The Business Outlook for the Metabolic Syndrome

1
The Business Outlook for the Metabolic Syndrome

• Sreten Bogdanovic,
• Managing Partner, Biophoenix, UK

2
Session Overview

• How Will the Metabolic Syndrome Impact Different
  Segments of the Pharmaceutical Industry?
• Sreten Bogdanovic, Consultant, Biophoenix/DMD
  Reports
• Opportunities for Metabolic Disease Therapeutics
  Forecast Problems and Solutions
• Walter Brooks,Vice President, Equinox Group
• Tapping the Metabolic Syndrome Market
  Opportunity Insight Into Payer and Clinician
  Attitudes
• Carilee Berg, Director, Metabolic Diseases,
  Decision Resources
• Physician Prescribing as an Indicator of
  Metabolic Syndrome Markets
• Michel Denari, Practice Leader, Market Dynamics,
  IMS Management Consulting

3
Good news for patients and pharma industry

• MS persists for many years before the onset of
  its complications, giving ample opportunity for
  intervention
• accepted as a discrete disease entity (ICD 277.7)
• presents a constellation of treatable
  abnormalities requiring long-term medication
• treatment of one abnormality often improves
  others
• even moderate improvements can reduce risk of
  progression to diabetes and/or heart disease
• many marketed and experimental products may have
  a role to play in diagnosis and treatment

4
How will the metabolic syndrome impact different
segments of the pharmaceutical industry?

• Sreten Bogdanovic and Beata Langlands, Partners,
  Biophoenix

5
DMD Report
6
Pharma Industry Segments

• In vitro diagnostics
• Lipids
• Diabetes
• Cardiology
• Hypertension
• Dyslipidemia
• Metabolism
• Obesity
• Diabetes
• Others
• Consider MS-related side-effects when prescribing
  any medicine (metabolism friendliness)

7
Opportunities to link diagnostics and therapeutics

• MS remains largely undiagnosed and there will
  need to be increased provision of diagnostic
  services
• could dramatically increase the number of
  patients needing drug therapy
• tests available to identify the classic metabolic
  components
• greater usage of laboratory tests for insulin and
  related substances (e.g. C-peptide) to assess
  insulin sensitivity needed
• more sensitive assessments of cardiovascular risk
  needed
• traditional lipid profiling, plus lipoprotein
  subfractionation profiling to detect changes in
  LDL, HDL, and VLDL subclasses
• apolipoprotein B/A-1 (ratio), LP(a), CRP,
  fibrinogen, Lp-PLA2, and homocysteine
• pharmacogenomic tests for responsiveness to drugs
  needed, particularly in dyslipidemia and
  hypertension

8
Metabolic syndrome IVD markets

• Predominantly diabetes and lipid diagnostics at
  present
• Diabetes diagnostic and treatment market sizes
  are becoming comparable
• The diabetes diagnostic market includes reagent
  strips, readers, and laboratory tests
• Most glucose-testing products are aimed at the
  home user
• The US market for cholesterol testing approaches
  300 million annual tests and is poised for
  explosive growth.
• Triglyceride and cholesterol lab tests are
  generally done together on the same samples
• Analytes such as lipoproteins and CRP cost more
  per test, but are assayed in far smaller numbers.
  Continued high growth is expected.

9
World Metabolic Syndrome IVD Markets, 2003 and
2008
(Figures are in US billions and exclude
inflation)
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Pharma market segments relevant to MS

• Currently these disorders are treated the same in
  the general population as in people with MS
• Drug manufacturers should consider strategies to
  target key patient subgroups, such as the obese
  and at-risk ethnic groups

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The hypertension therapeutic sector

• Principal antihypertensive drug classes currently
  on the market
• Alpha blockers
• Centrally-acting hypertensives
• Diuretics
• Beta blockers
• Calcium channel blockers
• Angiotensin converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• ongoing debate over the best first-line therapy
  because of contradictory results from major
  studies
• Antihypertensive drugs in clinical development
  include
• angiotensin, endothelin, vasopressin, and
  aldosterone antagonists
• dopamine, imidazoline, bradykinin B2, and
  adenosine agonists
• inhibitors of renin, neutral endopeptidase,
  vaso-endopeptidase, NO synthase, Na/K ATPase,
  endothelin-converting enzyme, and Rho/Rho-kinase
• blockers of chloride channels
• vaccines against angiotensin
• gene therapies

12
Treatment of hypertension in MS

• some anti-hypertensives (diuretics,
  beta-blockers) worsen glycemic control and may
  not be suitable for long-term use in MS
• drugs of choice in MS may be ACE-inhibitors, and
  possibly ARBs
• ACE-inhibitors (and ARBs) are free of potentially
  diabetogenic side-effects and seem to have
  pleiotropic antidiabetic properties
• Use of ACE-inhibitors with beta-blockers and/or
  diuretics may cancel out the diabetogenic effects
  of the latter

13
The dyslipidemia sector

• The major drug classes currently marketed for use
  in dyslipidemia
• Statins (primarily lower LDL-C)
• Fibrates (lower triglycerides and modestly raise
  HDL-C)
• Niacin (raises HDL-C and decreases atherogenic
  lipoproteins)
• Bile acid sequestrants (mainly lower LDL-C, may
  increase TG)
• Cholesterol absorption inhibitors (primarily
  lower LDL-C, also lower TG new class, only
  Merck/Schering-Plough's Zetia)
• some of these agents are also available in
  combination (e.g. Kos Pharma's Advicor combines
  extended release niacin and lovastatin)

14
Treatment of dyslipidemia in MS

• ATP III identified MS as a secondary target for
  lipid-altering therapy after the primary
  treatment of LDL-C abnormalities
• Around half of patients with LDL-C levels which
  qualify for drug therapy also have MS
• MS patients with raised LDL-C may particularly
  benefit from statin therapy
• Pfizer's Lipitor (atorvastatin) has been shown to
  halt progression of heart disease (REVERSAL
  study)
• AstraZeneca's Crestor (rosuvastatin) has a more
  favourable effect on lipid and lipoprotein
  profiles than the same or higher doses of other
  statins (STELLAR and MERCURY I trials)
• Niacin and fibrates, which elevate HDL and lower
  triglycerides, are ideally suited for
  applications in MS

15
New approaches to the treatment of dyslipidemia

• Targets for HDL-C raising drugs
• Cholesteryl ester transfer protein (CETP)
  inhibitors (e.g. Pfizer's torcetrapib is in Phase
  III trials)
• ATP-binding cassette transporter A1
• Liver X Receptors
• Nuclear retinoid X receptor
• Targets for triglyceride lowering drugs
• Microsomal triglyceride transfer protein
• Stearoyl-CoA desaturase-1
• Dual PPAR alpha/gamma agonists
• e.g. AstraZenecas tesaglitazar (initially for
  use in type 2 diabetes)
• Other selected lipid modulators in development
• Superstatins
• Ileal bile acid transport inhibitors
• Acyl-coenzyme A-cholesterol acyltransferase
  inhibitors
• Lipoprotein-associated phospholipase inhibitors

16
Hypertension and dyslipidemia market forecasts

• The pharmaceutical market for hypertension is the
  largest single therapeutic sector in the world,
  with sales of 21 billion per annum
• further growth will result mainly from increased
  prescribing of available agents
• over half of all hypertensives are expected to be
  receiving treatment by 2008
• however, some experts do not believe that
  hypertension makes any noticeable contribution to
  MS
• The market for lipid lowering agents is now
  almost as large statins alone are worth about
  20 billion
• only an estimated one third of Americans in need
  of cholesterol-lowering treatment are currently
  receiving it
• companies such as Pfizer believe that there
  continue to be opportunities for further growth
  in the dyslipidemia market other sources have
  suggested that growth rates are falling
• We expect the dyslipidemia market to comfortably
  outpace the antihypertensive market by 2008

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World Hypertension and Dyslipidemia Markets, 2003
and 2008
(Figures are in US billions and exclude
inflation)
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The obesity sector

• Conventional diets are associated with high
  recidivism rates
• There are 6 drugs in widespread use, including 2
  agents approved specifically for obesity
  (diethylpropion, phentermine, phendimetrazine,
  mazindol, sibutramine, and orlistat)
• It is highly likely that even an ideal drug would
  have to be taken indefinitely due to the chronic
  nature of obesity
• MS diagnosis allows identification of overweight
  individuals most in need of sustained weight loss
  therapy

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Pharmacological approaches to obesity

• Drugs which decrease food intake
• Dopaminergic and serotoninergic drugs
• Cholecystokinin-promoting agents
• Leptin-promoting agents
• Agouti-related protein
• Glucagon-like peptide 1
• PYY3-36 peptide
• Melanocortin-4 receptor agonists
• CRF receptor agonists
• Neuropeptide Y receptor antagonists
• Ghrelin receptor antagonists
• Orexin receptor antagonists
• Galanin receptor antagonists
• Fatty acid synthase inhibitors

• Cannabinoid receptor antagonist
• Cactus-derived P57
• Drugs which inhibit nutrient absorption
• Lipase inhibitors
• Alpha-glucosidase inhibitors
• Drugs which increase energy expenditure
• Beta3-adrenoceptor agonists
• Uncoupling proteins
• Thyroid hormone receptor modulators
• Human growth hormone fragment
• Human steroidal hormone

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Antiobesity agents launched or in Phase III
trials

• Abbott's Meridia
• Launched
• serotonin and norepinephrine reuptake inhibitor
• reduces food intake
• shown to improve glycemic control in diabetes
• raises blood pressure and increases heart rate in
  some patients FDA advisory?
• Regenerons Axokine
• Phase III
• patented form of Ciliary Neurotrophic Factor
• reduces food intake
• 11 of patients lost over 10 of body weight in
  one year
• may trigger immune response

• Sanofi-Aventis' Acomplia
• Phase III
• Cannabinoid receptor antagonist reduces food
  intake
• average weight loss (2 years) 16lbs (placebo
  5.5lb)
• patients with MS 42 at start of trial, 21 after
  two years
• Roche's Xenical
• Launched
• Lipase inhibitor inhibits nutrient absorption
  from the gut
• more effective than diet alone in improving all
  five MS abnormalities (XENDOS study)
• shown to reduce the risk of diabetes in MS
  patients

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Marketed antidiabetic agents

• Insulin
• no alternative exists where the capacity of the
  pancreas to secrete insulin has been lost
• Sulfonylureas
• stimulate insulin secretion
• Biguanides (metformin)
• inhibit gluconeogenesis and glycogenolysis
• Glucosidase inhibitors
• slow digestion of carbohydrates
• Meglitinides
• stimulate early phase glucose-induced insulin
  secretion
• Thiazolidinediones (TZDs)
• increase insulin sensitivity

22
Treatment of type 2 diabetes in MS patients

• 5-10 of patients with MS develop type 2
  diabetes every year
• Type 2 diabetics who lack any other MS features
  (approx. 10) have the same risk of
  cardiovascular disease as nondiabetics -
  treatments should be aimed at any underlying MS
• Insulin and sulfonylureas should be used with
  care in patients with MS, as they cause weight
  gain. Metformin promotes weight loss and reduces
  triglycerides
• Insulin sensitisers are of particular interest in
  MS
• The Metabolic Syndrome Alliance advocates early
  and aggressive treatment of patients with type 2
  diabetes and MS, using interventions that target
  insulin resistance
• Subcutaneous, not visceral, fat appears to be
  increased by TZDs
• TZDs may cause potentially serious side effects
  and need to be used with caution

23
New approaches to the treatment of type 2 diabetes

• Agonists for PPAR gamma, alpha, and delta are
  under development
• Dual PPAR gamma/PPAR alpha agonists show promise
  in treating a broad spectrum of metabolic
  abnormalities
• During 2004, the FDA recommended that two-year
  carcinogenicity studies be completed before
  initiation of clinical studies with PPAR agonists
  lasting more than six months
• Some other insulin sensitizers target the insulin
  receptor directly yet others target regulatory
  phosphatases
• Hypoglycemic agents which enhance incretin action
  include glucagon-like peptide (GLP-1) analogs and
  dipeptidyl peptidase 4 (DPP4) inhibitors
• Drug discovery programs are increasingly aimed at
  the identification of drug targets common to both
  obesity and diabetes

24
Antidiabetic agents in Phase III trials

• PPAR Agonists
• BM Squibb/Merck Cos muraglitazar
• NDA submitted
• Dual alpha gamma agonist
• AstraZenecas Galida (tesaglitazar)
• Phase III
• dual alpha gamma agonist
• Roche's R-483
• Phase III (on hold pending carcinogenicity
  studies)
• mainly gamma agonist
• Novo-Nordisk's ragaglitazar
• Phase III (on hold pending carcinogenicity
  studies)
• dual alpha gamma agonist

• Incretin Enhancers
• Amylin Pharmaceuticals' exenatide
• NDA submitted
• GLP-1 analog
• improves insulin sensitivity in insulin-resistant
  Zucker rats
• lowers weight (5 lb over 5 months of clinical
  trial)
• Novartis' LAF237
• Phase III
• DPP-4 inhibitor

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Diabetes market forecasts

• Diabetes treatment, which overwhelmingly involves
  type 2 diabetes, is a multi-billion dollar world
  market
• The best-selling antidiabetic agents are the
  various types of insulin, together with metformin
  and sulfonylureas
• To focus on type 2 diabetes, we excluded insulin
  and sulfonylureas from our forecasts
• Insulin sensitisers have already gained 25 of
  market share
• Future growth in the diabetes market will be
  driven partly by the increasing uptake of newer
  and more expensive therapies such as the TZDs

26
Obesity market forecasts

• The range of estimates for prescription
  antiobesity drugs is very wide, between 3
  billion and 10 billion
• A considerable amount of antiobesity prescribing
  involves the off-label use of drugs such as
  stimulants
• Future growth in the obesity market will be
  primarily as a result of increased usage of the
  available agents

27
World Diabetes and Obesity Treatment Markets,
2003 and 2008
(Figures are in US billions and exclude
inflation)
28
New horizons diabetes prevention

• Several studies have shown an elevated risk of
  cardiovascular disease prior to clinical
  diagnosis of type 2 diabetes
• West of Scotland Coronary Prevention Study the
  risk of diabetes increases with the number of
  metabolic abnormalities
• IGT is usually only the fourth or fifth
  abnormality to appear in the development of MS
• Several drugs have been shown to slow progression
  from IGT to diabetes, eg metformin, TZDs, and
  alpha-glucosidase inhibitors
• many doctors give off-label prescriptions for
  metformin or TZDs to selected patients diagnosed
  with IGT
• Currently available antidiabetic drugs all have
  side effects
• only trials with subjects screened for MS are
  likely to satisfy future FDA requirements for an
  indication to treat this patient population

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Market outlook Summing-up

• Drugs (and associated IVDs) targeted at specific
  components of MS represented a 54 billion world
  wide market in 2003 and are forecast to grow to
  98 billion by 2008
• Presently this market is dominated by
  antihypertensive and lipid-lowering drugs, but by
  2008 lipid-lowering drugs will have established a
  decisive lead, taking nearly half the market

30
World Metabolic Syndrome Markets by Application,
2003 and 2008
(Figures are in US billions and exclude
inflation)
31
World MS Market by Application in 2003
Size 54.3 billion
32
World MS Market by Application in 2008
Size 97.7 billion
33
World Metabolic Syndrome Markets by Region, 2003
and 2008
(Figures are in US billions and exclude
inflation)
34
World MS Market by Region in 2003
Size 54.3 billion (97.7 bn in 2008)
35
Optimizing treatment outcomes

• Selection of an appropriate agent, for example in
  hypertension, should consider its effects on
  lipid and glucose metabolism
• Since metabolic syndrome is a complicated
  disorder, multiple treatment regimes may be
  required
• Drug companies must continue to investigate
  combination therapies, since monotherapy is often
  ineffective
• Combination products such as Pfizer's Caduet
  (amlodipine and atorvastatin) are likely to make
  an impact by treating two of the most common risk
  factors simultaneously
• The metabolic syndrome market is likely to expand
  to include pharmacogenomic tests and drugs which
  offer multi-modal mechanisms of action. Ideally
  drugs should also directly address insulin
  resistance.

36
Targeting insulin resistance

• Insulin resistance may persist 10-20 years before
  the onset of type 2 diabetes
• Treatment of conditions which occur in
  combination in MS may not address the central
  role of insulin resistance
• There is insufficient data to support widespread
  pharmacological therapy of insulin resistant
  individuals
• Drug developers will need to demonstrate the
  effectiveness of novel insulin sensitizers in
  large-scale population studies
• Recently oxidative stress has been implicated in
  insulin resistance
• In future, management of insulin resistance may
  be possible with combinations of exercise
  training, insulin sensitizers and antioxidants
  (such as alpha-lipoic acid)

37
Likely impact of MS on other pharma sectors

• The emergence of the metabolic syndrome as a
  clinical entity is likely to have profound
  implications for developers of all drugs
• An unwelcome spotlight will fall on drugs which
  cause weight gain, and/or other metabolic
  abnormalities associated with MS
• Studies should seek to establish how different
  drugs induce weight gain and other metabolic
  abnormalities, because drug-associated weight
  gain and insulin resistance may be preventable
• e.g. glucocorticoid-induced insulin resistance
  appears to be caused by hepatic activation of
  PPAR-alpha, and not by central obesity
• All drugs entering clinical trials should be
  evaluated for their effects on weight and on
  glucose and fatty acid metabolism, ideally in
  patients with MS

38
Metabolism friendly drugs
39
Promoting metabolism-friendly drugs

• Manufacturers of existing drugs shown not to
  cause weight gain or metabolic abnormalities
  should be considering strategies to promote their
  products to the medical profession as
  "metabolism-friendly"
• Post-marketing trials of drugs believed not to
  cause weight gain could be conducted to underpin
  new promotional strategies

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The End