Novel Antiplatelet Drugs in Clinical Development
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868 Theme Issue Article Novel antiplatelet drugs in clinical development Martin Ungerer; Götz Münch AdvanceCor GmbH (previously, Procorde GmbH), Martinsried, Germany Summary bleeding risk they incur. This ratio is especially important in the treat- The clinical value of antiplatelet compounds strongly depends on the ment of cerebro-vascular disease. Several novel compounds in clinical benefit-risk balance between their anti-thrombotic effects and the development hold promise to improve this benefit-risk ratio. translational implications translational Correspondence to: Received: February 1, 2013 Platelets: basic mechanisms and Platelets: M. Ungerer or G. Münch Accepted after major revision: September 4, 2013 Advancecor GmbH Prepublished online: October 10, 2013 Fraunhofer Str. 17 doi:10.1160/TH13-02-0084 82152 Martinsried, Germany Thromb Haemost 2013; 110: 868-875 E-mail: [email protected], [email protected] Introduction approved drugs, and additional compounds are in clinical devel- opment for each of these target mechanisms. Atherothrombotic disease and, more specifically, plaque rupture lead to platelet activation and, consecutively, to thrombus formation. Therefore, platelets play a very relevant role in many Inhibitors of platelet P2Y12 receptors acute and chronic cardiovascular diseases. Acute coronary syn- dromes (ACS), such as myocardial infarction (MI), have been suc- Platelet ADP receptor inhibitors have been introduced into the cessfully treated with platelet inhibitors. Treatment of stroke with treatment of patients who suffer from cardiovascular diseases, and these compounds, however, was less successful, mainly due to an have been shown to provide relevant benefit in large clinical over proportionate increase in bleeding complications. Ischaemic studies. Several novel drugs as well as novel formulations of exist- stroke is the most frequent disabling disease and a leading cause of ing compounds are in clinical development (see ▶ Table 1 for death above the age of 60 years (1). Frequently, the underlying overview). cause is rupture of atherosclerotic plaques which leads to platelet Cangrelor (The Medicines Company, Parsippany, NJ, USA) is ad- adhesion and thrombus formation or embolisation into cerebral ministered intravenously, and is being studied as a pharmacologi- arteries. A significant medical need remains for the treatment of cally directly active, reversible P2Y12 antagonist (5). This non- this condition. thienopyridine is characterised by a rapid reversal of effects after A large amount of surface receptors and intraplatelet molecules the end of the infusion – a specific peculiarity which is not found support and regulate platelet activation, which has been inten- with the other currently approved P2Y12 antagonists. Similar to sively investigated during the recent decades. These findings led to prasugrel and ticagrelor, cangrelor is characterised by a faster onset the development of novel antiplatelet agents. Because of limited of action and stronger platelet inhibition than clopidogrel, and space, this review only focuses on novel platelet drugs in clinical showed no significant increase in major bleeding compared with development which have so far not been approved for the treat- clopidogrel in phase II studies (5). Cangrelor has already been ment of patients, including those whose clinical development has studied in two phase III trials, CHAMPION-PCI and CHAM- recently been terminated (see overview in ▶ Figure 1). We PION-PLATFORM, which were, however, both stopped early be- thought that such a combined overview should enhance the cause of lacking efficacy (6, 7). According to the authors of the understanding of the current state, as well as of benefits, pitfalls, study reports, this negative outcome might be due to an inappro- pros and cons of these novel drug classes. Therefore, many recent priate inclusion based on biomarkers of MI. Cangrelor has also achievements including, but not limited to platelet ADP receptor been studied as a bridge for patients on clopidogrel who need to inhibitors clopidogrel, prasugrel, ticagrelor, as well as to novel gly- terminate treatment before surgery (8) – the results included pro- coprotein (GP)IIb/IIIa antagonists and directly acting thrombin longed platelet inhibition with cangrelor. Cangrelor is currently and factor Xa inhibitors are not described in this review article, being investigated in the CHAMPION-PHOENIX phase III trial, and are outlined in many recent excellent reviews elsewhere (for which is still enrolling patients (trial NCT01156571; www.clinical example, please see references [2–4]). trials.gov/ct2/show/NCT01156571). The trial compares the effi- In the flowing arterial or venous blood, platelet activation can cacy and safety profile of cangrelor with standard of care (clopido- be triggered by several extra-cellular agonists, such as thrombox- grel) in patients who require percutaneous coronary intervention ane A2, ADP and thrombin. All these mechanisms are targeted by (PCI). Thrombosis and Haemostasis 110.5/2013 © Schattauer 2013 Downloaded from www.thrombosis-online.com on 2013-11-01 | IP: 88.162.114.204 For personal or educational use only. No other uses without permission. All rights reserved. Ungerer, Münch: Novel antiplatelet drugs 869 Elinogrel (PRT060128; Novartis, purchased from Portola, San tor 1 (PAR-1) and PAR-4 (13), and strongly activates several pla- Francisco, CA, USA) is also a non-thienopyridine, directly active, telet signalling pathways. PAR-1 is activated by lower concen- reversible P2Y12 antagonist, which can be administered orally or trations of thrombin than PAR-4 and mediates a more rapid pla- intravenously (9). It has been shown that patients who are subject telet activation response (14). PAR-1 antagonists are therefore in- to high remaining platelet reactivity to ADP after administration hibitors of thrombin-induced platelet activation but not of throm- of clopidogrel can be reversibly treated with elinogrel (10). It was bin-induced cleavage of fibrinogen (the final step in coagulation). shown in a phase II study that elinogrel, as compared to clopido- Preclinical studies have shown that selective PAR-1 blockade with grel, did not increase the general incidence of bleeding, although a an analogue to vorapaxar (SCH 530348; Schering-Plough, now specific endpoint of infarction-combined bleeding which required Merck Inc., Whitehouse Station, NJ, USA) results in a potent re- medical attention was more common (INNOVATE-PCI, 11). Nov- duction of platelet aggregation mediated by thrombin, but pre- artis therefore communicated a discontinuation of further devel- served haemostasis (15). Administration of vorapaxar had a sys- opment in 2012. temic effect in vivo and specifically suppressed thrombin-induced implications translational LG Life Science develops the reversible P2Y12 receptor antag- aggregation ex vivo (16). basic mechanisms and Platelets: onist LG 231306 in phase I, for a future indication in atherothrom- The PAR-1 antagonist vorapaxar, a tricyclic 3-phenylpyridine, bosis. is administered orally, and is rapidly absorbed (16). The molecule In summary, novel ADP receptor blockers are promising, but binds almost irreversibly to an unusual superficial binding pocket any increases in efficacy were always accompanied by an increased of the receptor protein (17). The phase II trial TRA-PCI demon- bleeding risk. This problem was even more obvious when combi- strated that vorapaxar inhibited thrombin receptor activating pep- nations of these drugs with other antiplatelet agents were used in tide (TRAP)–induced platelet aggregation in a dose-dependent clinical or in previous preclinical animal studies (12). manner, was generally well tolerated, and did not cause an increase In addition to the new chemical entities, novel formulations of in major bleeding, also when administered concomitantly with as- the drug clopidogrel are being studied. A clopidogrel formulation pirin or clopidogrel (18). Two phase III trials of vorapaxar have to be used for intravenous administration is being investigated in a been recently completed: TRACER (19) and TRA 2P-TIMI 50 phase III trial by The Medicines Company. Fixed dose combi- (20). TRACER was a randomised double-blinded trial comparing nations of clopidogrel and aspirin are being investigated by YuHan vorapaxar with placebo in addition to standard therapy in 12,944 and by Dong A Pharmaceuticals. patients who had ACS without ST segment elevation. The TRACER study was terminated early because of safety concerns. There was a significant reduction to 14.7% (vs 16.4% in controls) Thrombin receptor PAR-1 antagonists in a composite endpoint of death from cardiovascular causes, MI, or stroke. However, there was increased risk of moderate or severe Besides its activity in the coagulation cascade, thrombin acts on bleeding, as well as of intracranial haemorrhage (ICH). The trial two platelet G-protein coupled receptors, protease-activated recep- did not result in any change in all cause mortality. Figure 1: Schematic overview of new anti- platelet drugs in clini- cal development which inhibit platelet surface receptors and signal- ling pathways. The initial step of platelet activation depends on plaques and arterial lesions, and occurs mainly via vWF-GPIb and GPVI, which then lead to intra- platelet signal activation, and consecutive release of agents thrombin, ADP, thromboxane and others. These agents can then stimulate the respective receptors on the same and other platelets, and activate