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Discovering and developing pharmaceuticals Obesity : the ‘new’ health issue Overview of therapeutics in the area Dr Richard Palmer CEO and R&D Director.

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Presentation on theme: "Discovering and developing pharmaceuticals Obesity : the ‘new’ health issue Overview of therapeutics in the area Dr Richard Palmer CEO and R&D Director."— Presentation transcript:

1 Discovering and developing pharmaceuticals Obesity : the ‘new’ health issue Overview of therapeutics in the area Dr Richard Palmer CEO and R&D Director Alizyme plc

2 Obesity : The Problem  Globally > 1 billion overweight adults and > 3 million obese  Major risk for chronic disease  Type II diabetes  Cardiovascular disease  Hypertension  Arthritis  Cancer  Key causes are  Increased consumption of energy dense food high in fat and sugar  Reduced physical activity

3 Prevalence of Adult Obesity in Europe BMI  30 Kgm 2

4 Prevalence of Overweight Children Aged Between 4-11 years by Country, Latest Available Year, Europe Prevalence of overweight children aged between 4-11 years by country, latest available year, Europe Russia Scotland Poland Germany Czech Republic Yugoslavia France Sweden England Portugal Greece Italy % overwieght International Obesity Task Force (WHO 2004)

5 Factors Influencing the Development of Obesity Kopelman, P.G.: Nature 404: 635 – 643, 2000

6 Obesity Drugs in Phase II and III Clinical Development RimonabantCB1 antagonistSanofi-Aventis CetilistatLipase inhibitorAlizyme PramlintideInsulin enhancerAmylin AOD 9604Growth Hormone Fraction Metabolic APD 3565-HT2c agonistArena

7 Sites to Approach Obesity Treatments Appetite Suppressants Calorie Absorption Adipose Tissue Calorie Consumption

8 Obesity : Solutions? Marketed Obesity Pharmaceuticals DRUGDosingMOAEfficacyAdverse Effects Sibutramine (Meridia, Abbott) Approved 11/97 10 mg po, qd (5 to 15 mg) Norepinephrine, dopamine, serotonin reuptake inhibitor 2 – 10 kg weight loss Elevated BP & heart rate Orlistat (Xenical ®, Roche) Approved 4/ mg po, tid prior to meals Inhibits pancreatic lipase blocking fat absorption 2 – 10 kg weight loss Oily, loose stools, anal leakage, fat soluble vitamins reduced Only ONE phase 3 drug in development – CB1R antagonist Rimonabant

9 Obesity Targets Central 5-HT2c agonists CB1 antagonists Appetite suppressant GI Tract Lipase inhibition GLP-1/DPP-IV Ghrelin CCK agonist PYY agonist NPY antagonist Reduced calorie intake Satiety Appetite suppressant Peripheral MC4R  3 adrenoceptors DGAT 1 Leptin 11  HSD-1 Acetyl CoA carboxylase inhibitor Appetite suppressant Metabolic activator Triglyceride synthesis Appetite/metabolism Reduced cortisol Lipid metabolism

10 Rimonabant (Acomplia™) Endocanabinoid system CB1 receptors :brain, adipocytes, liver Rimonabant :inhibits food intake reduces weight, waist circumference improves insulin sensitivity central vs. peripheral effects?

11 Weight loss from baseline months12 months Weight loss (kg) Cetilistat placeboCetilistatXenical® placeboXenical® Acomplia  placeboAcomplia  Meridia placebo Meridia Efficacy similar for all agents Comparative Efficacy of Weight Loss Drugs

12 Utility of Lipase Inhibitors in Clinical Practice  Inhibition of gastrointestinal lipases attenuates digestion and absorption of dietary fat  Lipase inhibition has proven efficacy in obese patients  Weight loss  Maintenance of lost weight  Secondary benefits of lipase inhibition: prevention and treatment of co-morbid conditions  Non-insulin-dependent diabetes mellitus  Dyslipidaemia  Hypertension

13 Cetilistat: Urine/Faeces Excretion Profile in Healthy Volunteers Total Radioactivity Cetilistat is poorly absorbed

14 Cetilistat Phase I

15 Cetilistat: Phase Ib Programme: Objectives  To demonstrate Cetilistat inhibits GI lipases in healthy volunteers  To demonstrate Cetilistat is safe and well tolerated  To establish doses for further evaluation in Phase II efficacy studies

16 Cetilistat: Phase Ib Programme: Design  Three studies  Double blind, randomised, placebo-controlled, parallel group  Cohorts of 7-9 healthy male volunteers, resident in Phase I unit  Treatment administered 3 times daily (t.i.d.) with food for 5 days  Cetilistat ( mg t.i.d)  Orlistat (120 mg t.i.d)  Calorie controlled diet (2300 kcal/d, 30% fat) Ref: Dunk et al (2002) Int. J. Obes. Relat. Metab. Disord. 26, Suppl.1, S2-245

17 Cetilistat: Phase Ib Study End Points  Primary End Point  Faecal Fat (g/24h)  Secondary End Points  Safety: adverse events, vital signs, ECG, clinical laboratory parameters  Tolerability: gastrointestinal adverse events

18 Over view of Preliminary Unaudited Results Pharmacodynamic Effects of Cetilistat and Orlistat (Xenical ® ) Placebo n = 24 Cetilistat n = 66 Orlistat n = 9 Adverse events (per volunteer)

19 Correlation of Faecal Fat Excretion and Episodes of Oily Stool Faecal fat excretion (g/24h) Total episodes of oily stool Cetilistat Orlistat

20 Cetilistat Phase IIb Study Ref: Cetilistat (ATL-962), a novel lipase inhibitor : a 12 week randomized placebo controlled study of weight reduction in obese patients. Kopelman et al (submitted)

21 Cetilistat: Design  20 centres, 5 European countries (UK, Sweden, Finland, Denmark, France)  Placebo, 60 mg tid, 120 mg tid, 240 mg tid  12 weeks treatment  BMI >= 30 kg/m 2 with no co-morbidities  BMI > 28 kg/m 2 with established untreated co-morbidities  Male and female 18 – 65 years  Calorie deficit (~500 kcal/day)  ~30% calories as fat  Behavioural and dietary counselling

22 Cetilistat: Phase IIb Endpoints Primary endpoint  Weight loss Secondary endpoints  Proportion of patients who achieved 10% weight loss  Reduction in waist/hip ratio  Body Mass Index  Indicators of co-morbidity Triglyceride, cholesterol, (HDL/LDL) Fasting glucose, insulin, HbA 1c  Quality of life  Safety and tolerability Adverse events, vital signs, fat-soluble vitamins

23 Absolute Weight Loss CetilistatXenical ® Ref: FDA Medical Review p<0.002 Week 12 LS Mean change p< P=0.005

24 Comparison of Cetilistat vs Xenical ® over Time Cetilistat week 12 Mean change Weeks Weight loss (kg) Xenical PlaceboXenical 60mg tidXenical 120mg tidCetilistat/Placebo Cetilistat 60mg tidCetilistat 120mg tidCetilistat 240 tid

25 Comparison of Cetilistat vs Rimonabant over Time Cetilistat week 12 Mean change Rimonabant Placebo Rimonabant 5mg Cetilistat/Placebo Cetilistat 60mg tid Cetilistat 120mg tid Cetilistat 240 tid Rimonabant 20mg Weeks Weight loss (kg) ITT population Rimonabant weight loss data from completers

26 % of Patients Completing Treatment who Lost >5% Body Weight Xenical ® at one year (FDA Medical Review) Cetilistat at 12 weeks

27 Cetilistat vs Xenical ® : Frequency of GI Adverse Events Xenical ® reference: FDA Medical Review Frequency following 12 weeks treatment

28 Side Effects Of Anti-Obesity Products With obesity drugs:Efficacy is similar for all agents : Side effect profile is everything!

29 Cetilistat: Obese Diabetic Study - Design  30 centres, 5 European countries (UK, Sweden, Finland, Denmark, Netherlands)  Placebo, 40 mg tid, 80 mg tid, 120 mg tid for 12 weeks  Orlistat 120 mg tid for 12 weeks  BMI > 28 kg/m 2 and < 45 kg/m 2  Male and female 18 – 65 years  Type II diabetic and taking metformin  Calorie deficit (~500 kcal/day)  ~30% calories as fat  Behavioural and dietary counselling  Results December 2005

30 Cetilistat: Obese Diabetic Study - Endpoints Primary endpoint  weight loss Secondary endpoints  clinical parameters associated with obesity  safety and tolerability (versus placebo and orlistat)  efficacy of orlistat on clinical parameters associated with obesity

31 Context  Open IND in USA  PK/PD Phase I ongoing  80 obese subjects  14 days dosing  40, 80, 120, 240 mg t.i.d. Cetilistat: US Development

32 Conclusions  Obesity is a global epidemic  Drugs show similar efficacy  Side-effects are critical  Many mechanisms being explored  Limited progress over last 10 years  Cetilistat has potential as treatment in future There is a problem!

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