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

2. Globally > 1 billion overweight adults and > 3 million obese
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 Kgm2

4. Prevalence of Overweight Children Aged Between 4-11 years by Country, Latest Available Year, Europe40 35 30 25
% overwieght 20 15 10 5
Italy
Russia
Scotland
Poland
Germany
France
Yugoslavia
Sweden
England
Portugal
Greece
Czech Republic
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
Rimonabant
CB1 antagonist
Sanofi-Aventis
Cetilistat
Lipase inhibitor
Alizyme
Pramlintide
Insulin enhancer
Amylin
AOD 9604
Growth Hormone Fraction
Metabolic
APD 356
5-HT2c agonist
Arena

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

8. Marketed Obesity Pharmaceuticals
Obesity : Solutions?
Marketed Obesity Pharmaceuticals
DRUG
Dosing
MOA
Efficacy
Adverse 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 4/99
120 mg po, tid prior to meals
Inhibits pancreatic lipase blocking fat absorption
Oily, loose stools, anal leakage, fat soluble vitamins reduced
Only ONE phase 3 drug in development – CB1R antagonist Rimonabant

9. Obesity Targets Central GI Tract Peripheral 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
Peripheral
MC4R
3 adrenoceptors
DGAT1
Leptin
11 HSD-1
Acetyl CoA carboxylase inhibitor
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. Comparative Efficacy of Weight Loss Drugs9
Weight loss from baseline 7 5
Weight loss (kg) 3 1 -1
3 months
12 months
Cetilistat placebo
Cetilistat
Xenical® placebo
Xenical®
Meridia placebo
Acomplia placebo
Acomplia
Meridia
Efficacy similar for all agents

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)
2.88
2.77
7.33

19. Correlation of Faecal Fat Excretion and Episodes of Oily Stool12
Cetilistat 10
Orlistat 8
Total episodes of oily stool 6 4 2 5 10 15 20 25
Faecal fat excretion (g/24h)

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/m2 with no co-morbidities
BMI > 28 kg/m2 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 <5%, 5-10%, >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 Cetilistat Xenical® p<0.0003 p<0.002
Ref: FDA Medical Review
p<0.0003
p<0.002
P=0.005
Week 12 LS Mean change

24. Comparison of Cetilistat vs Xenical® over Time
Weeks 12 24 36 52 -1 -2 -3
Weight loss (kg) -4 -5 -6 -7
Xenical Placebo
Xenical 60mg tid
Xenical 120mg tid
Cetilistat/Placebo
Cetilistat 60mg tid
Cetilistat 120mg tid
Cetilistat 240 tid
Cetilistat week 12 Mean change

25. Comparison of Cetilistat vs Rimonabant over Time
Weeks 12 24 36 52 -1 -2 -3
Weight loss (kg) -4 -5 -6 -7 -8 -9
Rimonabant weight loss data from completers
ITT population
Rimonabant Placebo
Rimonabant 5mg
Rimonabant 20mg
Cetilistat/Placebo
Cetilistat 60mg tid
Cetilistat 120mg tid
Cetilistat 240 tid
Cetilistat week 12 Mean change

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

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

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/m2 and < 45 kg/m2
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. Cetilistat: US Development
Context
Open IND in USA
PK/PD Phase I ongoing
80 obese subjects
14 days dosing
40, 80, 120, 240 mg t.i.d.

32. There is a problem! 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!