DRUDIS-1487; No of Pages 4 Drug Discovery Today Volume 00, Number 00 September 2014
PERSPECTIVE
feature An analysis of FDA-approved drugs for cardiovascular diseases
Following the introduction of antibiotic therapy and widespread inoculations, cardiovascular diseases have leapt ahead of infectious diseases in terms of prevalence in much of the developed and developing world. Herein, we assess FDA-approved drugs for the treatment of cardiovascular diseases. The drug development enterprise around cardiovascular diseases has remained stable in contrast to turbulent changes in other therapeutic indications. However, upon closer inspection, the results identify narrow scope in terms of the breadth of targets and the mechanistic actions of new drugs. From the public health point of view, it is important to balance incremental change with orthogonal innovations that are needed to combat a leading cause of morbidity and mortality.
Background Human beings have constantly struggled to find new treatments for heart disease. The diagnosis of ‘hard pulse disease’ (today known as hypertension) was addressed more than four millennia ago in ancient China through the use blood letting or leeches to reduce blood volume [1]. The seminal publication of Anatomica de Motu Cordis et Sanguinis in Animalibusin by William Harvey provided the framework for the modern understanding of heart function and, consequently, a new means to target cardiovascular diseases [2]. Modern attempts to address heart diseases in their various manifestations have led to an accumulation of new drugs to address age-old challenges [3]. Burroughs Wellcome received the first FDA approval for a cardiovascular new molecular entity (NME), digoxin, in January 1937. Since that time, the FDA has approved 201 different NMEs through to the end of 2013
(Fig. 1a). When viewed over time, the average rate of introduction of NMEs has remained relatively steady since the 1950s, with an average of 2.7 NMEs per year (Fig. 1b). Likewise, the number of companies active in the cardiovascular NME research and development space has grown steadily over time (Fig. 1c). The number of organizations with active cardiovascular research and development shrank as a consequence of mergers and acquisitions but recently stabilized at a range of 35–45 companies. This relative constancy is somewhat surprising given the number of mergers of major pharmaceutical companies in the 1980s and 1990s. We evaluated the volatility by evaluating the number of active and independent companies that entered (as a result of gaining at least one FDA approval for a cardiovascular indication) and exited (as a result of a merger, acquisition or bankruptcy) the field. Indeed, there has been a large number of exits in recent years but this has
been offset by the introduction of new organizations (Fig. 1d). This steadiness differs dramatically from the impact that volatility has had upon infectious diseases but lacks the growth of companies in the oncology space [4,5]. Unlike the situation with all other disease areas evaluated to date, the pharmaceutical industry continues to dominate cardiovascular diseases. Biotechnology companies (defined herein as those founded after 1971) remain in the minority in terms of contributing the first patent, investigational new drug (IND) applications or participation in clinical trials. This could be explained at least in part by our recent findings that biotechnology companies tend to favor orphan indications and biologics. Indeed, only seven biologics (from a total of 94 biologics ever approved) were approved with an initial indication being in the field of cardiovascular disease. Moreover, only five cardiovascular NMEs have ever been approved with an initial orphan
www.drugdiscoverytoday.com 1 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.09.001
Features PERSPECTIVE
Michael S. Kinch, [email protected], [email protected], [email protected], Yulia Surovtseva and Denton Hoyer
DRUDIS-1487; No of Pages 4 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 September 2014
(a)
(b) 225
6 Average annual NMEs
Cumulative NMEs
200 175 150 125 100 75 50
5 4 3 2 1
25 0 1933
0 1943
1953
1963
1973 1983 Decade
1993
2003
2013
(c)
1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
(d) 6 Entry
45 40 35 30 25
4 2 0
20 15
Exit
10
–2 –4
5 1937 1941 1945 1949 1953 1957 1961 1965 1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013
0
–6
1937 1941 1945 1949 1953 1957 1961 1965 1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013
Net active organisations
50
Year
Year Drug Discovery Today
Features PERSPECTIVE
FIGURE 1
Growth of cardiovascular new molecular entities (NMEs) over time. (a) The accumulation of NMEs was evaluated on a year-to-year basis, revealing a total of 201 NMEs targeting cardiovascular diseases as their initial indication. (b) The average number of annual NMEs was assessed on a decade-by-decade basis. (c) The net number of organizations active and awarded at least one NME for a cardiovascular indication is shown, as is (d) the annual number of organizations entering or exiting the field.
disease indication, which is well below the average of more than one-third of all FDA-approved NMEs during the current decade. Having established the players and overall trends in the field, we began dissecting the indications and the mechanistic basis of NME approvals over the years. In terms of indications, drugs focused on blood pressure have dominated the field (Fig. 2a). One-hundred-and-five NMEs target blood pressure (primarily hypertension), which represents more than half (52.2%) of all cardiovascular medicines. At its peak in the 1950s, more than 80% of all cardiovascular-disease-focused NMEs targeted blood pressure. These numbers have been trending downwards and, today, the level of NMEs targeting blood pressure stands at 36.4%. Despite this decline, this level still represents more than one-third of all cardiovascular NMEs. The past few decades have witnessed increases in targeting of coagulation and thrombosis-related indications. Together, these indications currently represent over one-third of 2
NMEs approved for cardiovascular diseases in the current decade (Fig. 2b). Drugs targeting hyperlipidemia, first introduced in the 1960s, surged in the 1990s as a result of the development of statins targeting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. By contrast, emphasis on new arrhythmia drugs, which were first introduced in the 1940s and remained relatively prominent through the 1980s, has dropped in recent years. Changing trends in indications led us to ask about the classes of targets selected for intervention (Fig. 3a). Historically, G-protein-coupled receptors (GPCRs) represent the most common family of targets, accounting for 41% of all cardiovascular NMEs. These are followed by drugs targeting channels (21%: primarily sodium and potassium and calcium) and proteases (21%). Together, these three target types encompass more than four out of five NMEs approved for cardiovascular diseases. The disproportionate emphasis on a small subset of target types raised important
questions about potential bias. Follow-on (also known as ‘me-too’) drugs might have limited the breadth of cardiovascular targets emphasized by the biopharmaceutical industry [6,7]. For example, Merck gained FDA approval for the first HMG-CoA reductase inhibitor, lovastatin, in 1987. This was followed by pravastatin (Bristol-Myers Squibb, 1991), simvastatin (Merck, 1991), fluvastatin (Sandoz, 1993), atorvastatin (WarnerLambert, 1996), cerivastatin (Bayer, 1997), rosuvastatin (Astra-Zeneca, 2003) and pitavastatin (Kowa, 2009). Moreover, it is increasingly accepted that proof-of-concept from the standpoint of sales and marketing (i.e. demonstrating profitability) has favored the development of multiple generations of statins and antihypertensives, a trend that continues today. What is perhaps less well known is that unintentional bias might be introduced by past success. For example, the composition of screening libraries or investigator expertise with certain molecule types might favor emphasis on structures with which there is greater
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
DRUDIS-1487; No of Pages 4 Drug Discovery Today Volume 00, Number 00 September 2014
PERSPECTIVE
(a) 100%
80%
60%
40%
20%
0%
1940s
1950s
1960s
1970s
1980s
1990s
2000s
2010s
(b) 100% 80%
Acute coronary Hyperlipidemia
60%
Congestive heart disease 40%
Coagulation & thrombosis Erectile dysfunction
20%
Arrhythmia 0%
1940s
1950s
1960s
1970s
1980s
1990s
2000s
2010s Drug Discovery Today
institutional memory or experience [8]. Such a strategy can be defended because of experience with a predecessor molecular greater understanding of potential advantages (e.g. pharmacokinetics or dosing) and liabilities (e.g. toxicity, metabolic degradation). However, the application of finite resources upon incremental improvements raises questions as to whether potential orthogonal advances could be missed. To assess this idea further, we evaluated the specific targets impacted by the range of cardiovascular drugs approved to date (Fig. 3b). Overall, eight different targets (thrombin, phosphodiesterases, angiotensin-converting enzyme, acetylcholine, HMG-CoA reductase, adrenoreceptor, sodium and potassium ATPases and calcium channels) encompass 142 (70.6%) of all cardiovascular NMEs. The two largest (adrenoreceptors and sodium and potassium ATPases) alone account for 67 NMEs or one-third of all cardiovascular approvals. For an additional perspective, we evaluated how the emphasis on the dominant eight target types has changed over time (Fig. 3c). To ease the interpretation, all eight targets were grouped together and compared with all others. This analysis suggests that, although there has been a
historic preponderance on the eight aforementioned targets, more-recent emphasis, particularly since the beginning of the new millennium, has begun to emphasize other target types.
Concluding remarks: findings and implications The major finding of our present study is the demonstration that the approval rates for NMEs targeting cardiovascular diseases have been remarkably steady over time. Likewise, the number of organizations that have been awarded FDA approvals for cardiovascular diseases is stable. These trends are remarkable in light of the large number of mergers and acquisitions, starting in the 1990s, which has characterized the biopharmaceutical industry. Such outcomes also differ markedly from similar findings with antibiotics for bacterial infections or HIV/AIDS drugs, where the rate of NME approval and the number of participating organizations has dramatically declined. This initial optimistic view of the health of the cardiovascular drug discovery and development industry could be tempered somewhat upon closer inspection. Historically, a disproportionate
emphasis has been placed upon NMEs regulating blood pressure. Although recent trends suggest other cardiovascular indications are increasingly being addressed, blood pressure remains the focus of almost 40% of NMEs today. Many of these medicines are next-generation medicines and presumably are incremental improvements on their predecessors. If accurate, such approaches could decrease the development of orthogonal improvements in the management of cardiovascular diseases. A different but related question is raised upon assessment of the mechanistic basis of NMEs targeting cardiovascular diseases. The initial finding that three target classes (GPCRs, channels and proteases) comprise more than 80% of all cardiovascular NMEs led us to identify the particular targets and target types. The outcome of that analysis was that eight targets encompass the bulk of all NMEs introduced since 1937. Recent approvals suggest that new targets are the emphasis of recent NME approvals; the preponderance of a small subset of targets raises questions about innovation. From a business perspective, there is no question that the market has rewarded follow-on (me too), next-generation drugs [9,10]. From a global public
www.drugdiscoverytoday.com 3 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
Features PERSPECTIVE
FIGURE 2
Cardiovascular indications as targets of new molecular entities (NMEs). (a) The relative proportion of drugs targeting blood pressure and (b) all other major cardiovascular indications is evaluated on a decade-by-decade basis.
DRUDIS-1487; No of Pages 4 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 September 2014
(a) GPCR Channel Esterase Transporter Oxidase Protease
(b)
Thrombin PDE Angiotensin converting enzyme Acetylcholine HMG CoA Adrenoreceptor Na/K ATPase Calcium channel Other
(c)
Fraction of all cardiovascular NMEs
Nuclear receptor
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s
Decade Drug Discovery Today
FIGURE 3
Features PERSPECTIVE
Mechanistic basis of cardiovascular disease targeting. (a) The target classes for all cardiovascular new molecular entities (NMEs) were assessed, revealing greatest emphasis on G-protein-coupled receptors (GPCRs). (b) Diving deeper, eight target types [thrombin, phosphodiesterase, angiotensin-converting enzyme, 3hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, adrenoreceptors, Na ATPase and K ATPase and calcium channels] capture more than 70% of all cardiovascular drugs. (c) When assessed over time, the relative proportion of the top eight targets (red bars) relative to novel targets (black bars) has begun to decrease, suggesting renewed innovation.
health standpoint, it is important to balance incremental change with the orthogonal innovation that is needed to combat the leading cause of morbidity and mortality [11].
Acknowledgements This work was conducted as part of a project at the Yale Center for Molecular Discovery to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the authors if you or your organization would be interested in potential participation in this project. The authors thank Drs Peter Gareiss, Janie Merkel and Mark Plummer for crucial reading of the manuscript and helpful conversations.
4
References 1 Esunge, P. (1991) From blood pressure to hypertension: the history of research. J. R. Soc. Med. 84, 621 2 Harvey, W. (1737) Exercitatio anatomica de motu cordis et sanguinis in animalibus. oai:aleph.bib-bvb.de:BVB01017047835 3 Kaitin, K.I. et al. (1993) The role of the research-based pharmaceutical industry in medical progress in the United States. J. Clin. Pharmacol. 33, 412–417 4 Kinch, M.S. et al. (2014) An analysis of FDA-approved drugs for infectious diseases: antibacterial agents. pii: S1359-6446(14)00276-1 5 Kinch, M.S. (2014) An analysis of FDA-approved drugs for oncology. pii: S1359-6446(14)00334-1 6 Gagne, J.J. and Choudhry, N.K. (2011) How many ‘‘metoo’’ drugs is too many? JAMA 305, 711–712 7 Frothingham, R. (2004) ‘‘Me-too’’ products – friend or foe? N. Engl. J. Med. 350, 2100–2101 8 Hert, J. et al. (2009) Quantifying biogenic bias in screening libraries. Nat. Chem. Biol. 5, 479–483
9 Pekarsky, B. (2010) Should financial incentives be used to differentially reward ‘me-too’ and innovative drugs? PharmacoEconomics 28, 1–17 10 Giordanetto, F. et al. (2011) Follow-on drugs: how far should chemists look? Drug Discov. Today 16, 722–732 11 Mark, D.B. et al. (2007) Cardiovascular disease on a global scale: defining the path forward for research and practice. Eur. Heart J. 28, 2678–2684
Michael S. Kinch, Yulia Surovtseva, Denton Hoyer Yale Center for Molecular Discovery, West Haven, CT 06516, USA
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
PERSPECTIVE
feature An analysis of FDA-approved drugs for cardiovascular diseases
Following the introduction of antibiotic therapy and widespread inoculations, cardiovascular diseases have leapt ahead of infectious diseases in terms of prevalence in much of the developed and developing world. Herein, we assess FDA-approved drugs for the treatment of cardiovascular diseases. The drug development enterprise around cardiovascular diseases has remained stable in contrast to turbulent changes in other therapeutic indications. However, upon closer inspection, the results identify narrow scope in terms of the breadth of targets and the mechanistic actions of new drugs. From the public health point of view, it is important to balance incremental change with orthogonal innovations that are needed to combat a leading cause of morbidity and mortality.
Background Human beings have constantly struggled to find new treatments for heart disease. The diagnosis of ‘hard pulse disease’ (today known as hypertension) was addressed more than four millennia ago in ancient China through the use blood letting or leeches to reduce blood volume [1]. The seminal publication of Anatomica de Motu Cordis et Sanguinis in Animalibusin by William Harvey provided the framework for the modern understanding of heart function and, consequently, a new means to target cardiovascular diseases [2]. Modern attempts to address heart diseases in their various manifestations have led to an accumulation of new drugs to address age-old challenges [3]. Burroughs Wellcome received the first FDA approval for a cardiovascular new molecular entity (NME), digoxin, in January 1937. Since that time, the FDA has approved 201 different NMEs through to the end of 2013
(Fig. 1a). When viewed over time, the average rate of introduction of NMEs has remained relatively steady since the 1950s, with an average of 2.7 NMEs per year (Fig. 1b). Likewise, the number of companies active in the cardiovascular NME research and development space has grown steadily over time (Fig. 1c). The number of organizations with active cardiovascular research and development shrank as a consequence of mergers and acquisitions but recently stabilized at a range of 35–45 companies. This relative constancy is somewhat surprising given the number of mergers of major pharmaceutical companies in the 1980s and 1990s. We evaluated the volatility by evaluating the number of active and independent companies that entered (as a result of gaining at least one FDA approval for a cardiovascular indication) and exited (as a result of a merger, acquisition or bankruptcy) the field. Indeed, there has been a large number of exits in recent years but this has
been offset by the introduction of new organizations (Fig. 1d). This steadiness differs dramatically from the impact that volatility has had upon infectious diseases but lacks the growth of companies in the oncology space [4,5]. Unlike the situation with all other disease areas evaluated to date, the pharmaceutical industry continues to dominate cardiovascular diseases. Biotechnology companies (defined herein as those founded after 1971) remain in the minority in terms of contributing the first patent, investigational new drug (IND) applications or participation in clinical trials. This could be explained at least in part by our recent findings that biotechnology companies tend to favor orphan indications and biologics. Indeed, only seven biologics (from a total of 94 biologics ever approved) were approved with an initial indication being in the field of cardiovascular disease. Moreover, only five cardiovascular NMEs have ever been approved with an initial orphan
www.drugdiscoverytoday.com 1 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.09.001
Features PERSPECTIVE
Michael S. Kinch, [email protected], [email protected], [email protected], Yulia Surovtseva and Denton Hoyer
DRUDIS-1487; No of Pages 4 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 September 2014
(a)
(b) 225
6 Average annual NMEs
Cumulative NMEs
200 175 150 125 100 75 50
5 4 3 2 1
25 0 1933
0 1943
1953
1963
1973 1983 Decade
1993
2003
2013
(c)
1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
(d) 6 Entry
45 40 35 30 25
4 2 0
20 15
Exit
10
–2 –4
5 1937 1941 1945 1949 1953 1957 1961 1965 1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013
0
–6
1937 1941 1945 1949 1953 1957 1961 1965 1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013
Net active organisations
50
Year
Year Drug Discovery Today
Features PERSPECTIVE
FIGURE 1
Growth of cardiovascular new molecular entities (NMEs) over time. (a) The accumulation of NMEs was evaluated on a year-to-year basis, revealing a total of 201 NMEs targeting cardiovascular diseases as their initial indication. (b) The average number of annual NMEs was assessed on a decade-by-decade basis. (c) The net number of organizations active and awarded at least one NME for a cardiovascular indication is shown, as is (d) the annual number of organizations entering or exiting the field.
disease indication, which is well below the average of more than one-third of all FDA-approved NMEs during the current decade. Having established the players and overall trends in the field, we began dissecting the indications and the mechanistic basis of NME approvals over the years. In terms of indications, drugs focused on blood pressure have dominated the field (Fig. 2a). One-hundred-and-five NMEs target blood pressure (primarily hypertension), which represents more than half (52.2%) of all cardiovascular medicines. At its peak in the 1950s, more than 80% of all cardiovascular-disease-focused NMEs targeted blood pressure. These numbers have been trending downwards and, today, the level of NMEs targeting blood pressure stands at 36.4%. Despite this decline, this level still represents more than one-third of all cardiovascular NMEs. The past few decades have witnessed increases in targeting of coagulation and thrombosis-related indications. Together, these indications currently represent over one-third of 2
NMEs approved for cardiovascular diseases in the current decade (Fig. 2b). Drugs targeting hyperlipidemia, first introduced in the 1960s, surged in the 1990s as a result of the development of statins targeting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. By contrast, emphasis on new arrhythmia drugs, which were first introduced in the 1940s and remained relatively prominent through the 1980s, has dropped in recent years. Changing trends in indications led us to ask about the classes of targets selected for intervention (Fig. 3a). Historically, G-protein-coupled receptors (GPCRs) represent the most common family of targets, accounting for 41% of all cardiovascular NMEs. These are followed by drugs targeting channels (21%: primarily sodium and potassium and calcium) and proteases (21%). Together, these three target types encompass more than four out of five NMEs approved for cardiovascular diseases. The disproportionate emphasis on a small subset of target types raised important
questions about potential bias. Follow-on (also known as ‘me-too’) drugs might have limited the breadth of cardiovascular targets emphasized by the biopharmaceutical industry [6,7]. For example, Merck gained FDA approval for the first HMG-CoA reductase inhibitor, lovastatin, in 1987. This was followed by pravastatin (Bristol-Myers Squibb, 1991), simvastatin (Merck, 1991), fluvastatin (Sandoz, 1993), atorvastatin (WarnerLambert, 1996), cerivastatin (Bayer, 1997), rosuvastatin (Astra-Zeneca, 2003) and pitavastatin (Kowa, 2009). Moreover, it is increasingly accepted that proof-of-concept from the standpoint of sales and marketing (i.e. demonstrating profitability) has favored the development of multiple generations of statins and antihypertensives, a trend that continues today. What is perhaps less well known is that unintentional bias might be introduced by past success. For example, the composition of screening libraries or investigator expertise with certain molecule types might favor emphasis on structures with which there is greater
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
DRUDIS-1487; No of Pages 4 Drug Discovery Today Volume 00, Number 00 September 2014
PERSPECTIVE
(a) 100%
80%
60%
40%
20%
0%
1940s
1950s
1960s
1970s
1980s
1990s
2000s
2010s
(b) 100% 80%
Acute coronary Hyperlipidemia
60%
Congestive heart disease 40%
Coagulation & thrombosis Erectile dysfunction
20%
Arrhythmia 0%
1940s
1950s
1960s
1970s
1980s
1990s
2000s
2010s Drug Discovery Today
institutional memory or experience [8]. Such a strategy can be defended because of experience with a predecessor molecular greater understanding of potential advantages (e.g. pharmacokinetics or dosing) and liabilities (e.g. toxicity, metabolic degradation). However, the application of finite resources upon incremental improvements raises questions as to whether potential orthogonal advances could be missed. To assess this idea further, we evaluated the specific targets impacted by the range of cardiovascular drugs approved to date (Fig. 3b). Overall, eight different targets (thrombin, phosphodiesterases, angiotensin-converting enzyme, acetylcholine, HMG-CoA reductase, adrenoreceptor, sodium and potassium ATPases and calcium channels) encompass 142 (70.6%) of all cardiovascular NMEs. The two largest (adrenoreceptors and sodium and potassium ATPases) alone account for 67 NMEs or one-third of all cardiovascular approvals. For an additional perspective, we evaluated how the emphasis on the dominant eight target types has changed over time (Fig. 3c). To ease the interpretation, all eight targets were grouped together and compared with all others. This analysis suggests that, although there has been a
historic preponderance on the eight aforementioned targets, more-recent emphasis, particularly since the beginning of the new millennium, has begun to emphasize other target types.
Concluding remarks: findings and implications The major finding of our present study is the demonstration that the approval rates for NMEs targeting cardiovascular diseases have been remarkably steady over time. Likewise, the number of organizations that have been awarded FDA approvals for cardiovascular diseases is stable. These trends are remarkable in light of the large number of mergers and acquisitions, starting in the 1990s, which has characterized the biopharmaceutical industry. Such outcomes also differ markedly from similar findings with antibiotics for bacterial infections or HIV/AIDS drugs, where the rate of NME approval and the number of participating organizations has dramatically declined. This initial optimistic view of the health of the cardiovascular drug discovery and development industry could be tempered somewhat upon closer inspection. Historically, a disproportionate
emphasis has been placed upon NMEs regulating blood pressure. Although recent trends suggest other cardiovascular indications are increasingly being addressed, blood pressure remains the focus of almost 40% of NMEs today. Many of these medicines are next-generation medicines and presumably are incremental improvements on their predecessors. If accurate, such approaches could decrease the development of orthogonal improvements in the management of cardiovascular diseases. A different but related question is raised upon assessment of the mechanistic basis of NMEs targeting cardiovascular diseases. The initial finding that three target classes (GPCRs, channels and proteases) comprise more than 80% of all cardiovascular NMEs led us to identify the particular targets and target types. The outcome of that analysis was that eight targets encompass the bulk of all NMEs introduced since 1937. Recent approvals suggest that new targets are the emphasis of recent NME approvals; the preponderance of a small subset of targets raises questions about innovation. From a business perspective, there is no question that the market has rewarded follow-on (me too), next-generation drugs [9,10]. From a global public
www.drugdiscoverytoday.com 3 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
Features PERSPECTIVE
FIGURE 2
Cardiovascular indications as targets of new molecular entities (NMEs). (a) The relative proportion of drugs targeting blood pressure and (b) all other major cardiovascular indications is evaluated on a decade-by-decade basis.
DRUDIS-1487; No of Pages 4 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 September 2014
(a) GPCR Channel Esterase Transporter Oxidase Protease
(b)
Thrombin PDE Angiotensin converting enzyme Acetylcholine HMG CoA Adrenoreceptor Na/K ATPase Calcium channel Other
(c)
Fraction of all cardiovascular NMEs
Nuclear receptor
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s
Decade Drug Discovery Today
FIGURE 3
Features PERSPECTIVE
Mechanistic basis of cardiovascular disease targeting. (a) The target classes for all cardiovascular new molecular entities (NMEs) were assessed, revealing greatest emphasis on G-protein-coupled receptors (GPCRs). (b) Diving deeper, eight target types [thrombin, phosphodiesterase, angiotensin-converting enzyme, 3hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, adrenoreceptors, Na ATPase and K ATPase and calcium channels] capture more than 70% of all cardiovascular drugs. (c) When assessed over time, the relative proportion of the top eight targets (red bars) relative to novel targets (black bars) has begun to decrease, suggesting renewed innovation.
health standpoint, it is important to balance incremental change with the orthogonal innovation that is needed to combat the leading cause of morbidity and mortality [11].
Acknowledgements This work was conducted as part of a project at the Yale Center for Molecular Discovery to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the authors if you or your organization would be interested in potential participation in this project. The authors thank Drs Peter Gareiss, Janie Merkel and Mark Plummer for crucial reading of the manuscript and helpful conversations.
4
References 1 Esunge, P. (1991) From blood pressure to hypertension: the history of research. J. R. Soc. Med. 84, 621 2 Harvey, W. (1737) Exercitatio anatomica de motu cordis et sanguinis in animalibus. oai:aleph.bib-bvb.de:BVB01017047835 3 Kaitin, K.I. et al. (1993) The role of the research-based pharmaceutical industry in medical progress in the United States. J. Clin. Pharmacol. 33, 412–417 4 Kinch, M.S. et al. (2014) An analysis of FDA-approved drugs for infectious diseases: antibacterial agents. pii: S1359-6446(14)00276-1 5 Kinch, M.S. (2014) An analysis of FDA-approved drugs for oncology. pii: S1359-6446(14)00334-1 6 Gagne, J.J. and Choudhry, N.K. (2011) How many ‘‘metoo’’ drugs is too many? JAMA 305, 711–712 7 Frothingham, R. (2004) ‘‘Me-too’’ products – friend or foe? N. Engl. J. Med. 350, 2100–2101 8 Hert, J. et al. (2009) Quantifying biogenic bias in screening libraries. Nat. Chem. Biol. 5, 479–483
9 Pekarsky, B. (2010) Should financial incentives be used to differentially reward ‘me-too’ and innovative drugs? PharmacoEconomics 28, 1–17 10 Giordanetto, F. et al. (2011) Follow-on drugs: how far should chemists look? Drug Discov. Today 16, 722–732 11 Mark, D.B. et al. (2007) Cardiovascular disease on a global scale: defining the path forward for research and practice. Eur. Heart J. 28, 2678–2684
Michael S. Kinch, Yulia Surovtseva, Denton Hoyer Yale Center for Molecular Discovery, West Haven, CT 06516, USA
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for cardiovascular diseases, Drug Discov Today (2014), http://dx.doi.org/10.1016/ j.drudis.2014.09.001
