The Business Outlook for the Metabolic Syndrome

Sreten Bogdanovic, Managing Partner, Biophoenix, UK

Session Overview
How Will the Metabolic Syndrome Impact Different Segments of the Pharmaceutical Industry?
Sreten Bogdanovic, Consultant, Biophoenix/D&MD 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

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

How will the metabolic syndrome impact different segments of the pharmaceutical industry?
Sreten Bogdanovic and Beata Langlands, Partners, Biophoenix

D&MD Report

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)

Pharma market segments relevant to MS

Component Males (%) Females (%)
30 25 38 46 10 High blood pressure 37 Elevated triglycerides 35 Low HDL cholesterol 35 Excessive waist circumference 30 Raised fasting glucose 16 Source: NHANES III (8,800 individuals)

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

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/Rhokinase blockers of chloride channels vaccines against angiotensin gene therapies

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

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)

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

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

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

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

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?

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

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

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

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

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

Antidiabetic agents in Phase III trials

PPAR Agonists
BM Squibb/Merck & Cos muraglitazar
NDA submitted 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)

AstraZenecas Galida (tesaglitazar)

Phase III dual alpha gamma agonist

Roche's R-483
Phase III (on hold pending carcinogenicity studies) mainly gamma agonist

Novartis' LAF237
Phase III DPP-4 inhibitor

Novo-Nordisk's ragaglitazar
Phase III (on hold pending carcinogenicity studies) dual alpha gamma agonist

World Metabolic Syndrome Markets by Application, 2003 and 2008

Application 2003 Hypertension 21.0 Dyslipidemia 20.0 Diabetes 5.0 Obesity 3.0 Diabetes diagnostics 4.2 Lipid diagnostics 0.5 Totals: 54.3 Source: Biophoenix 2008 31.0 44.0 7.5 6.0 7.2 2.0 97.7

(Figures are in $US billions and exclude inflation)

World MS Market by Application in 2003

9% 6% Hypertension 9% 38% Dyslipidemia Diabetes Obesity Diabetes diagnostics Lipid diagnostics 1%

37%

Size: $54.3 billion

World MS Market by Application in 2008

7% 6% 32% 8% Hypertension Dyslipidemia Diabetes Obesity Diabetes diagnostics Lipid diagnostics 2%

45%

Size: $97.7 billion

World MS Market by Region in 2003

4% 8%

12%

North America European Union Rest of Europe

3%

51%

Japan Pacific Rim, Africa Latin America

22%

Size: $54.3 billion ($97.7 bn in 2008)

Metabolism friendly drugs

Indication
Epilepsy Depression Psychosis

Common Drug(s)
Valproate, Gabapentin Paroxetine, Fluoxetine, Tricyclics Olanzapine, Clozapine Insulin

MS Effects

Friendly Alternative(s)

Weight gain, IGT Topiramate, Lamotrigine Weight gain, IGT Bupropion Weight gain, IGT Ziprasidone, Aripiperazole Weight gain Weight gain Weight gain Metformin Acarbose, Miglitol Orlistat, Sibutramine

Diabetes

Sulfonylureas Thiazolidinediones Corticosteroids

Weight gain, IGT Selected NSAIDs HBP, IGT Naproxen + PPI

Inflammation

COX-2 inhibitors Antihistamines

Weight gain, IGT Decongestants Mainly IGT ACEIs, ARBs, Ca2+ antagonists

Hypertension Osteoporosis

-Blockers, Thiazide diuretics Raloxifene

Weight gain, IGT Aledronate, Calcitonin Source: Compiled by Biophoenix

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

The End