Metabolic Syndrome: New Opportunities in Diagnostics and Therapeutics.

Metabolic Syndrome: New Opportunities in Diagnostics and Therapeutics.

Publisher:	D&MD Publications Inc
Year of publication:	2004
Type of publication:	Management report
Publisher's reference (if any):	D&MD9135
Author(s):	Sreten Bogdanovic and Beata Langlands
Approximate page count:	250
Price when published:	$4,950
Remarks: Page numbers, where given, refer to the draft manuscript (which may differ from the published version). The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed. The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices. On 6 May 2005, Sreten Bogdanovic gave a talk, "How will the metabolic syndrome impact different segments of the pharmaceutical industry?" at IBC's third Targeting Metabolic Syndrome conference in Cambridge, MA, USA.
METABOLIC SYNDROME: NEW OPPORTUNITIES IN DIAGNOSTICS AND THERAPEUTICS TABLE OF CONTENTS EXECUTIVE SUMMARY CHAPTER 1 INTRODUCTION TO THE METABOLIC SYNDROME 1.1 Metabolic syndrome overview 1.2 Associated disease risks 1.3 Prevalence and etiology 1.4 Central defect of insulin resistance (IR) 1.4.1 Mechanisms 1.4.2 Hyperinsulinemia 1.4.3 Progression to diabetes 1.5 Major components of the metabolic syndrome 1.5.1 Glucose intolerance and IR 1.5.2 Obesity 1.5.2.1 Association with IR 1.5.3 Dyslipidemia 1.5.3.1 Association with IR 1.5.4 Hypertension 1.5.4.1 Association with IR 1.6 Metabolic cardiology: role of IR 1.7 Therapeutic lifestyle goals 1.8 Scope of this report 1.8.1 Diagnostic opportunities 1.8.2 Therapeutic opportunities CHAPTER 2 IN VITRO DIAGNOSTICS FOR THE METABOLIC SYNDROME 2.1 Diagnosing the metabolic syndrome 2.1.1 WHO diagnostic criteria 2.1.2 NCEP-ATPIII diagnostic criteria 2.1.3 ACE/AACE diagnostic criteria 2.1.4 A wealth of diagnostic and risk markers 2.2 Markers of insulin resistance 2.2.1 Euglycemic insulin clamp 2.2.2 GTT/Modified GTT 3.2.3 Fasting plasma insulin and glucose 3.2.3.1 HOMA method 2.2.4 Fasting plasma proinsulin 2.2.5 Labelled glucose breath test 2.2.6 Diagnosis of diabetes and prediabetes 2.3 Markers of cardiovascular risk 2.3.1 Introduction 2.3.2 Dyslipidemia of metabolic syndrome 2.3.3 Lipid profiling 2.3.3.1 Limitations of current lipid panels 2.3.3.2 Trends in lipid panels 2.3.4 Lipoprotein subclass particle analysis 2.3.4.1 Subclasses in insulin resistance 2.3.5 Other lipid and lipoprotein markers 2.3.5.1 Apolipoproteins B and A-1 2.3.5.2 Lipoprotein(a) 2.3.5.3 Oxidised LDL 2.3.5.4 Sphingolipids 2.3.6 Proinflammatory/prothrombotic markers 2.3.6.1 Overview 2.3.6.2 CRP 2.3.6.3 Fibrinogen 2.3.6.4 Lp-PLA2 2.3.6.5 PAI-1 2.3.6.6 Activated complement 2.3.6.7 Activated Factor XII 2.3.6.8 Anti-phospholipid antibodies 2.3.6.9 MIF 2.3.6.10 Il-10 anti-inflammatory protein 2.3.7 Markers of endothelial dysfunction 2.3.7.1 ADMA 2.3.7.2 Cellular adhesion molecules 2.3.7.3 Homocysteine 2.3.8 Other markers 2.3.8.1 Urinary albumin 2.3.8.2 Plasma uric acid 2.4 Genetic markers of disease susceptibility 2.4.1 Insulin resistance 2.4.2 Cardiovascular disease 2.4.2.1 Hypertension 2.4.2.2 Examples of other gene markers 2.4.3 Genes predisposing to NASH 2.5 Genetic markers of drug responsiveness 2.5.1 Statins 2.5.2 ACE inhibitors 2.5.3 Antidiabetic drugs 2.5.4 Prediction of adverse reactions CHAPTER 3 DRUGS FOR OBESITY 3.1 Central obesity and metabolic risk factors 3.2 Weight loss: a key therapeutic objective 3.3 Pharmacologic treatment of obesity 3.4 Control of energy homeostasis 3.4.1 Control of food intake 3.4.1 Anorexigenic and orexigenic peptides 3.5 Drugs on the market 3.5.1 Roche's Xenical 3.5.1.1 Xenical in metabolic syndrome 3.5.2 Abbott's Meridia 3.6 Drugs in development 3.6.1 Drugs which decrease food intake 3.6.1.1 Dopaminergic agents 3.6.1.2 Serotoninergic drugs 3.6.1.3 Cholecystokinin-promoting agents 3.6.1.4 Leptin-promoting agents 3.6.1.5 Agouti-related protein 3.6.1.6 Ciliary Neurotrophic Factor 3.6.1.7 Glucagon-like peptide 1 3.6.1.8 PYY3-36 peptide 3.6.1.9 Melanocortin-4 receptor agonists 3.6.1.10 CRF receptor agonists 3.6.1.11 Neuropeptide Y receptor antagonists 3.6.1.12 Ghrelin receptor antagonists 3.6.1.13 Orexin receptor antagonists 3.6.1.14 Galanin receptor antagonists 3.6.1.15 Fatty acid synthase inhibitors 3.6.1.16 Cannabinoid receptor antagonist 3.6.1.17 Cactus-derived P57 3.6.1.18 Other agents 3.6.2 Drugs which inhibit nutrient absorption 3.6.2.1 Lipase inhibitors 3.6.2.2 Alpha-glucosidase inhibitors 3.6.3 Drugs which increase energy expenditure 3.6.3.1 Beta3-adrenoceptor agonists 3.6.3.2 Uncoupling proteins 3.6.3.3 Thyroid hormone receptor modulators 3.6.3.4 Human growth hormone fragment 3.6.3.5 Human steroidal hormone 3.6.3.6 BT compounds CHAPTER 4 DRUGS FOR INSULIN RESISTANCE AND TYPE 2 DIABETES 4.1 Insulin abnormalities and diabetes 4.2 Drugs on the market 4.2.1 Sulfonylureas 4.2.2 Biguanides 4.2.3 Insulin 4.2.4 Glucosidase inhibitors 4.2.5 Meglitinides 4.2.6 Thiazolidinediones 4.2.7 Combination therapies 4.2.8 Limitations of current therapies 4.2.9 Potential for diabetes prevention 4.3 Insulin sensitizers in development 4.3.1 Introduction 4.3.2 PPAR agonists 4.3.2.1 PPAR gamma agonists 4.3.2.2 PPAR alpha agonists 4.3.2.3 Dual PPAR gamma/PPAR alpha agonists 4.3.2.4 PPAR delta agonists 4.3.3 Potentiators of insulin signaling 4.3.3.1 Targeting the insulin receptor 4.3.3.2 Targeting the regulatory phosphatases 4.3.3.3 Other approaches 4.3.4 Miscellaneous agents 4.4 Other antidiabetics in development 4.4.1 GLP-1 analogs 4.4.2 DPP-IV inhibitors 4.4.4 Miscellaneous 4.5 Drug discovery programs in obesity and diabetes CHAPTER 5 DRUGS FOR METABOLIC CARDIOLOGY 5.1 Treatment goals in metabolic cardiology 5.1.1 Goals in dyslipidemia 5.1.2 Goals in hypertension 5.2 Focus on dyslipidemia 5.2.2 Drugs on the market 5.2.2.1 Statins 5.2.2.2 Bile acid sequestrants 5.2.2.3 Fibrates 5.2.2.4 Niacin 5.2.2.5 Cholesterol absorption inhibitors 5.2.2.6 Combination therapies 5.2.2.7 Limitations of current therapies 5.2.2.8 Effectiveness in metabolic syndrome 5.2.3 HDL raising drugs in development 5.2.3.1 Drugs targeting ABCA-1, LXR, and RXR 5.2.3.2 ApoA-I isoforms 5.2.3.3 CETP inhibitors 5.2.3.4 Other agents 5.2.4 Triglyceride lowering drugs in development 5.2.4.1 MTP inhibitors 5.2.4.2 SCD1 inhibitors 5.2.4.3 Natural products and analogs 5.2.4.4 Other agents 5.2.5 PPAR agonists in development 5.2.6 Other lipid modulators in development 5.2.6.1 Superstatins 5.2.6.2 IBAT inhibitors 5.2.6.3 ACAT inhibitors 5.2.6.4 Lp-PLA2 inhibitors 5.2.6.5 Antiatherosclerotic agents 5.2.6.6 Other agents 5.3 Focus on hypertension 5.3.1 Drugs on the market 5.3.1.1 Diuretics 5.3.1.2 Sympathetic nervous system agents 5.3.1.3 Calcium blockers 5.3.1.4 ACE inhibitors 5.3.1.5 Angiotensin II receptor antagonists 5.3.1.6 Combination therapies 5.3.1.7 Limitations of current therapies 5.3.1.8 Effectiveness in metabolic syndrome 5.3.2 Drugs in development 5.3.2.1 Aldosterone receptor antagonists 5.3.2.2 Vaso-endopeptidase inhibitors 5.3.2.3 AGE crosslink breakers 5.3.2.4 Angiotensin vaccine 5.3.2.5 Other agents 5.4 Focus on combined dyslipidemia/hypertension 5.5 Multi-modal monotherapies for metabolic syndrome 5.5.1 Marketed drugs 5.5.2 PPAR modulators 5.5.3 New approaches CHAPTER 6 METABOLIC SYNDROME MARKETS AND FORECASTS 6.1 Introduction 6.2 Prevalence of metabolic syndrome 6.3 The metabolic syndrome and diabetes 6.4 Markets for metabolic syndrome 6.5 Prevalence of diabetes 6.6 Markets for diabetes 6.7 Prevalence of obesity 6.8 Markets for obesity 6.9 Prevalence of cardiovascular disease 6.9.1 Overview 6.9.2 The metabolic syndrome and heart disease 6.9.3 Hypertension 6.9.4 Hyperlipidemia 6.10 Markets in cardiovascular disease 6.10.1 Hypertension 6.10.2 Dyslipidaemia 6.11 Market forecasts to 2008 CHAPTER 7 COMPANY PROFILES 7.0 Introduction 7.1 Aeson Therapeutics Inc 7.2 AGT Biosciences 7.3 Amylin Pharmaceuticals Inc 7.4 Atherotech Inc 7.5 Biovitrum AB 7.6 Cholestech Corporation 7.7 Clingenix Inc. 7.8 DeveloGen AG 7.9 FASgen Inc 7.10 Genaissance Pharmaceuticals Inc 7.11 HollisEden Pharmaceuticals Inc 7.12 Interleukin Genetics Inc 7.13 Isis Pharmaceuticals Inc 7.14 Isotechnika Inc 7.15 Keryx Biopharmaceuticals Inc 7.16 Kos Pharmaceuticals Inc 7.17 Metabolic Pharmaceuticals Ltd 7.18 Novo Nordisk A/S 7.19 Pfizer Inc 7.20 Phenomix Corporation 7.21 Pilot Therapeutics Holdings Inc 7.22 Quark Biotech Inc 7.23 Regeneron Pharmaceuticals Inc 7.24 Ribonomics Inc 7.25 Roche 7.26 Telik Inc 7.27 Theratechnologies 7.28 Xantos Biomedicine GmbH 7.29 X-Ceptor Therapeutics Inc 7.30 Xenon Genetics Inc CHAPTER 8 TRENDS AND OPPORTUNITIES 8.1 Metabolic syndrome overall 8.1.1 Evolution of the market 8.1.2 Implications for drug companies 8.1.3 Implications for diagnostic companies 8.2 Obesity focus 8.2.1 Promoting "metabolism-friendly" drugs 8.3 Diabetes focus 8.3.1 Diabetes prevention as a new indication 8.4 Cardiovascular disease focus 8.4.1 Optimizing treatment outcomes EXECUTIVE SUMMARY The metabolic syndrome describes a cluster of metabolic abnormalities centered on insulin resistance. Because individuals with the metabolic syndrome have a significantly increased risk of death from cardiovascular disease, and because they are also prone to develop type 2 diabetes and other serious medical conditions, identification and pharmacological management of this highly prevalent condition is vitally important and presents a significant market opportunity. At present there are no drugs to treat the metabolic syndrome as such. However, drugs (and associated in vitro diagnostic tests) targeted at specific components of the syndrome, such as dyslipidaemia, hypertension, and obesity, represented a $54 billion worlwide market in 2003 and are forecast to grow to $98 billion by 2008. Presently this market is dominated by antihypertensive and lipid-lowering drugs, with shares of about 37% each, but by 2008 lipid-lowering drugs will have established a decisive lead, taking nearly half the market. Early detection of the metabolic syndrome is essential to enable effective intervention. The report therefore begins with a review of in vitro diagnostics for the metabolic syndrome. Chapter 2 outlines basic tests used to identify the classic abnormalities of insulin, glucose and lipid metabolism associated with the syndrome and assesses trends in this area. In particular, there have been important developments in the methods used to detect the dyslipidemia characteristic of the metabolic syndrome and to assess cardiovascular risk with the aid of the new biomarkers. Since it is well recognized that the development of metabolic syndrome has genetic components, new tests based on markers of disease susceptibility and markers of drug responsiveness are also reviewed in this chapter. Metabolic syndrome represents one of the most debilitating and costly complications of obesity. Diagnosis of the metabolic syndrome allows identification of overweight individuals most in need of sustained weight loss therapy. Chapter 3 therefore focuses on antiobesity agents currently under commercial investigation. It is apparent that the traditional approach to anti-obesity pharmacological therapy, restriction of energy intake, is still the most popular approach. One appetite-suppressant has been approved and at least two additional drugs may be close to market. Alternative anti-obesity strategies may also result in additional product approvals, although therapies are generally at an earlier stage of development. One strategy seeks to limit nutrient absorption in the gastrointestinal track; one lipase inhibitor has been approved and another one is advancing in clinical trials. Yet another strategy seeks to increase an individual's energy expenditure; promising agents in this category are also reviewed in this chapter. Metabolic syndrome is the principal precursor state for type 2 diabetes. Chapter 4 therefore focuses on antidiabetic agents, both on the market and in development, and their potential for diabetes prevention. In type 2 diabetes, insulin sensitisers have already gained significant market share and these agentsshow great promise for the treatment of the metabolic syndrome. The first class of insulin sensitizers to reach the market were the thiazolidinediones, synthetic ligands for nuclear peroxisome proliferator-activated receptor (PPAR) gamma subtype. Synthetic ligands for other PPAR subtypes are also under development. Other insulin sensitizers have different modes of action; for example some potentiate insulin signaling by targeting the insulin receptor directly or by targeting the regulatory phosphatases. There is also a wide variety of other hypoglycemic agents in development, including several glucagon-like peptide (GLP-1) analogs and dipeptidyl peptidase 4 (DPP4) inhibitors. Since the risk of developing diabetes rises exponentially with body weight, drug discovery programs are increasingly aimed at the identification of drug targets common to both obesity and diabetes; examples of promising proprietary approaches are discussed. The cardiovascular area sees the metabolic syndrome as primarily a precursor state for cardiovascular disease. Pharmacological treatment aimed at reducing cardiovascular risk in patients with the metabolic syndrome may be directed at the individual manifestations such as dyslipidemia and hypertension and involves the use of lipid-modifying or antihypertensive agents. As Chapter 5 reports, the effectiveness of existing agents is limited, and many new agents are in development as this area. In particular, the search for new agents that increase high density lipoprotein (HDL) has intensified. Current treatments for elevated triglycerides are also unable to meet the needs of all metabolic syndrome patients and novel triglyceride-lowering therapies are under investigation. A survey of antihypertensives indicates that there is also a great need for more effective antihypertensive drugs. Promising new antihypertensives include aldosterone receptor antagonists and drugs with multiple mechanisms of action such as vasopeptidase inhibitors. Although many of the drugs discussed in the report target a specific indication such as diabetes, dyslipidemia or hypertension, some clearly impact more than one component of the metabolic syndrome. Efforts are also underway to develop multi-modal monotherapies which would offer a more holistic therapeutic mode. A number of companies are investigating dual PPAR alpha/gamma agonists and PPARpan agonists which also target PPAR-delta, while others are investigating various proprietary drug targets. The report profiles 30 diagnostic, pharmaceutical and biotech companies active in one or more of the diverse but increasingly converging areas relevant to the metabolic syndrome. These areas encompass in vitro diagnosis and treatments aimed at obesity, diabetes, dyslipidemia and hypertension. The emergence of the metabolic syndrome as a clinical entity is predicted to have profound implications for developers of all drugs. Unlike many drugs currently in widespread use, future drugs will need to be more "metabolism-friendly" and seen not to induce weight gain or exert a negative impact on glucose and fatty acid metabolism.

Publisher:

D&MD Publications Inc

Year of publication:

2004

Type of publication:

Management report

Publisher's reference (if any):

D&MD9135

Author(s):

Sreten Bogdanovic and Beata Langlands

Approximate page count:

250

Price when published:

$4,950

Remarks:

Page numbers, where given, refer to the draft manuscript (which may differ from the published version).
The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed.
The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices.
On 6 May 2005, Sreten Bogdanovic gave a talk, "How will the metabolic syndrome impact different segments of the pharmaceutical industry?" at IBC's third Targeting Metabolic Syndrome conference in Cambridge, MA, USA.

                              METABOLIC SYNDROME:
                NEW OPPORTUNITIES IN DIAGNOSTICS AND THERAPEUTICS

                               TABLE OF CONTENTS

         EXECUTIVE SUMMARY

         CHAPTER 1  INTRODUCTION TO THE METABOLIC SYNDROME

         1.1 Metabolic syndrome overview

         1.2 Associated disease risks

         1.3 Prevalence and etiology

         1.4 Central defect of insulin resistance (IR)
            1.4.1 Mechanisms
            1.4.2 Hyperinsulinemia
            1.4.3 Progression to diabetes

         1.5 Major components of the metabolic syndrome
            1.5.1 Glucose intolerance and IR
            1.5.2  Obesity
              1.5.2.1 Association with IR
            1.5.3 Dyslipidemia
              1.5.3.1 Association with IR
            1.5.4 Hypertension
              1.5.4.1 Association with IR

         1.6 Metabolic cardiology: role of IR

         1.7 Therapeutic lifestyle goals

         1.8 Scope of this report
            1.8.1 Diagnostic opportunities
            1.8.2 Therapeutic opportunities

         CHAPTER 2  IN VITRO DIAGNOSTICS FOR THE METABOLIC SYNDROME

         2.1 Diagnosing the metabolic syndrome
            2.1.1 WHO diagnostic criteria
            2.1.2 NCEP-ATPIII diagnostic criteria
            2.1.3 ACE/AACE diagnostic criteria
            2.1.4 A wealth of diagnostic and risk markers

         2.2 Markers of insulin resistance
            2.2.1 Euglycemic insulin clamp
            2.2.2 GTT/Modified GTT
            3.2.3 Fasting plasma insulin and glucose
              3.2.3.1 HOMA method
            2.2.4 Fasting plasma proinsulin
            2.2.5 Labelled glucose breath test
            2.2.6 Diagnosis of diabetes and prediabetes

         2.3 Markers of cardiovascular risk
            2.3.1 Introduction
            2.3.2 Dyslipidemia of metabolic syndrome
            2.3.3 Lipid profiling
              2.3.3.1 Limitations of current lipid panels
              2.3.3.2 Trends in lipid panels
            2.3.4 Lipoprotein subclass particle analysis
              2.3.4.1 Subclasses in insulin resistance
            2.3.5 Other lipid and lipoprotein markers
              2.3.5.1 Apolipoproteins B and A-1
              2.3.5.2 Lipoprotein(a)
              2.3.5.3 Oxidised LDL
              2.3.5.4 Sphingolipids
            2.3.6 Proinflammatory/prothrombotic markers
              2.3.6.1 Overview
              2.3.6.2 CRP
              2.3.6.3 Fibrinogen
              2.3.6.4 Lp-PLA2
              2.3.6.5 PAI-1
              2.3.6.6 Activated complement
              2.3.6.7 Activated Factor XII
              2.3.6.8 Anti-phospholipid antibodies
              2.3.6.9 MIF
              2.3.6.10 Il-10 anti-inflammatory protein
            2.3.7 Markers of endothelial dysfunction
              2.3.7.1 ADMA
              2.3.7.2 Cellular adhesion molecules
              2.3.7.3 Homocysteine
            2.3.8 Other markers
              2.3.8.1 Urinary albumin
              2.3.8.2 Plasma uric acid

         2.4 Genetic markers of disease susceptibility
            2.4.1 Insulin resistance
            2.4.2 Cardiovascular disease
              2.4.2.1 Hypertension
              2.4.2.2 Examples of other gene markers
            2.4.3 Genes predisposing to NASH

         2.5 Genetic markers of drug responsiveness
            2.5.1 Statins
            2.5.2 ACE inhibitors
            2.5.3 Antidiabetic drugs
            2.5.4 Prediction of adverse reactions

         CHAPTER 3  DRUGS FOR OBESITY

         3.1 Central obesity and metabolic risk factors

         3.2 Weight loss: a key therapeutic objective

         3.3 Pharmacologic treatment of obesity

         3.4 Control of energy homeostasis
            3.4.1 Control of food intake
            3.4.1 Anorexigenic and orexigenic peptides

         3.5 Drugs on the market
            3.5.1 Roche's Xenical
              3.5.1.1 Xenical in metabolic syndrome
            3.5.2 Abbott's Meridia

         3.6 Drugs in development
            3.6.1 Drugs which decrease food intake
              3.6.1.1 Dopaminergic agents
              3.6.1.2 Serotoninergic drugs
              3.6.1.3 Cholecystokinin-promoting agents
              3.6.1.4 Leptin-promoting agents
              3.6.1.5 Agouti-related protein
              3.6.1.6 Ciliary Neurotrophic Factor
              3.6.1.7 Glucagon-like peptide 1
              3.6.1.8 PYY3-36 peptide
              3.6.1.9 Melanocortin-4 receptor agonists
              3.6.1.10 CRF receptor agonists
              3.6.1.11 Neuropeptide Y receptor antagonists
              3.6.1.12 Ghrelin receptor antagonists
              3.6.1.13 Orexin receptor antagonists
              3.6.1.14 Galanin receptor antagonists
              3.6.1.15 Fatty acid synthase inhibitors
              3.6.1.16 Cannabinoid receptor antagonist
              3.6.1.17 Cactus-derived P57
              3.6.1.18 Other agents
            3.6.2 Drugs which inhibit nutrient absorption
              3.6.2.1 Lipase inhibitors
              3.6.2.2 Alpha-glucosidase inhibitors
            3.6.3 Drugs which increase energy expenditure
              3.6.3.1 Beta3-adrenoceptor agonists
              3.6.3.2 Uncoupling proteins
              3.6.3.3 Thyroid hormone receptor modulators
              3.6.3.4 Human growth hormone fragment
              3.6.3.5 Human steroidal hormone
              3.6.3.6 BT compounds

         CHAPTER 4  DRUGS FOR INSULIN RESISTANCE AND TYPE 2 DIABETES

         4.1 Insulin abnormalities and diabetes

         4.2 Drugs on the market
            4.2.1 Sulfonylureas
            4.2.2 Biguanides
            4.2.3 Insulin
            4.2.4 Glucosidase inhibitors
            4.2.5 Meglitinides
            4.2.6 Thiazolidinediones
            4.2.7 Combination therapies
            4.2.8 Limitations of current therapies
            4.2.9 Potential for diabetes prevention

         4.3 Insulin sensitizers in development
            4.3.1 Introduction
            4.3.2 PPAR agonists
              4.3.2.1 PPAR gamma agonists
              4.3.2.2 PPAR alpha agonists
              4.3.2.3 Dual PPAR gamma/PPAR alpha agonists
              4.3.2.4 PPAR delta agonists
            4.3.3 Potentiators of insulin signaling
              4.3.3.1 Targeting the insulin receptor
              4.3.3.2 Targeting the regulatory phosphatases
              4.3.3.3 Other approaches
            4.3.4 Miscellaneous agents

         4.4 Other antidiabetics in development
            4.4.1 GLP-1 analogs
            4.4.2 DPP-IV inhibitors
            4.4.4 Miscellaneous

         4.5 Drug discovery programs in obesity and diabetes

         CHAPTER 5  DRUGS FOR METABOLIC CARDIOLOGY

         5.1 Treatment goals in metabolic cardiology
            5.1.1 Goals in dyslipidemia
            5.1.2 Goals in hypertension

         5.2 Focus on dyslipidemia
            5.2.2 Drugs on the market
              5.2.2.1 Statins
              5.2.2.2 Bile acid sequestrants
              5.2.2.3 Fibrates
              5.2.2.4 Niacin
              5.2.2.5 Cholesterol absorption inhibitors
              5.2.2.6 Combination therapies
              5.2.2.7 Limitations of current therapies
              5.2.2.8 Effectiveness in metabolic syndrome
            5.2.3 HDL raising drugs in development
              5.2.3.1 Drugs targeting ABCA-1, LXR, and RXR
              5.2.3.2 ApoA-I isoforms
              5.2.3.3 CETP inhibitors
              5.2.3.4 Other agents
            5.2.4 Triglyceride lowering drugs in development
              5.2.4.1 MTP inhibitors
              5.2.4.2 SCD1 inhibitors
              5.2.4.3 Natural products and analogs
              5.2.4.4 Other agents
            5.2.5 PPAR agonists in development
            5.2.6 Other lipid modulators in development
              5.2.6.1 Superstatins
              5.2.6.2 IBAT inhibitors
              5.2.6.3 ACAT inhibitors
              5.2.6.4 Lp-PLA2 inhibitors
              5.2.6.5 Antiatherosclerotic agents
              5.2.6.6 Other agents

         5.3 Focus on hypertension
            5.3.1 Drugs on the market
              5.3.1.1 Diuretics
              5.3.1.2 Sympathetic nervous system agents
              5.3.1.3 Calcium blockers
              5.3.1.4 ACE inhibitors
              5.3.1.5 Angiotensin II receptor antagonists
              5.3.1.6 Combination therapies
              5.3.1.7 Limitations of current therapies
              5.3.1.8 Effectiveness in metabolic syndrome
            5.3.2 Drugs in development
              5.3.2.1 Aldosterone receptor antagonists
              5.3.2.2 Vaso-endopeptidase inhibitors
              5.3.2.3 AGE crosslink breakers
              5.3.2.4 Angiotensin vaccine
              5.3.2.5 Other agents

         5.4 Focus on combined dyslipidemia/hypertension

         5.5 Multi-modal monotherapies for metabolic syndrome
            5.5.1 Marketed drugs
            5.5.2 PPAR modulators
            5.5.3 New approaches

         CHAPTER 6  METABOLIC SYNDROME MARKETS AND FORECASTS

         6.1  Introduction

         6.2  Prevalence of metabolic syndrome

         6.3  The metabolic syndrome and diabetes

         6.4  Markets for metabolic syndrome

         6.5  Prevalence of diabetes

         6.6  Markets for diabetes

         6.7  Prevalence of obesity

         6.8  Markets for obesity

         6.9  Prevalence of cardiovascular disease
            6.9.1  Overview
            6.9.2  The metabolic syndrome and heart disease
            6.9.3  Hypertension
            6.9.4  Hyperlipidemia

         6.10  Markets in cardiovascular disease
            6.10.1  Hypertension
            6.10.2  Dyslipidaemia

         6.11  Market forecasts to 2008

         CHAPTER 7  COMPANY PROFILES

         7.0  Introduction
         7.1  Aeson Therapeutics Inc
         7.2  AGT Biosciences
         7.3  Amylin Pharmaceuticals Inc
         7.4  Atherotech Inc
         7.5  Biovitrum AB
         7.6  Cholestech Corporation
         7.7  Clingenix Inc.
         7.8  DeveloGen AG
         7.9  FASgen Inc
         7.10  Genaissance Pharmaceuticals Inc
         7.11  HollisEden Pharmaceuticals Inc
         7.12  Interleukin Genetics Inc
         7.13  Isis Pharmaceuticals Inc
         7.14  Isotechnika Inc
         7.15  Keryx Biopharmaceuticals Inc
         7.16  Kos Pharmaceuticals Inc
         7.17  Metabolic Pharmaceuticals Ltd
         7.18  Novo Nordisk A/S
         7.19  Pfizer Inc
         7.20  Phenomix Corporation
         7.21  Pilot Therapeutics Holdings Inc
         7.22  Quark Biotech Inc
         7.23  Regeneron Pharmaceuticals Inc
         7.24  Ribonomics Inc
         7.25  Roche
         7.26  Telik Inc
         7.27  Theratechnologies
         7.28  Xantos Biomedicine GmbH
         7.29  X-Ceptor Therapeutics Inc
         7.30  Xenon Genetics Inc

         CHAPTER 8  TRENDS AND OPPORTUNITIES

         8.1 Metabolic syndrome overall
            8.1.1 Evolution of the market
            8.1.2 Implications for drug companies
            8.1.3 Implications for diagnostic companies

         8.2 Obesity focus
            8.2.1 Promoting "metabolism-friendly" drugs

         8.3 Diabetes focus
            8.3.1 Diabetes prevention as a new indication

         8.4 Cardiovascular disease focus
            8.4.1 Optimizing treatment outcomes

EXECUTIVE SUMMARY
The metabolic syndrome describes a cluster of metabolic abnormalities centered on insulin resistance. Because individuals with the metabolic syndrome have a significantly increased risk of death from cardiovascular disease, and because they are also prone to develop type 2 diabetes and other serious medical conditions, identification and pharmacological management of this highly prevalent condition is vitally important and presents a significant market opportunity.
At present there are no drugs to treat the metabolic syndrome as such. However, drugs (and associated in vitro diagnostic tests) targeted at specific components of the syndrome, such as dyslipidaemia, hypertension, and obesity, represented a $54 billion worlwide market in 2003 and are forecast to grow to $98 billion by 2008. Presently this market is dominated by antihypertensive and lipid-lowering drugs, with shares of about 37% each, but by 2008 lipid-lowering drugs will have established a decisive lead, taking nearly half the market.
Early detection of the metabolic syndrome is essential to enable effective intervention. The report therefore begins with a review of in vitro diagnostics for the metabolic syndrome. Chapter 2 outlines basic tests used to identify the classic abnormalities of insulin, glucose and lipid metabolism associated with the syndrome and assesses trends in this area. In particular, there have been important developments in the methods used to detect the dyslipidemia characteristic of the metabolic syndrome and to assess cardiovascular risk with the aid of the new biomarkers. Since it is well recognized that the development of metabolic syndrome has genetic components, new tests based on markers of disease susceptibility and markers of drug responsiveness are also reviewed in this chapter.
Metabolic syndrome represents one of the most debilitating and costly complications of obesity. Diagnosis of the metabolic syndrome allows identification of overweight individuals most in need of sustained weight loss therapy. Chapter 3 therefore focuses on antiobesity agents currently under commercial investigation. It is apparent that the traditional approach to anti-obesity pharmacological therapy, restriction of energy intake, is still the most popular approach. One appetite-suppressant has been approved and at least two additional drugs may be close to market. Alternative anti-obesity strategies may also result in additional product approvals, although therapies are generally at an earlier stage of development. One strategy seeks to limit nutrient absorption in the gastrointestinal track; one lipase inhibitor has been approved and another one is advancing in clinical trials. Yet another strategy seeks to increase an individual's energy expenditure; promising agents in this category are also reviewed in this chapter.
Metabolic syndrome is the principal precursor state for type 2 diabetes. Chapter 4 therefore focuses on antidiabetic agents, both on the market and in development, and their potential for diabetes prevention. In type 2 diabetes, insulin sensitisers have already gained significant market share and these agentsshow great promise for the treatment of the metabolic syndrome. The first class of insulin sensitizers to reach the market were the thiazolidinediones, synthetic ligands for nuclear peroxisome proliferator-activated receptor (PPAR) gamma subtype. Synthetic ligands for other PPAR subtypes are also under development. Other insulin sensitizers have different modes of action; for example some potentiate insulin signaling by targeting the insulin receptor directly or by targeting the regulatory phosphatases. There is also a wide variety of other hypoglycemic agents in development, including several glucagon-like peptide (GLP-1) analogs and dipeptidyl peptidase 4 (DPP4) inhibitors. Since the risk of developing diabetes rises exponentially with body weight, drug discovery programs are increasingly aimed at the identification of drug targets common to both obesity and diabetes; examples of promising proprietary approaches are discussed.
The cardiovascular area sees the metabolic syndrome as primarily a precursor state for cardiovascular disease. Pharmacological treatment aimed at reducing cardiovascular risk in patients with the metabolic syndrome may be directed at the individual manifestations such as dyslipidemia and hypertension and involves the use of lipid-modifying or antihypertensive agents. As Chapter 5 reports, the effectiveness of existing agents is limited, and many new agents are in development as this area. In particular, the search for new agents that increase high density lipoprotein (HDL) has intensified. Current treatments for elevated triglycerides are also unable to meet the needs of all metabolic syndrome patients and novel triglyceride-lowering therapies are under investigation. A survey of antihypertensives indicates that there is also a great need for more effective antihypertensive drugs. Promising new antihypertensives include aldosterone receptor antagonists and drugs with multiple mechanisms of action such as vasopeptidase inhibitors.
Although many of the drugs discussed in the report target a specific indication such as diabetes, dyslipidemia or hypertension, some clearly impact more than one component of the metabolic syndrome. Efforts are also underway to develop multi-modal monotherapies which would offer a more holistic therapeutic mode. A number of companies are investigating dual PPAR alpha/gamma agonists and PPARpan agonists which also target PPAR-delta, while others are investigating various proprietary drug targets.
The report profiles 30 diagnostic, pharmaceutical and biotech companies active in one or more of the diverse but increasingly converging areas relevant to the metabolic syndrome. These areas encompass in vitro diagnosis and treatments aimed at obesity, diabetes, dyslipidemia and hypertension.
The emergence of the metabolic syndrome as a clinical entity is predicted to have profound implications for developers of all drugs. Unlike many drugs currently in widespread use, future drugs will need to be more "metabolism-friendly" and seen not to induce weight gain or exert a negative impact on glucose and fatty acid metabolism.