Metabolic Syndrome Talk

7/29/2019 Metabolic Syndrome Talk

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The Business Outlook for the

Metabolic Syndrome

Sreten Bogdanovic,

Managing Partner, Biophoenix, UK


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Session Overview

How Will the Metabolic Syndrome Impact DifferentSegments 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 MetabolicSyndrome Markets

Michel Denari, Practice Leader, Market Dynamics, IMSManagement Consulting


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Good news for patients and pharma industry

MS persists for many years before the onset of itscomplications, giving ample opportunity for intervention

accepted as a discrete disease entity (ICD 277.7)

presents a constellation of treatable abnormalitiesrequiring 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


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How will the metabolic syndrome

impact different segments of thepharmaceutical industry?

Sreten Bogdanovic and BeataLanglands, Partners, Biophoenix


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D&MD Report


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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)


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Pharma market segments relevant to MS

Currently these disorders are treated the same in the generalpopulation as in people with MS

Drug manufacturers should consider strategies to target key patientsubgroups, such as the obese and at-risk ethnic groups

Component Males (%) Females (%)High blood pressure 37 30

Elevated triglycerides 35 25

Low HDL cholesterol 35 38

Excessive waist circumference 30 46

Raised fasting glucose 16 10

Source: NHANES III (8,800 individuals)


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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 ofcontradictory 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, NOsynthase, Na/K ATPase, endothelin-converting enzyme, and Rho/Rho-kinase

blockers of chloride channels vaccines against angiotensin gene therapies


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Treatment of hypertension in MS

some anti-hypertensives (diuretics, beta-blockers)worsen glycemic control and may not be suitable forlong-term use in MS

drugs of choice in MS may be ACE-inhibitors, andpossibly ARBs

ACE-inhibitors (and ARBs) are free of potentiallydiabetogenic side-effects and seem to have pleiotropicantidiabetic properties

Use of ACE-inhibitors with beta-blockers and/or diureticsmay cancel out the diabetogenic effects of the latter


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The dyslipidemia sector

The major drug classes currently marketed for use indyslipidemia:

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, alsolower 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 extendedrelease niacin and lovastatin)


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Treatment of dyslipidemia in MS

ATP III identified MS as a secondary target for lipid-alteringtherapy after the primary treatment of LDL-C abnormalities

Around half of patients with LDL-C levels which qualify for drugtherapy 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 effecton 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


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New approaches to the treatment of

dyslipidemia

Targets for HDL-C raising drugs

Cholesteryl ester transfer protein (CETP) inhibitors (e.g. Pfizer's torcetrapibis 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


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The obesity sector

Conventional diets are associated with high recidivismrates

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 betaken indefinitely due to the chronic nature of obesity

MS diagnosis allows identification of overweightindividuals most in need of sustained weight loss therapy


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Pharmacological approaches to obesity

Drugs which decrease foodintake

Dopaminergic and serotoninergicdrugs

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 nutrientabsorption

Lipase inhibitors Alpha-glucosidase inhibitors

Drugs which increase energyexpenditure

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 somepatients; FDA advisory?

Regenerons Axokine

Phase III

patented form of CiliaryNeurotrophic 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 inimproving all five MSabnormalities (XENDOS study)

shown to reduce the risk ofdiabetes 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


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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 weightloss 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 beused with caution


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New approaches to the treatment of

type 2 diabetes

Agonists for PPAR gamma, alpha, and delta are underdevelopment

Dual PPAR gamma/PPAR alpha agonists show promise in treating abroad spectrum of metabolic abnormalities

During 2004, the FDA recommended that two-year carcinogenicity

studies be completed before initiation of clinical studies with PPARagonists 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 theidentification of drug targets common to both obesity and diabetes


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Antidiabetic agents in Phase III trials

PPAR Agonists

BM Squibb/Merck & Cosmuraglitazar 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 ininsulin-resistant Zucker rats

lowers weight (5 lb over 5months of clinical trial)

Novartis' LAF237 Phase III

DPP-4 inhibitor


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World Metabolic Syndrome Markets by

Application, 2003 and 2008

Application 2003 2008

Hypertension 21.0 31.0

Dyslipidemia 20.0 44.0

Diabetes 5.0 7.5

Obesity 3.0 6.0Diabetes diagnostics 4.2 7.2

Lipid diagnostics 0.5 2.0

Totals: 54.3 97.7

Source: Biophoenix

(Figures are in $US billions and exclude inflation)


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World MS Market by Application in 2003

38%

37%

9%

6%

9% 1%

Hypertension

Dyslipidemia

Diabetes

Obesity

Diabetes diagnostics

Lipid diagnostics

Size: $54.3 billion


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World MS Market by Application in 2008

32%

45%

8%

6%

7% 2%

Hypertension

DyslipidemiaDiabetes

Obesity

Diabetes diagnostics

Lipid diagnostics

Size: $97.7 billion


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World MS Market by Region in 2003

51%

22%

3%

12%

8%4%

North America

European UnionRest of Europe

Japan

Pacific Rim, Africa

Latin America

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


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Metabolism friendly drugs

Indication Common Drug(s) MS Effects Friendly Alternative(s)

Epilepsy Valproate, Gabapentin Weight gain, IGT Topiramate, Lamotrigine

Depression Paroxetine, Fluoxetine, Tricyclics Weight gain, IGT Bupropion

Psychosis Olanzapine, Clozapine Weight gain, IGT Ziprasidone, Aripiperazole

Insulin Weight gain Metformin

Sulfonylureas Weight gain Acarbose, MiglitolDiabetes

Thiazolidinediones Weight gain Orlistat, Sibutramine

Corticosteroids Weight gain, IGT Selected NSAIDs

COX-2 inhibitors HBP, IGT Naproxen + PPIInflammation

Antihistamines Weight gain, IGT Decongestants

Hypertension -Blockers, Thiazide diuretics Mainly IGT ACEIs, ARBs, Ca2+ antagonists

Osteoporosis Raloxifene Weight gain, IGT Aledronate, Calcitonin

Source: Compiled by Biophoenix


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Promoting metabolism-friendly drugs

Manufacturers of existing drugs shown not tocause weight gain or metabolic abnormalitiesshould 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 tounderpin new promotional strategies


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The End

Metabolic Syndrome Talk

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