Drug Discovery Today Volume 19, Number 9 September 2014
EDITORIAL
editorial William A. Schumacher
Xinkang Wang
Pancras C. Wong
New advances in treating thrombotic diseases
This issue of Drug Discovery Today: Therapeutic Strategies reviews therapeutic targets for the treatment of thrombotic diseases which are either in preclinical study, or at early phase clinical trials. There has been impressive progress in the recent FDA Advisory Committee reviews and/or FDA approvals of drugs that target platelets, such as the protease-activated receptor-1 antagonist vorapaxar, and those that target blood coagulation, including the Factor Xa inhibitors rivaroxaban, apixaban and edoxaban. However, it is not obvious that these and other new arrivals to the antithrombotic arsenal will provide the optimal combination of efficacy and safety required for the full range thrombo-embolic diseases. The quest continues to identify a therapeutic agent which can prevent vascular occlusion that leads to tissue injury, while at the same time preserve haemostasis. Each of the reviewed targets offers an opportunity to achieve this goal and satisfy unmet medical needs. The first four reviews address anticoagulant targets, all of which are serine proteases that have critical roles in the cascade of enzymatic reactions that lead to the formation of a fibrin clot. Factor IXa is presented by Dia Smiley and Richard Becker who are medical practitioners and researchers at the University of Cincinnati College of Medicine in Ohio. They describe Factor IXa as an opportunity where therapies offering rapid onset of inhibition can be balanced by selective and immediate reversal as dictated by clinical need. Charles Bane and David Gailani hail from Vanderbilt University in Nashville, Tennessee. They present Factor XIa as coagulation factor which plays a predominant role in thrombosis, but which may have limited impact on bleeding. Ellinor Kenne and Thomas Renne´ are investigators at the Karolinska Institutet in Stockholm, Sweden. Their discussion of Factor XIIa is a fitting complement to the presentation of Factor XIa. Both Factor XIa and XIIa have human deficiencies that are well tolerated, suggesting that therapeutic intervention may be relatively safe. Factors IXa, XIa and XIIa comprise proteases that constitute the classical ‘intrinsic pathway’ of the coagulation cascade. Another coagulation target reviewed here is FVIIa, which contributes to the initiation of the ‘extrinsic pathway’ by tissue factor (TF). Scott Priestly is a chemist at Bristol-Myers Squibb in Pennington, New Jersey. He presents a review of predominately small molecule inhibitors of Factor VIIa/TF. These four coagulation targets provide examples of therapies that cover the gamut of small molecules, peptides, antibodies and oligonucleotides. Both synthetic and naturally occurring substances are considered. The
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.06.015
www.drugdiscoverytoday.com
1433
EDITORIAL
Drug Discovery Today Volume 19, Number 9 September 2014
Editorial
biochemistry and physiology of each target are reviewed, including perspectives from classical and cell based models of coagulation. To date, selective and direct protease inhibitor drugs available for clinical use are limited to Factor Xa and IIa (thrombin), which comprise the final common pathway of the cascade. The fifth review complements anticoagulant targets by addressing reversal agents that are either currently available or in development. Deborah Siegal, from McMaster University in Hamilton, Ontario, Canada, and Adam Cuker, from the University of Pennsylvania in Philadelphia, are hematologists whose review covers both preclinical and clinical aspects of this topic. Included are non-specific agents that are applicable to traditional anticoagulants, such as heparins and warfarin, and the more recent agents that are compound or protease specific. One platelet target is presented by Peng Jiang and Martine JandrotPerrus from INSERM and the University of Paris Diderot in Paris, France. They review glycoprotein VI (GP VI) which is a predominant platelet receptor for collagen, long recognized as an important pathway of platelet aggregation. Unlike G-protein coupled receptors (ADP:P2Y12 and thrombin:PAR-1) that have been successfully targeted with small molecule antagonists, GP VI has necessitated mechanisms which disrupt protein–protein interactions. Our final review addresses modulation of the fibrinolytic system which functions to dissolve thrombi in vivo. Tine Wysecure and Paul Declerck from KU Leuven in Leuven, Belgium, discuss mechanisms to enhance the activity of either the endogenous system or exogenously administered therapeutic lytics, such as recombinant tissue plasminogen activator (tPA). Emphasis is placed on methods to disrupt endogenous inhibitors of fibrinolysis including plasminogen activator inhibitor-1 (PAI-1) and thrombin-activated fibrinolysis inhibitor (TAFI). Targeting PAI-1 and TAFI may provide an alternative to direct tPA therapy where overdosing can result in life-threatening hemorrhage. Labelling restrictions and clinical studies with recent antithrombotic drugs has identified reduction of bleeding liability and the retention or enhancement of efficacy as opportunities for next generation therapies. The targets described in this issue may offer such improvements and are worthy of pharmaceutical research.
William Schumacher, PhD, FAHA is a research fellow in cardiovascular discovery at BristolMyers Squibb Company with primary responsibility for characterizing the in vivo pharmacology of antithrombotic drug candidates, including the factor Xa inhibitor Eliquis. He has 30 years of drug discovery experience having started at E.R. Squibb & Sons right after completing a post-doc in the laboratory of Dr Benedict Lucchesi at the University of Michigan. Dr Schumacher received a doctorate in pharmacology from the University of Minnesota, and a bachelor’s degree in biology from the University of California at Irvine. He has been a long time member of the American Heart Association, the American Society for Pharmacology and Experimental Therapeutics and the International Society on Thrombosis and Haemostasis. In addition to publishing over 80 peerreviewed articles, he is an ongoing contributor to the peer-review process.
With best wishes, William Schumacher, Xinkang Wang, and Pancras Wong
*Corresponding author: email: [email protected]
1434
www.drugdiscoverytoday.com
Xinkang Wang, PhD, FAHA is a Principal Scientist in cardiometabolic disease area at Merck Research Laboratories responsible for novel antithrombotic drug discovery and development. Before joining Merck in August 2012, he was a Director of Translational Science at Agennix, USA contributed to strategic drug development and mechanism of action for novel biological therapeutic at late stage clinical studies for the treatment of non-small cell lung carcinoma and severe sepsis in patients. Dr Wang started with his drug discovery career at SmithKline Beecham and Bristol-Myers Squibb in cardiovascular disease area, and later was a head of the core imaging biomarker lab to support multiple drug discovery programs in various therapeutic areas at Wyeth prior to joining Agennix. Dr Wang earned his BS from Zhejiang University and his PhD from the University of Pennsylvania in Biology. He received post-doctoral training at the University of Pennsylvania and SmithKline Beecham. He has published more than 130 peer-reviewed articles, review articles/book chapters and has edited an eBook entitled ‘Translational Animal Models of Disease for Drug Discovery and Development’. He has served as a reviewer for multiple peer-reviewed journals. Pancras C. Wong, PhD, FAHA, is a senior research fellow in Cardiovascular Discovery at BristolMyers Squibb Company. Dr Wong has dedicated 30 years to drug discovery research and has codiscovered two marketed drugs, losartan (Cozaar) for the treatment of hypertension and heart failure, and apixaban (Eliquis) for the reduction of risk of stroke and systemic embolism in atrial fibrillation. Dr Wong, a native of Hong Kong, received his BA degree in Chemistry from the University of Oregon, Eugene, Oregon, and PhD in Pharmacology from the University of Minnesota, Minneapolis, Minnesota. Before joining Bristol-Myers Squibb in 2001, he started his pharmaceutical career in Hoechst-Roussell Pharmaceuticals and the DuPont Company. Dr Wong has authored 161 papers and 73 abstracts. He was named an inventor in 15 patents and applications. The American Society for Information Science and Technology designated Dr Wong in 2001 as a Highly Cited Scientist for being among the top one-hundred most cited Pharmacologists in the world over the past two decades. Dr Wong received a number of prestigious awards, including Bacaner Basic Science Award from the University of Minnesota (1982), American Chemical Society Award for Team Innovation (1997), Shideman Distinguished Alumnus Award from the University of Minnesota (2001), Ondetti & Cushman Award for Scientific Excellence from Bristol-Myers Squibb (2011) and Robert R. Ruffolo Career Achievement Award in Pharmacology from the American Society for Pharmacological Experimental Therapeutics (2013). Dr Wong is an elected Fellow of the American Heart Association and a member of the American Society for Pharmacological Experimental Therapeutics and the British Society of Pharmacology.
William A. Schumacher1, Xinkang Wang2, Pancras C. Wong1,* 1 Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA 2 Thrombosis Biology, Merck Research Lab, 2015 Galloping Hill Road, K15-C302, Kenilworth, NJ 07033, USA
EDITORIAL
editorial William A. Schumacher
Xinkang Wang
Pancras C. Wong
New advances in treating thrombotic diseases
This issue of Drug Discovery Today: Therapeutic Strategies reviews therapeutic targets for the treatment of thrombotic diseases which are either in preclinical study, or at early phase clinical trials. There has been impressive progress in the recent FDA Advisory Committee reviews and/or FDA approvals of drugs that target platelets, such as the protease-activated receptor-1 antagonist vorapaxar, and those that target blood coagulation, including the Factor Xa inhibitors rivaroxaban, apixaban and edoxaban. However, it is not obvious that these and other new arrivals to the antithrombotic arsenal will provide the optimal combination of efficacy and safety required for the full range thrombo-embolic diseases. The quest continues to identify a therapeutic agent which can prevent vascular occlusion that leads to tissue injury, while at the same time preserve haemostasis. Each of the reviewed targets offers an opportunity to achieve this goal and satisfy unmet medical needs. The first four reviews address anticoagulant targets, all of which are serine proteases that have critical roles in the cascade of enzymatic reactions that lead to the formation of a fibrin clot. Factor IXa is presented by Dia Smiley and Richard Becker who are medical practitioners and researchers at the University of Cincinnati College of Medicine in Ohio. They describe Factor IXa as an opportunity where therapies offering rapid onset of inhibition can be balanced by selective and immediate reversal as dictated by clinical need. Charles Bane and David Gailani hail from Vanderbilt University in Nashville, Tennessee. They present Factor XIa as coagulation factor which plays a predominant role in thrombosis, but which may have limited impact on bleeding. Ellinor Kenne and Thomas Renne´ are investigators at the Karolinska Institutet in Stockholm, Sweden. Their discussion of Factor XIIa is a fitting complement to the presentation of Factor XIa. Both Factor XIa and XIIa have human deficiencies that are well tolerated, suggesting that therapeutic intervention may be relatively safe. Factors IXa, XIa and XIIa comprise proteases that constitute the classical ‘intrinsic pathway’ of the coagulation cascade. Another coagulation target reviewed here is FVIIa, which contributes to the initiation of the ‘extrinsic pathway’ by tissue factor (TF). Scott Priestly is a chemist at Bristol-Myers Squibb in Pennington, New Jersey. He presents a review of predominately small molecule inhibitors of Factor VIIa/TF. These four coagulation targets provide examples of therapies that cover the gamut of small molecules, peptides, antibodies and oligonucleotides. Both synthetic and naturally occurring substances are considered. The
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.06.015
www.drugdiscoverytoday.com
1433
EDITORIAL
Drug Discovery Today Volume 19, Number 9 September 2014
Editorial
biochemistry and physiology of each target are reviewed, including perspectives from classical and cell based models of coagulation. To date, selective and direct protease inhibitor drugs available for clinical use are limited to Factor Xa and IIa (thrombin), which comprise the final common pathway of the cascade. The fifth review complements anticoagulant targets by addressing reversal agents that are either currently available or in development. Deborah Siegal, from McMaster University in Hamilton, Ontario, Canada, and Adam Cuker, from the University of Pennsylvania in Philadelphia, are hematologists whose review covers both preclinical and clinical aspects of this topic. Included are non-specific agents that are applicable to traditional anticoagulants, such as heparins and warfarin, and the more recent agents that are compound or protease specific. One platelet target is presented by Peng Jiang and Martine JandrotPerrus from INSERM and the University of Paris Diderot in Paris, France. They review glycoprotein VI (GP VI) which is a predominant platelet receptor for collagen, long recognized as an important pathway of platelet aggregation. Unlike G-protein coupled receptors (ADP:P2Y12 and thrombin:PAR-1) that have been successfully targeted with small molecule antagonists, GP VI has necessitated mechanisms which disrupt protein–protein interactions. Our final review addresses modulation of the fibrinolytic system which functions to dissolve thrombi in vivo. Tine Wysecure and Paul Declerck from KU Leuven in Leuven, Belgium, discuss mechanisms to enhance the activity of either the endogenous system or exogenously administered therapeutic lytics, such as recombinant tissue plasminogen activator (tPA). Emphasis is placed on methods to disrupt endogenous inhibitors of fibrinolysis including plasminogen activator inhibitor-1 (PAI-1) and thrombin-activated fibrinolysis inhibitor (TAFI). Targeting PAI-1 and TAFI may provide an alternative to direct tPA therapy where overdosing can result in life-threatening hemorrhage. Labelling restrictions and clinical studies with recent antithrombotic drugs has identified reduction of bleeding liability and the retention or enhancement of efficacy as opportunities for next generation therapies. The targets described in this issue may offer such improvements and are worthy of pharmaceutical research.
William Schumacher, PhD, FAHA is a research fellow in cardiovascular discovery at BristolMyers Squibb Company with primary responsibility for characterizing the in vivo pharmacology of antithrombotic drug candidates, including the factor Xa inhibitor Eliquis. He has 30 years of drug discovery experience having started at E.R. Squibb & Sons right after completing a post-doc in the laboratory of Dr Benedict Lucchesi at the University of Michigan. Dr Schumacher received a doctorate in pharmacology from the University of Minnesota, and a bachelor’s degree in biology from the University of California at Irvine. He has been a long time member of the American Heart Association, the American Society for Pharmacology and Experimental Therapeutics and the International Society on Thrombosis and Haemostasis. In addition to publishing over 80 peerreviewed articles, he is an ongoing contributor to the peer-review process.
With best wishes, William Schumacher, Xinkang Wang, and Pancras Wong
*Corresponding author: email: [email protected]
1434
www.drugdiscoverytoday.com
Xinkang Wang, PhD, FAHA is a Principal Scientist in cardiometabolic disease area at Merck Research Laboratories responsible for novel antithrombotic drug discovery and development. Before joining Merck in August 2012, he was a Director of Translational Science at Agennix, USA contributed to strategic drug development and mechanism of action for novel biological therapeutic at late stage clinical studies for the treatment of non-small cell lung carcinoma and severe sepsis in patients. Dr Wang started with his drug discovery career at SmithKline Beecham and Bristol-Myers Squibb in cardiovascular disease area, and later was a head of the core imaging biomarker lab to support multiple drug discovery programs in various therapeutic areas at Wyeth prior to joining Agennix. Dr Wang earned his BS from Zhejiang University and his PhD from the University of Pennsylvania in Biology. He received post-doctoral training at the University of Pennsylvania and SmithKline Beecham. He has published more than 130 peer-reviewed articles, review articles/book chapters and has edited an eBook entitled ‘Translational Animal Models of Disease for Drug Discovery and Development’. He has served as a reviewer for multiple peer-reviewed journals. Pancras C. Wong, PhD, FAHA, is a senior research fellow in Cardiovascular Discovery at BristolMyers Squibb Company. Dr Wong has dedicated 30 years to drug discovery research and has codiscovered two marketed drugs, losartan (Cozaar) for the treatment of hypertension and heart failure, and apixaban (Eliquis) for the reduction of risk of stroke and systemic embolism in atrial fibrillation. Dr Wong, a native of Hong Kong, received his BA degree in Chemistry from the University of Oregon, Eugene, Oregon, and PhD in Pharmacology from the University of Minnesota, Minneapolis, Minnesota. Before joining Bristol-Myers Squibb in 2001, he started his pharmaceutical career in Hoechst-Roussell Pharmaceuticals and the DuPont Company. Dr Wong has authored 161 papers and 73 abstracts. He was named an inventor in 15 patents and applications. The American Society for Information Science and Technology designated Dr Wong in 2001 as a Highly Cited Scientist for being among the top one-hundred most cited Pharmacologists in the world over the past two decades. Dr Wong received a number of prestigious awards, including Bacaner Basic Science Award from the University of Minnesota (1982), American Chemical Society Award for Team Innovation (1997), Shideman Distinguished Alumnus Award from the University of Minnesota (2001), Ondetti & Cushman Award for Scientific Excellence from Bristol-Myers Squibb (2011) and Robert R. Ruffolo Career Achievement Award in Pharmacology from the American Society for Pharmacological Experimental Therapeutics (2013). Dr Wong is an elected Fellow of the American Heart Association and a member of the American Society for Pharmacological Experimental Therapeutics and the British Society of Pharmacology.
William A. Schumacher1, Xinkang Wang2, Pancras C. Wong1,* 1 Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA 2 Thrombosis Biology, Merck Research Lab, 2015 Galloping Hill Road, K15-C302, Kenilworth, NJ 07033, USA
