The scientific premise on which a direct factor Xa inhibitor might help to reduce the burden associated with thromboembolic disorders across a range of medical conditions is also presented.

  • Successful early validation studies, conducted with naturally occurring inhibitors of factor Xa, led to the initiation in 1998 of a medicinal chemistry programme to develop oral selective synthetic factor Xa inhibitors. The article details the medicinal chemistry that culminated in the synthesis of rivaroxaban — a molecule that combines both potent, specific inhibition of factor Xa and good oral bioavailability.

  • Rivaroxaban's preclinical profile and subsequent Phase I studies showed that it has many of the characteristics required to address unmet clinical needs: high oral bioavailability, a fast onset/offset of action, dose-dependent pharmacokinetics and pharmacodynamics, few drug–drug or drug–food interactions and, as a result of these, no requirement for routine coagulation monitoring.

  • The extensive clinical-development programme, which will enrol over 65,000 patients, is reviewed and covers the four completed studies for VTE prevention after elective hip or knee replacement; the completed and ongoing VTE treatment studies; and the three ongoing studies for stroke prevention in patients with atrial fibrillation, prevention of recurrent events in acute coronary syndromes and VTE prevention in patients with an acute medical illness.

  • In closing, the article provides an overview of other oral anticoagulants in development and discusses their clinical potential with a view to the impact they may have in improving outcomes for patients affected by thromboembolic disorders.

Abstract

The activated serine protease factor Xa is a promising target for new anticoagulants. After studies on naturally occurring factor Xa inhibitors indicated that such agents could be effective and safe, research focused on small-molecule direct inhibitors of factor Xa that might address the major clinical need for improved oral anticoagulants. In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first such compound to be approved for clinical use. This article presents the history of rivaroxaban's development, from the structure–activity relationship studies that led to its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.

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Figure 1: Development of anticoagulants over the past century.
Figure 2: Simplified schematic for the blood coagulation cascade.
Figure 3: Structures of various factor Xa inhibitors.
Figure 4: Optimization of oxazolidinone factor Xa inhibitors.
Figure 5: Efficacy and safety dose–response relationships.

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Acknowledgements

The authors would like to acknowledge S. Salaria and S. McMillan, who provided medical writing services, with funding from Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development. We would also like to thank Proteros Biostructures, Planegg-Martinsried, Germany, for performing the X-ray crystal structure work on rivaroxaban.

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Correspondence to Elisabeth Perzborn.

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E.P., S.R., A.S., D.K. and F.M. are employed at Bayer HealthCare. E.P., S.R., A.S. and F.M. are shareholders.

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FURTHER INFORMATION

ClinicalTrials.gov

Bayer HealthCare Xarelto (rivaroxaban) Summary of Product Characteristics

GlaxoSmithKline, Arixtra (fondaparinux) prescribing information

Janssen Pharmaceutica Products, Nizoral (ketoconazole) tablets prescribing information

Abbott Laboratories, Norvir (ritonavir) prescribing information

EMA CHMP Assessment Report for Xarelto (rivaroxaban)

Bristol-Myers Squibb press release 18 Nov 2010 (APPRAISE-2 study with investigational compound apixaban in acute coronary syndrome discontinued)

Rocket AF study

Glossary

Thromboembolic disorders

A group of conditions characterized by an increased incidence of thrombi in the vasculature, such as deep-vein thrombosis, pulmonary embolism, systemic embolism or coronary and cerebral ischaemia.

Unfractionated heparin

(UFH). An anticoagulant administered intravenously or subcutaneously. It binds to antithrombin, greatly increasing its activity and resulting in the inhibition of factors Xa, IXa, XIa, XIIa and thrombin (factor IIa).

Heparin-induced thrombocytopaenia

The process by which antibodies against the complex of heparin and platelet factor 4 activate platelets, resulting in a decrease in platelet numbers of more than 50%.

Low-molecular-weight heparins

(LMWHs). A class of anticoagulants derived from unfractionated heparin by chemical or enzymatic degradation. They induce a conformational change in antithrombin that greatly increases its anticoagulant activity.

Thrombin

Thrombin (also known as factor IIa) is the terminal enzyme of the coagulation cascade and converts fibrinogen into fibrin, which forms clot fibres. Thrombin also activates several other coagulation factors, as well as protein C.

Antithrombin

An endogenous glycoprotein that binds covalently to thrombin and other coagulation factors, resulting in their inhibition. Antithrombin functions as a natural anticoagulant, and its inhibitory action is accelerated by heparin.

Warfarin

A vitamin K antagonist that is currently the most commonly used oral anticoagulant.

Vitamin K antagonist

A class of compounds that inhibit the vitamin K-dependent carboxylation of specific coagulation factors, resulting in decreased levels of the affected coagulation factors, leading to anticoagulation.

Therapeutic window

The interval between the lowest dose of a drug that is sufficient for clinical effectiveness and a higher dose at which adverse events or toxicity become unacceptable.

International normalized ratio

(INR). Because prothrombin time-test results vary according to the activity of the thromboplastin used, the INR conversion is used to normalize results for any thromboplastin preparation. It is valid only with vitamin K antagonists.

Thromboprophylaxis

A measure taken to prevent the development of a thrombus. It can be pharmaceutical or mechanical.

Tissue factor

A cell-membrane-bound receptor protein that is exposed to the circulating blood during vessel injury. Pre-existing factor VIIa in the blood binds to tissue factor, initiating the coagulation cascade.

Direct thrombin inhibitors

A class of anticoagulants that bind directly to thrombin and block the interaction with its substrate, fibrinogen, thereby inhibiting the generation of fibrin and clot formation.

Thrombomodulin

A membrane-bound thrombin receptor that, when bound to thrombin, functions as a cofactor in the thrombin-induced activation of protein C.

Protein C

The inactive precursor of activated protein C (APC). APC, with its cofactor protein S, inactivates factor Va and factor VIIIa, thus providing an important anticoagulant feedback function.

Factor Xa inhibitor

A class of anticoagulants that inhibit factor Xa in the coagulation cascade, either by binding directly, or indirectly through antithrombin. Inhibition of factor Xa reduces the production of thrombin.

Venous thromboembolism

(VTE). A condition in which a blood clot (thrombus) that has formed in the venous system breaks free (becoming an embolus) and migrates through the circulation to lodge in and block another blood vessel.

Deep-vein thrombosis

(DVT). A blood clot in a deep vein, usually in the leg. Distal DVT occurs in the calf, whereas proximal DVT occurs above the knee.

Pulmonary embolism

A blood clot or thromboembolus in a pulmonary blood vessel. Such emboli generally originate from a deep-vein thrombosis and can cause permanent lung damage, chronic pulmonary hypertension and death.

Haemostasis

The complex process that leads to the formation of a blood clot, causing bleeding to stop.

Fibrinogen

A soluble plasma protein that, in the final phase of the coagulation process, is converted to fibrin by thrombin. Fibrin then polymerizes and forms the fibrous network base of a clot.

Oral bioavailability

The total proportion of pharmacologically active drug that enters the systemic circulation after oral administration. It is affected by both absorption and local metabolic inactivation.

Prothrombin time

A laboratory test that measures clotting time in the presence of tissue factor (thromboplastin). It is used to assess the activity of the extrinsic coagulation pathway.

Activated partial thromboplastin time

A laboratory test that measures the clotting time of plasma after contact activation. It assesses the function of the intrinsic coagulation pathway.

CYP450 isoforms

Many therapeutic drugs are metabolized by cytochrome P450 (CYP450) enzymes, a 'superfamily' of related but distinct enzymes that differ in their substrate specificity.

Creatinine clearance

The rate at which the kidney clears the blood of creatinine (a waste product from muscles that is excreted at a fairly constant rate). Creatinine clearance is used as an approximation of the glomerular filtration rate.

Chromogenic assay

An enzymatic assay in which a colour develops during the course of the reaction, which can then be measured spectrophotometrically. Colour development is reduced in the presence of an inhibitor.

Venography

Radiography of the veins after intravenous injection of a radioactive isotope or contrast dye. This can be used to confirm the presence of deep-vein thromboses.

Index event

The acute event that leads to a patient's initial presentation. The term can also refer to the initial event resulting in a patient's inclusion in a follow-up study, such as a survey of recurrent strokes.

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Perzborn, E., Roehrig, S., Straub, A. et al. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 10, 61–75 (2011). https://doi.org/10.1038/nrd3185

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