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Repositioning of Drugs in Cardiometabolic Disorders: Importance and Current Scenario Parmeshwar B. Katare and Sanjay K. Banerjee* Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India Please provide Abstract: Cardiometabolic disorder (CMD) is a cluster of diseases, including cardiovascular diseases corresponding author(s) photograph (CVDs), metabolic syndrome (MS) and diabetes mellitus (DM). Cardiometabolic disorders (CMDs) size should be 4" x 4" inches remain the principal cause of death in both developed and developing countries, accounting for nearly 32% of all deaths worldwide per year. In addition, dyslipidemia, angina, arrhythmia, cardiac failure, myocardial infarction (MI), and diabetes mellitus represent the leading killer with an estimated 19 million people died from CMDs in 2012. By 2030 more than 23 million people will die annually from CVDs. Existing drugs are not efficient enough to reduce the disease burden as well as mortality. Therefore, there is an urgent demand for new drugs in this area to reduce the mortality and control the associated disability. Nonetheless, new drug discovery (NDD) in CMDs has become more challenging for last couple of decades due to increased expenses and decreased success rate. In such a scenario, drug repositioning in the CMDs appears promising for introducing existing drugs for new therapeutic indication. Repositioning is quite an old strategy dating back to 1960s and mainly followed by serendipitous observations during clinical use of drugs. A major advantage of repositioning is that the safety profile of the drug is well established thus reducing the chances to fail due to adverse toxic effects. In addition, repositioning requires less time and investment than NDD. Considering these facts, pharmaceutical companies are now becoming increasingly interested in drug repositioning. In this follow-up, we have talked about the concept of repositioning with important examples of repositioned drugs in cardiometabolic disorder.
Keywords: Cardiometabolic disorders, Cardiovascular disease, Diabetes mellitus, Drug development, Drug discovery, Repositioning. 1. INTRODUCTION In today's world, change in lifestyle and food habits have led to a remarkable change in the morbidity and mortality statistics making cardiometabolic disorders (CMDs) as one of the leading killer. A total 56 million deaths occurred worldwide in 2012, of which, noncommunicable diseases (NCDs) accounts more deaths than all other causes combined [1]. Among deaths from NCDs, 52% deaths occur between the ages of 30 to 70 year, of which 85% are from developing countries (Fig. 1A). Out of total death caused by NCDs, cardiometabolic disorders contributes the largest share of 42% mortality under the age of 70 years (Fig. 1B) [2; 3]. Cardiometabolic disorder (CMD) remains the principal cause of death in both developed and developing countries [3]. In addition, dyslipidemia, angina, arrhythmia, cardiac failure, myocardial infarction (MI), and diabetes mellitus represent the leading killer with an estimated 19 million people died from CMDs in 2012. By 2030 more than 23 million people will die annually from CVDs [3;7]. It is estimated that approximately 6.4 million US citizens have car *Address correspondence to this author at the Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, 121001, India; Tel: +917042354595; E-mails:
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Fig. (1). Percentage of mortality in global scenario, by cause of death; (A) Percentage of total mortality under the age of 70 in global scenario, by cause of death (B) Percentage of total global deaths from noncommunicable diseases under the age of 70 (Fig. 1 is modified from ref. [2]). © 2016 Bentham Science Publishers
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diovascular diseases, which accounts for 40% of all deaths in US (American Heart Association, 2004). This emerging cardiometabolic epidemic imposes a significant burden on quality of life and health care systems. In 2010, the total cost of treatment of cardiovascular diseases in the United States were estimated to be $444 billion [8]. This shows the social and economic impact of CMDs on global population. Cardiometabolic disorder (CMD) is a cluster of diseases, including cardiovascular diseases (CVDs), metabolic syndrome (MS) and diabetes mellitus (DM) [4]. Many of the cardiometabolic diseases are very closely associated and most of the time their occurrence is concurrent. Nearly 65% of the patients suffering with metabolic diseases or diabetes die because of cardiovascular complication [5]. This metabolic and cardiovascular deregulation independently and interdependently leads to increase in CMDs morbidity and mortality [6]. Existing drugs are not efficient enough to control the disease burden as well as mortality. Thus, there is a great need of new drug in this field to reduce the incidence of these diseases and control the disability burden on the society. However, new drug discovery in CMDs is facing difficulty for the last couple of decades (Fig. 2). Drug repositioning in the CMDs appears promising for introducing existing drugs for new indication. Drug repositioning mainly refers to the finding of new uses for the existing, shelved or pipelined drugs. On the other hand, drug repositioning faces challenges itself due to IP rights of the existing drugs.
Katare and Banerjee
2. DRUG REPOSITIONING: THE CONCEPT Drug repositioning is a process of bringing existing drugs for an indication other than the established one. Many drugs have very complex and multiple activities, which makes it difficult to understand them completely and in each such cases there is always a possibility of repositioning [9]. Repositioning is quite an old strategy in drug discovery, dating back to 1960s and increasingly getting importance in the field due to its advantages over conventional drug discovery. Recently National Institute of Health (NIH) has launched a National Centre for Advancing Translational Science (NCATS) program, to accelerate research in drug repositioning. The objective of the program is to discover new therapeutic uses of existing molecules and nurture the collaboration between academic scientists and pharmaceutical companies to reposition the shelved drugs effectively [10]. Breakdown of NCATS assets for repurposing provides nearly 19% share for discovery in the field of CMD (Fig. 3) [11].
Fig. (3). National Institute of Helath’s (NIH) asset distribution of NCATS program for repositioning according to therapeutic area. Cardiometabolic disorders (CMDs) takes second largest share after central nervous system (CNS). (Fig. 3 is modified from ref. [11]).
Cost of new drug development has been increased more than double in the last decade. A study conducted in 2003 estimated that the cost of new drug development was around $ 800 million. In 2013 the cost has increased to $2.6 billion, up by three fold in just a decade [12]. An average time required for new drug development right from its discovery to entry in the market is ten to fourteen years. Generally, a researcher gets 20 years exclusive rights (in terms of patent) as a reward towards discovery, out of which ten to fourteen years are spent in developmental stages until the drug enters the market. Thus, drug development consumes economically most important time of patent life of a drug. A repositioned drug does not need to pass through the initial six to nine years of the development as a new drug but instead enters directly to the clinical phase of development, thus reducing time and cost of development (Fig. 4).
Fig. (2). A recent trend in drug development in cardiometabolic disorder (CMD); (A) Approval of new drugs for the treatment of cardiometabolic disorder from 1995 to 2014. The graph shows a substantial decrease in the new drug entries made in the market. (B) Number of new drugs approved per bn$ R&D spends from 1995 to 2014 in cardiometabolic disorder (inflation adjusted).
When we speak about the likelihood of entry of a drug in the market, we actually consider the success rate of compound to enter into the market. Despite all the technological advancement in drug discovery, the success rate of lead compounds to enter into the market as a drug molecule has decreased from 21% to 16% in last 20 years [13]. It shows the pitholes in discovery progress and decreased efficiency of drug discovery, which needs a careful intervention. More
Repositioning of Drugs in Cardiometabolic Disorders
Current Topics in Medicinal Chemistry, 2016, Vol. 16, No. 22
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New drug d iscove ry an d r epositioning Con ve n tion al d rug d isc ove ry an d d eve lop me nt •
