- Email: [email protected]
An analysis of FDA-approved drugs for metabolic diseases
DRUDIS 1578 1–4 Drug Discovery Today Volume 00, Number 00 March 2015
PERSPECTIVE
feature An analysis of FDA-approved drugs for metabolic diseases Metabolic diseases encompass a constellation of maladies including obesity and diabetes that are among the fastest growing epidemics throughout the world. An analysis of new molecular entities (NMEs) targeting metabolic diseases reveals the rate of approval for new drugs increased in the mid-1990s and now stands at approximately two per year. The increase is largely attributed to a recent emphasis on treatments for inborn errors of metabolism. In particular, biotechnology companies have focused on rare genetic disorders, which are often treated with biologic-based NMEs that target novel pathways and qualify for orphan drug status. By contrast, NME development by pharmaceutical companies tended toward conventional small molecular targeting of nongenetic disorders such as diabetes.
Metabolic disease history Q2 Twenty years after a medical student, Paul
Langerhans, asked his instructor about a series of previously unknown islets throughout the pancreas, in 1889 Oscar Minkowski observed that flies fed upon the urine of dogs following removal of their pancreas [1,2]. He later determined that sugar in the urine had attracted the flies. In 1920, Frederick Banting was inspired by this observation to isolate the pancreatic factor that reduced blood sugar [3]. This substance, now known as insulin, was tested first in 1922 at Toronto General Hospital [4]. In an apocryphal story, Banting and his collaborators, Charles Best and James Collip, entered a ward of unconscious children who were dying of diabetic ketoacidosis. The story goes that the three scientists heard cries of joy as children emerged from comas even as they were injecting the last of the patients. Spurred by such dramatic outcomes, Eli Lilly improved the efficiency and purity of insulin 1359-6446/ß 2015 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2015.02.002
isolation from pigs, which gained approval in 1923 as Iletin1, not only the first effective medicine for diabetes but also arguably the best known medication for any metabolic disease and the first biologic-based new molecular entity (NME) of any drug indication. The indication of metabolic diseases includes all disorders that alter normal metabolism, the process of converting food to energy. Given the myriad enzymes and pathways involved in cellular metabolism, it is not surprising that metabolic diseases include a broad array of maladies that span from inherited diseases to lifestyleinduced disorders. Lifestyle-induced metabolic diseases are among the fastest-growing medical indications [5,6]. The World Health Organization (WHO) estimates that at least half a billion people worldwide (greater than 10% of the global population) suffer from obesity [7,8]. Of even greater concern is that the rates of severe obesity
are increasing rapidly worldwide. These outcomes are particularly problematic because being afflicted with one metabolic disease often gives rise to others as evidenced by the linkages among obesity, metabolic syndrome and diabetes mellitus [9,10]. The resulting constellations of metabolic diseases now represent a leading cause of human morbidity and mortality.
Metabolic disease medications In an effort to evaluate the responsiveness of the biopharmaceutical industry to recent increases in the rates of metabolic diseases, we assessed the number NMEs targeted against metabolic disease. The first metabolic disease drug in the post-insulin era was probenecid, for which an approval was awarded to Merck in April 1951. Since that time, a total of 76 NMEs have been approved for metabolic disorders (Figure 1a). Evaluated over time, a biphasic rate of NMEs is observed. For the following four decades (from
www.drugdiscoverytoday.com 1 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
Features PERSPECTIVE
Q1 Michael S. Kinch , [email protected], Sheila Umlauf and Mark Plummer
DRUDIS 1578 1–4 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 March 2015
(a)
(b) Cumulative metabolic disease NMEs
80 70 Other, 14
60
Genetic disorder, 18
50 40 Type 2 diabetes, 26
30
Obesity, 11
20 10 Diabetes insipidus, 2
0 1951 1956 1961 1966 1971 1976 1981 1986 1991 1996 2001 2006 2011
Type 1 diabetes, 5
Year
Drug Discovery Today
FIGURE 1
Overview of FDA-approved new molecular entities (NMEs) for metabolic diseases. (a) The cumulative number of NMEs focused on metabolic diseases was assessed on an annual basis. Note the increased rate of approval beginning in the mid-1990s. (b) The distribution of indications targeted by all 76 NMEs is indicated.
the 1950s to the mid-1990s), approvals averaged 1.3 NMEs per year. Thereafter, the rate of new approvals has increased to a current average of approximately 2.3 NMEs per year. (a)
The indications targeted by the metabolic subset of NMEs can be grouped into around five sets of indications (Figure 1b). Drugs targeting type 2 diabetes represent one-third of all met-
Diabetes mellitus
(c)
abolic disease drugs followed by obesity (14%), type 1 diabetes (7%) and diabetes insipidus (3%). Together, diabetes and obesity capture more than half of all NMEs approved for metabolic
Diabetes mellitus
Features PERSPECTIVE
Average annual NMEs
1.2 1 Protease, 4 Other, 4
0.8
Nuclear receptor, 3
0.6 0.4
Growth factor, 3
0.2 0
Channel, 9
GPCR, 5
1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
Genetic disorders
Average annual NMEs
(b)
(d)
Genetic disorders
1.4 1.2 1 0.8 0.6
Other, 18
0.4 0.2 0 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
Drug Discovery Today
FIGURE 2
Comparison of new molecular entities (NMEs) targeting diabetes and genetic diseases. (a) The average annual rate of approval for NMEs targeting diabetes mellitus is indicated and compared with (b) the average NMEs approved for genetic disorders. (c) The distribution of targets impacted by drugs targeting diabetes mellitus and genetic disorders (d) is shown. 2
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
DRUDIS 1578 1–4 Drug Discovery Today Volume 00, Number 00 March 2015
spanning the 1950s through the 1980s (Figure 2a). At its peak in the 1990s, 1.2 NMEs were introduced per year although this rate has been rather volatile. During the present decade, an average of one new diabetes mellitus NME is introduced each year. The rate of NMEs targeting metabolic diseases caused by genetic disorders also increased in recent years (Figure 2b). The first NME addressing this subset of metabolic indications was Thiola1, a treatment for cystinuria, approved in 1988. The rate of new approvals climbed rapidly and seems to have peaked at an annual rate of 1.1 NMEs per year during the first decade of the new millennium. Interestingly, the period since 2011 has witnessed a noticeable decline in NMEs targeting genetic disorders, with a current average of one every three years. It remains to be seen whether this trend is an aberration or continues through the remainder of the decade.
The types of cellular targets also distinguish NMEs targeting diabetes from those directed against inherited metabolic diseases (Figure 2c). As has been observed throughout our analyses of NMEs, a subset of five-to-six target types captures the majority of NMEs for indications such as cancer, cardiovascular and infectious disease. A similar trend exists with diabetes drugs. Five sets of molecular targets [channels, G protein-coupled receptors (GPCRs), proteases, nuclear receptors and growth factors] account for 86% of all metabolic disease NMEs. By remarkable contrast, none of these target types was included among NMEs for genetic disorders (Figure 2d). Rather, the targets for these inherited indications were a diverse array of unrelated enzymes. When evaluating the data with great resolution, we did detect duplication in molecular targets within indications (e.g. almost all Gaucher’s disease drugs target the same
40%
30% Nongenetic Genetic
20%
10%
Orphan
Biologics
100%
(c)
Genetic indications Fraction of genetic disease NMEs
Fraction of nongenetic disease NMEs
Nongenetic indications
80% 60% 40% 20% 0% Patent
Q3
50%
0%
(b)
Q4
Features PERSPECTIVE
(a)
Fraction of metabolic disease NMEs
diseases. The only other large subset of indications includes diseases directly attributable to genetic disorders [11]. Although many diseases have genetic links, we define herein genetic or inherited diseases as inborn errors of metabolism. Approximately one-quarter of all metabolic disease NMEs targeted genetic disorders, most commonly enzyme deficiencies (Figure 1b). The growth of this subset of NMEs was remarkable, particularly from the mid-1990s through to 2010 and explains the aforementioned increased number of metabolic disease NMEs approved during that time period. The preponderance of NMEs targeting diabetes mellitus and inherited metabolic diseases, which account for almost two-thirds of all metabolic disease NMEs, provided an opportunity to compare and contrast these two major sets of indications. When analyzed over time, diabetes NMEs were relatively sporadic from the period
PERSPECTIVE
IND Milestone
Approval
100% 80% 60% Biotech 40%
Pharma Acad
20% 0% Patent
IND
Approval
Milestone Drug Discovery Today
FIGURE 3
Contrasting new molecular entities (NMEs) for genetic and nongenetic metabolic diseases. (a) The fraction of genetic and nongenetic metabolic disease NMEs that are biologics or received an initial approval under orphan drug status is indicated. The relative contributions of academia (blue), pharmaceutical (red) and biotechnology (green) organizations to different milestones of the NME approval process is indicated for (b) nongenetic and (c) genetic diseases. www.drugdiscoverytoday.com 3 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
DRUDIS 1578 1–4 PERSPECTIVE
Features PERSPECTIVE
molecule: glucosylceramidase). Overall, the diversity of targets associated with inherited diseases was otherwise dissimilar to the trends noted with all other indications evaluated to date. Thus, inherited metabolic diseases represent an exception to the rule that most NMEs target a small subset of cellular target types (e.g. GPCRs, channels, kinases, proteases, etc.). The differences between diabetes and genetic diseases led us to question further the differences between genetic and nongenetic indications. To this end, we evaluated the types of NMEs utilized for each class of indications. Whereas biologics were a small fraction (7%) of NMEs for nongenetic indications, almost half (44%) of NMEs for genetic diseases were biologics (Figure 3a). Unlike most indications, where biologics are primarily represented by monoclonal antibodies, biologics for inherited diseases were generally purified forms of replacement enzymes. Unsurprisingly (given the rarity of most inborn errors of metabolism), almost half of NMEs for genetic diseases were approved as orphan drugs (Figure 3a). Most non-orphan drugs for this subset of indications were followon compounds for indications that had already been the subject of an orphan approval (e.g. five NMEs target Gaucher’s disease). In contrast to the prevalence of orphan designations for genetic metabolic disease, a small fraction (5%) of NMEs addressing nongenetic metabolic diseases (e.g. obesity, diabetes) was approved as orphan drugs. The types of organizations participating in NME development also differed greatly when comparing genetic and nongenetic metabolic diseases. To assess the organizations that contributed to key milestones of the approval process, we broadly distinguished the contributors as academia, pharmaceutical or biotechnology companies. Biotechnology was defined as any organization founded on or after the year 1971, using rationale defined previously [12]. The key milestones assessed in these analyses included the filing of the pivotal first patent for the NME, filing of the investigational new drug application (IND) and participation in clinical trials or awarding of the final NME approval. The R&D of NMEs for nongenetic indications was primarily conducted by, and the NMEs were generally awarded to, pharmaceutical organizations (Figure 3b). By contrast, biotechnology organizations dominated the research, development and approvals for NMEs targeting genetic indications (Figure 3c). Biotechnology companies
4
Drug Discovery Today Volume 00, Number 00 March 2015
participated in the preclinical or clinical development of at least 80% of NMEs targeting inherited metabolic diseases and likewise received the final approvals for most of this subset of indications. The dominance of biotechnology companies in gaining the award for NMEs targeting genetic forms of metabolic diseases differs markedly from the situation observed with all other disease types evaluated to date. In all other cases, we have observed that biotechnology companies generally dominate in terms of early-stage development (e.g. patent filing through to end of Phase II clinical trials) [12]. However, the final award of an NME usually goes to a more established pharmaceutical organization. It will be worth assessing whether this course continues given a recent trend that established pharmaceutical companies are emphasizing orphan indications, which often convey advantages in terms of clinical development time and financial incentives.
Concluding remarks: findings and implications The number of NMEs targeting metabolic diseases has accelerated since the mid-1990s. It is also clear that metabolic diseases can be broadly distinguished into genetic and nongenetic indications. The major finding of our present study is that, when viewed separately, these two disease categories demonstrate considerable differences in terms of the types of treatments utilized (biologics versus small molecules), the organizations conducting the research (biotechnology versus pharmaceutical) and the selection of targets for each drug. Although at an all-time high, the present rate of just over two NMEs per year seems modest in light of the rapid growth in obesity and metabolic syndrome in North America and Europe. This contrasts with an average of ten oncology NMEs per year despite the fact that the incidence of cancer is comparatively stable relative to the steady rise in metabolic diseases. The rise and apparent decline in NMEs treating genetic diseases is another notable finding of the present study. As we have reported recently, biotechnology companies have more commonly utilized opportunities arising from the 1983 Orphan Drug Act and inherited metabolic diseases are a prominent example of this outcome [13]. Many biotechnology organizations have been acquired by pharmaceutical companies. Relative to our present study, Genzyme was a key
innovator (receiving four NMEs for genetic diseases) before its acquisition by Sanofi in 2011. Although it is too soon to predict whether this will impact future innovation, combined with the seeming downturn in NMEs in the first part of the current decade, such changes might presage a future decline in new treatments for genetic diseases.
Acknowledgments 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.
References 1 Sakula, A. (1988) Paul Langerhans (1847–1888): a centenary tribute. J. R. Soc. Med. 81, 414–415 2 Luft, R. (1989) Oskar Minkowski: discovery of the pancreatic origin of diabetes. Diabetologia 32, 399–401 3 Banting, F.G. et al. (1922) The preparation of pancreatic extracts containing insulin. Trans. R. Soc. Can. 16, 27–29 4 Bliss, M. and Purkis, R., eds) (1982) The Discovery of Insulin, University of Chicago Press 5 Ford, E.S. et al. (2002) Prevalence of the metabolic syndrome among us adults: findings from the third national health and nutrition examination survey. JAMA 287, 356–359 6 Alwan, A. (2011) Global Status Report on Noncommunicable Diseases 2010. World Health Organization 7 World Health Organization (2009) Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. 8 World Health Organization (2013) Obesity and Overweight. 9 Katzmarzyk, P.T. et al. (2005) Metabolic syndrome, obesity, and mortality impact of cardiorespiratory fitness. Diabetes Care 28, 391–397 10 Grundy, S.M. et al. (2004) Definition of metabolic syndrome report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on scientific issues related to definition. Circulation 109, 433–438 11 Aronson, A.R. (1996) Physicians’ guide to rare diseases. JAMA 275, 1286 12 Kinch, M.S. (2014) The rise (and decline?) of biotechnology. Drug Discov. Today 19, 1686–1690 13 Kinch, M.S. et al. (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039
Michael S. Kinch, Sheila Umlauf, Mark Plummer 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 metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
PERSPECTIVE
feature An analysis of FDA-approved drugs for metabolic diseases Metabolic diseases encompass a constellation of maladies including obesity and diabetes that are among the fastest growing epidemics throughout the world. An analysis of new molecular entities (NMEs) targeting metabolic diseases reveals the rate of approval for new drugs increased in the mid-1990s and now stands at approximately two per year. The increase is largely attributed to a recent emphasis on treatments for inborn errors of metabolism. In particular, biotechnology companies have focused on rare genetic disorders, which are often treated with biologic-based NMEs that target novel pathways and qualify for orphan drug status. By contrast, NME development by pharmaceutical companies tended toward conventional small molecular targeting of nongenetic disorders such as diabetes.
Metabolic disease history Q2 Twenty years after a medical student, Paul
Langerhans, asked his instructor about a series of previously unknown islets throughout the pancreas, in 1889 Oscar Minkowski observed that flies fed upon the urine of dogs following removal of their pancreas [1,2]. He later determined that sugar in the urine had attracted the flies. In 1920, Frederick Banting was inspired by this observation to isolate the pancreatic factor that reduced blood sugar [3]. This substance, now known as insulin, was tested first in 1922 at Toronto General Hospital [4]. In an apocryphal story, Banting and his collaborators, Charles Best and James Collip, entered a ward of unconscious children who were dying of diabetic ketoacidosis. The story goes that the three scientists heard cries of joy as children emerged from comas even as they were injecting the last of the patients. Spurred by such dramatic outcomes, Eli Lilly improved the efficiency and purity of insulin 1359-6446/ß 2015 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2015.02.002
isolation from pigs, which gained approval in 1923 as Iletin1, not only the first effective medicine for diabetes but also arguably the best known medication for any metabolic disease and the first biologic-based new molecular entity (NME) of any drug indication. The indication of metabolic diseases includes all disorders that alter normal metabolism, the process of converting food to energy. Given the myriad enzymes and pathways involved in cellular metabolism, it is not surprising that metabolic diseases include a broad array of maladies that span from inherited diseases to lifestyleinduced disorders. Lifestyle-induced metabolic diseases are among the fastest-growing medical indications [5,6]. The World Health Organization (WHO) estimates that at least half a billion people worldwide (greater than 10% of the global population) suffer from obesity [7,8]. Of even greater concern is that the rates of severe obesity
are increasing rapidly worldwide. These outcomes are particularly problematic because being afflicted with one metabolic disease often gives rise to others as evidenced by the linkages among obesity, metabolic syndrome and diabetes mellitus [9,10]. The resulting constellations of metabolic diseases now represent a leading cause of human morbidity and mortality.
Metabolic disease medications In an effort to evaluate the responsiveness of the biopharmaceutical industry to recent increases in the rates of metabolic diseases, we assessed the number NMEs targeted against metabolic disease. The first metabolic disease drug in the post-insulin era was probenecid, for which an approval was awarded to Merck in April 1951. Since that time, a total of 76 NMEs have been approved for metabolic disorders (Figure 1a). Evaluated over time, a biphasic rate of NMEs is observed. For the following four decades (from
www.drugdiscoverytoday.com 1 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
Features PERSPECTIVE
Q1 Michael S. Kinch , [email protected], Sheila Umlauf and Mark Plummer
DRUDIS 1578 1–4 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 March 2015
(a)
(b) Cumulative metabolic disease NMEs
80 70 Other, 14
60
Genetic disorder, 18
50 40 Type 2 diabetes, 26
30
Obesity, 11
20 10 Diabetes insipidus, 2
0 1951 1956 1961 1966 1971 1976 1981 1986 1991 1996 2001 2006 2011
Type 1 diabetes, 5
Year
Drug Discovery Today
FIGURE 1
Overview of FDA-approved new molecular entities (NMEs) for metabolic diseases. (a) The cumulative number of NMEs focused on metabolic diseases was assessed on an annual basis. Note the increased rate of approval beginning in the mid-1990s. (b) The distribution of indications targeted by all 76 NMEs is indicated.
the 1950s to the mid-1990s), approvals averaged 1.3 NMEs per year. Thereafter, the rate of new approvals has increased to a current average of approximately 2.3 NMEs per year. (a)
The indications targeted by the metabolic subset of NMEs can be grouped into around five sets of indications (Figure 1b). Drugs targeting type 2 diabetes represent one-third of all met-
Diabetes mellitus
(c)
abolic disease drugs followed by obesity (14%), type 1 diabetes (7%) and diabetes insipidus (3%). Together, diabetes and obesity capture more than half of all NMEs approved for metabolic
Diabetes mellitus
Features PERSPECTIVE
Average annual NMEs
1.2 1 Protease, 4 Other, 4
0.8
Nuclear receptor, 3
0.6 0.4
Growth factor, 3
0.2 0
Channel, 9
GPCR, 5
1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
Genetic disorders
Average annual NMEs
(b)
(d)
Genetic disorders
1.4 1.2 1 0.8 0.6
Other, 18
0.4 0.2 0 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
Drug Discovery Today
FIGURE 2
Comparison of new molecular entities (NMEs) targeting diabetes and genetic diseases. (a) The average annual rate of approval for NMEs targeting diabetes mellitus is indicated and compared with (b) the average NMEs approved for genetic disorders. (c) The distribution of targets impacted by drugs targeting diabetes mellitus and genetic disorders (d) is shown. 2
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
DRUDIS 1578 1–4 Drug Discovery Today Volume 00, Number 00 March 2015
spanning the 1950s through the 1980s (Figure 2a). At its peak in the 1990s, 1.2 NMEs were introduced per year although this rate has been rather volatile. During the present decade, an average of one new diabetes mellitus NME is introduced each year. The rate of NMEs targeting metabolic diseases caused by genetic disorders also increased in recent years (Figure 2b). The first NME addressing this subset of metabolic indications was Thiola1, a treatment for cystinuria, approved in 1988. The rate of new approvals climbed rapidly and seems to have peaked at an annual rate of 1.1 NMEs per year during the first decade of the new millennium. Interestingly, the period since 2011 has witnessed a noticeable decline in NMEs targeting genetic disorders, with a current average of one every three years. It remains to be seen whether this trend is an aberration or continues through the remainder of the decade.
The types of cellular targets also distinguish NMEs targeting diabetes from those directed against inherited metabolic diseases (Figure 2c). As has been observed throughout our analyses of NMEs, a subset of five-to-six target types captures the majority of NMEs for indications such as cancer, cardiovascular and infectious disease. A similar trend exists with diabetes drugs. Five sets of molecular targets [channels, G protein-coupled receptors (GPCRs), proteases, nuclear receptors and growth factors] account for 86% of all metabolic disease NMEs. By remarkable contrast, none of these target types was included among NMEs for genetic disorders (Figure 2d). Rather, the targets for these inherited indications were a diverse array of unrelated enzymes. When evaluating the data with great resolution, we did detect duplication in molecular targets within indications (e.g. almost all Gaucher’s disease drugs target the same
40%
30% Nongenetic Genetic
20%
10%
Orphan
Biologics
100%
(c)
Genetic indications Fraction of genetic disease NMEs
Fraction of nongenetic disease NMEs
Nongenetic indications
80% 60% 40% 20% 0% Patent
Q3
50%
0%
(b)
Q4
Features PERSPECTIVE
(a)
Fraction of metabolic disease NMEs
diseases. The only other large subset of indications includes diseases directly attributable to genetic disorders [11]. Although many diseases have genetic links, we define herein genetic or inherited diseases as inborn errors of metabolism. Approximately one-quarter of all metabolic disease NMEs targeted genetic disorders, most commonly enzyme deficiencies (Figure 1b). The growth of this subset of NMEs was remarkable, particularly from the mid-1990s through to 2010 and explains the aforementioned increased number of metabolic disease NMEs approved during that time period. The preponderance of NMEs targeting diabetes mellitus and inherited metabolic diseases, which account for almost two-thirds of all metabolic disease NMEs, provided an opportunity to compare and contrast these two major sets of indications. When analyzed over time, diabetes NMEs were relatively sporadic from the period
PERSPECTIVE
IND Milestone
Approval
100% 80% 60% Biotech 40%
Pharma Acad
20% 0% Patent
IND
Approval
Milestone Drug Discovery Today
FIGURE 3
Contrasting new molecular entities (NMEs) for genetic and nongenetic metabolic diseases. (a) The fraction of genetic and nongenetic metabolic disease NMEs that are biologics or received an initial approval under orphan drug status is indicated. The relative contributions of academia (blue), pharmaceutical (red) and biotechnology (green) organizations to different milestones of the NME approval process is indicated for (b) nongenetic and (c) genetic diseases. www.drugdiscoverytoday.com 3 Please cite this article in press as: Kinch, M.S. et al. An analysis of FDA-approved drugs for metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002
DRUDIS 1578 1–4 PERSPECTIVE
Features PERSPECTIVE
molecule: glucosylceramidase). Overall, the diversity of targets associated with inherited diseases was otherwise dissimilar to the trends noted with all other indications evaluated to date. Thus, inherited metabolic diseases represent an exception to the rule that most NMEs target a small subset of cellular target types (e.g. GPCRs, channels, kinases, proteases, etc.). The differences between diabetes and genetic diseases led us to question further the differences between genetic and nongenetic indications. To this end, we evaluated the types of NMEs utilized for each class of indications. Whereas biologics were a small fraction (7%) of NMEs for nongenetic indications, almost half (44%) of NMEs for genetic diseases were biologics (Figure 3a). Unlike most indications, where biologics are primarily represented by monoclonal antibodies, biologics for inherited diseases were generally purified forms of replacement enzymes. Unsurprisingly (given the rarity of most inborn errors of metabolism), almost half of NMEs for genetic diseases were approved as orphan drugs (Figure 3a). Most non-orphan drugs for this subset of indications were followon compounds for indications that had already been the subject of an orphan approval (e.g. five NMEs target Gaucher’s disease). In contrast to the prevalence of orphan designations for genetic metabolic disease, a small fraction (5%) of NMEs addressing nongenetic metabolic diseases (e.g. obesity, diabetes) was approved as orphan drugs. The types of organizations participating in NME development also differed greatly when comparing genetic and nongenetic metabolic diseases. To assess the organizations that contributed to key milestones of the approval process, we broadly distinguished the contributors as academia, pharmaceutical or biotechnology companies. Biotechnology was defined as any organization founded on or after the year 1971, using rationale defined previously [12]. The key milestones assessed in these analyses included the filing of the pivotal first patent for the NME, filing of the investigational new drug application (IND) and participation in clinical trials or awarding of the final NME approval. The R&D of NMEs for nongenetic indications was primarily conducted by, and the NMEs were generally awarded to, pharmaceutical organizations (Figure 3b). By contrast, biotechnology organizations dominated the research, development and approvals for NMEs targeting genetic indications (Figure 3c). Biotechnology companies
4
Drug Discovery Today Volume 00, Number 00 March 2015
participated in the preclinical or clinical development of at least 80% of NMEs targeting inherited metabolic diseases and likewise received the final approvals for most of this subset of indications. The dominance of biotechnology companies in gaining the award for NMEs targeting genetic forms of metabolic diseases differs markedly from the situation observed with all other disease types evaluated to date. In all other cases, we have observed that biotechnology companies generally dominate in terms of early-stage development (e.g. patent filing through to end of Phase II clinical trials) [12]. However, the final award of an NME usually goes to a more established pharmaceutical organization. It will be worth assessing whether this course continues given a recent trend that established pharmaceutical companies are emphasizing orphan indications, which often convey advantages in terms of clinical development time and financial incentives.
Concluding remarks: findings and implications The number of NMEs targeting metabolic diseases has accelerated since the mid-1990s. It is also clear that metabolic diseases can be broadly distinguished into genetic and nongenetic indications. The major finding of our present study is that, when viewed separately, these two disease categories demonstrate considerable differences in terms of the types of treatments utilized (biologics versus small molecules), the organizations conducting the research (biotechnology versus pharmaceutical) and the selection of targets for each drug. Although at an all-time high, the present rate of just over two NMEs per year seems modest in light of the rapid growth in obesity and metabolic syndrome in North America and Europe. This contrasts with an average of ten oncology NMEs per year despite the fact that the incidence of cancer is comparatively stable relative to the steady rise in metabolic diseases. The rise and apparent decline in NMEs treating genetic diseases is another notable finding of the present study. As we have reported recently, biotechnology companies have more commonly utilized opportunities arising from the 1983 Orphan Drug Act and inherited metabolic diseases are a prominent example of this outcome [13]. Many biotechnology organizations have been acquired by pharmaceutical companies. Relative to our present study, Genzyme was a key
innovator (receiving four NMEs for genetic diseases) before its acquisition by Sanofi in 2011. Although it is too soon to predict whether this will impact future innovation, combined with the seeming downturn in NMEs in the first part of the current decade, such changes might presage a future decline in new treatments for genetic diseases.
Acknowledgments 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.
References 1 Sakula, A. (1988) Paul Langerhans (1847–1888): a centenary tribute. J. R. Soc. Med. 81, 414–415 2 Luft, R. (1989) Oskar Minkowski: discovery of the pancreatic origin of diabetes. Diabetologia 32, 399–401 3 Banting, F.G. et al. (1922) The preparation of pancreatic extracts containing insulin. Trans. R. Soc. Can. 16, 27–29 4 Bliss, M. and Purkis, R., eds) (1982) The Discovery of Insulin, University of Chicago Press 5 Ford, E.S. et al. (2002) Prevalence of the metabolic syndrome among us adults: findings from the third national health and nutrition examination survey. JAMA 287, 356–359 6 Alwan, A. (2011) Global Status Report on Noncommunicable Diseases 2010. World Health Organization 7 World Health Organization (2009) Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. 8 World Health Organization (2013) Obesity and Overweight. 9 Katzmarzyk, P.T. et al. (2005) Metabolic syndrome, obesity, and mortality impact of cardiorespiratory fitness. Diabetes Care 28, 391–397 10 Grundy, S.M. et al. (2004) Definition of metabolic syndrome report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on scientific issues related to definition. Circulation 109, 433–438 11 Aronson, A.R. (1996) Physicians’ guide to rare diseases. JAMA 275, 1286 12 Kinch, M.S. (2014) The rise (and decline?) of biotechnology. Drug Discov. Today 19, 1686–1690 13 Kinch, M.S. et al. (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039
Michael S. Kinch, Sheila Umlauf, Mark Plummer 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 metabolic diseases, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.02.002