Obesity : the new health issue Overview of therapeutics in the area Dr Richard Palmer CEO and R

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Obesity the new health issueOverview of
therapeutics in the areaDr Richard PalmerCEO
and RD DirectorAlizyme plc
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Obesity The Problem

• Globally gt 1 billion overweight adults and gt 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

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Prevalence of Adult Obesity in Europe BMI ? 30
Kgm2
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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
40
35
30
25
overwieght
20
15
10
5
0
Italy
Russia
Poland
France
Greece
Sweden
England
Portugal
Scotland
Germany
Yugoslavia
Czech Republic
International Obesity Task Force (WHO 2004)
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Factors Influencing the Development of Obesity
Kopelman, P.G. Nature 404 635 643, 2000
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Obesity Drugs in Phase II and III Clinical
Development
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Sites to Approach Obesity Treatments

• Appetite Suppressants

Appetite Suppressants Calorie Absorption
Adipose Tissue
Calorie Consumption
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Obesity Solutions?

• Marketed Obesity Pharmaceuticals

Only ONE phase 3 drug in development CB1R
antagonist Rimonabant
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Obesity Targets
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Rimonabant (Acomplia)

• Endocanabinoid system
• CB1 receptors brain, adipocytes, liver
• Rimonabant inhibits food intake
• reduces weight, waist circumference
• improves insulin sensitivity
• central vs. peripheral effects?

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Comparative Efficacy of Weight Loss Drugs
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Weight loss from baseline
7
5
Weight loss (kg)
3
1
-1
3 months
12 months
Cetilistat placebo
Cetilistat
Xenical placebo
Xenical
Meridia placebo
Meridia
Acomplia? placebo
Acomplia?
Efficacy similar for all agents
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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

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Cetilistat Urine/Faeces Excretion Profile in
Healthy Volunteers
Total Radioactivity
Cetilistat is poorly absorbed
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Cetilistat Phase I
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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

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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 (50-300 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
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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

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Over view of Preliminary Unaudited Results
Pharmacodynamic Effects of Cetilistat and
Orlistat (Xenical)
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Correlation of Faecal Fat Excretion and Episodes
of Oily Stool
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Cetilistat
10
Orlistat
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Total episodes of oily stool
6
4
2
0
0
5
10
15
20
25
Faecal fat excretion (g/24h)
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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)
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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 gt 30 kg/m2 with no co-morbidities
• BMI gt 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

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Cetilistat Phase IIb Endpoints

• Primary endpoint
• Weight loss
• Secondary endpoints
• Proportion of patients who achieved lt5, 5-10,
  gt10 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

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Absolute Weight Loss
Cetilistat
Xenical Ref FDA Medical Review
plt0.0003
plt0.002
P0.005
Week 12 LS Mean change
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Comparison of Cetilistat vs Xenical over Time
Weeks
0
12
24
36
52
0
-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
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Comparison of Cetilistat vs Rimonabant over Time
Weeks
0
12
24
36
52
0
-1
-2
-3
-4
Weight loss (kg)
-5
-6
-7
-8
-9
Rimonabant weight loss data from completers
ITT population
Rimonabant 20mg
Rimonabant 5mg
Rimonabant Placebo
Cetilistat/Placebo
Cetilistat 60mg tid
Cetilistat 120mg tid
Cetilistat 240 tid
Cetilistat week 12 Mean change
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of Patients Completing Treatment who Lost gt5
Body Weight
Xenical at one year (FDA Medical Review)
Cetilistat at 12 weeks
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Cetilistat vs Xenical Frequency of GI Adverse
Events
Frequency following 12 weeks treatment
Xenical reference FDA Medical Review
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Side Effects Of Anti-Obesity Products

• With obesity drugs Efficacy is similar for all
  agents
• Side effect profile is everything!

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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 gt 28 kg/m2 and lt 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

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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

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Context
Cetilistat US Development

• Open IND in USA
• PK/PD Phase I ongoing
• 80 obese subjects
• 14 days dosing
• 40, 80, 120, 240 mg t.i.d.
  
  

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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!