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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
Alizyme plc
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
Prevalence of Adult Obesity in Europe BMI  30 Kgm2
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
% overwieght
30
25
20
15
10
5
0
International Obesity Task Force (WHO 2004)
Factors Influencing the Development of Obesity
Kopelman, P.G.: Nature 404: 635 – 643, 2000
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
Sites to Approach Obesity Treatments
Appetite Suppressants
Appetite Suppressants
Calorie Absorption
Adipose Tissue
Calorie Consumption
Obesity : Solutions?
Marketed Obesity Pharmaceuticals
DRUG
Dosing
MOA
Efficacy
Sibutramine
10 mg po, qd
(5 to 15 mg)
Norepinephrine,
dopamine,
serotonin
reuptake inhibitor
2 – 10 kg Elevated BP &
weight
heart rate
loss
120 mg po, tid
prior to meals
Inhibits
pancreatic lipase
blocking fat
absorption
2 – 10 kg Oily, loose
weight
stools, anal
loss
leakage, fat
soluble vitamins
reduced
(Meridia, Abbott)
Approved 11/97
Orlistat
(Xenical®, Roche)
Approved 4/99
Adverse
Effects
Only ONE phase 3 drug in development – CB1R antagonist Rimonabant
Obesity Targets
Central
GI Tract
Peripheral
5-HT2c agonists
Appetite suppressant
CB1 antagonists
Appetite suppressant
Lipase inhibition
Reduced calorie intake
GLP-1/DPP-IV
Satiety
Ghrelin
Appetite suppressant
CCK agonist
Appetite suppressant
PYY agonist
Appetite suppressant
NPY antagonist
Appetite suppressant
MC4R
Appetite suppressant
3 adrenoceptors
Metabolic activator
DGAT1
Triglyceride synthesis
Leptin
Appetite/metabolism
11 HSD-1
Reduced cortisol
Acetyl CoA
Lipid metabolism
carboxylase inhibitor
Rimonabant (Acomplia™)
Endocanabinoid system
CB1 receptors :
brain, adipocytes, liver
Rimonabant :
inhibits food intake
reduces weight, waist circumference
improves insulin sensitivity
central vs. peripheral effects?
Comparative Efficacy of Weight Loss Drugs
9
Weight loss from baseline
Weight loss (kg)
7
5
3
1
-1
3 months
Cetilistat placebo
Cetilistat
Acomplia placebo
Acomplia
12 months
Xenical® placebo
Meridia placebo
Efficacy similar for all agents
Xenical®
Meridia
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
Cetilistat: Urine/Faeces Excretion Profile in Healthy Volunteers
Total Radioactivity
100
% Administered Dose
90
80
70
60
50
Urine
Faeces
Total
40
30
20
10
0
0
24
48
72
96
120
Time Point (h)
Cetilistat is poorly absorbed
144
168
Cetilistat
Phase I
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
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
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
Pharmacodynamic
Effects
of Cetilistat
and Orlistat (Xenical®)
Over
view of Preliminary
Unaudited
Results
20
18
Faecal fat (g/24Hr)
16
14
12
10
8
6
4
2
0
0
50
100
150
200
250
300
350
[ATL-962] mg/tid
Adverse events
(per volunteer)
Orlistat
120mg
Placebo
n = 24
Cetilistat
n = 66
Orlistat
n=9
2.88
2.77
7.33
Correlation of Faecal Fat Excretion and Episodes of Oily Stool
Total episodes of oily stool
12
Cetilistat
10
Orlistat
8
6
4
2
0
0
5
10
15
Faecal fat excretion (g/24h)
20
25
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)
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
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
Absolute Weight Loss
8
Xenical®
Cetilistat
Ref: FDA Medical
Review
Weight loss (kg)
6
p<0.002
p<0.0003
P=0.005
4
2
0
Placebo 60mg
tid
120mg
tid
Week 12 LS Mean change
240mg
tid
Placebo 120mg
tid
Comparison of Cetilistat vs Xenical® over Time
Weeks
0
12
24
36
52
0
Weight loss (kg)
-1
-2
-3
-4
-5
-6
-7
Xenical Placebo
Xenical 60mg tid
Xenical 120mg tid
Cetilistat 60mg tid
Cetilistat 120mg tid
Cetilistat 240 tid
Cetilistat week 12 Mean change
Cetilistat/Placebo
Comparison of Cetilistat vs Rimonabant over Time
Weight loss (kg)
0
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
12
Weeks
24
36
Rimonabant weight loss data from completers
Rimonabant Placebo
Rimonabant 5mg
Cetilistat/Placebo
Cetilistat 60mg tid
Cetilistat 240 tid
Cetilistat week 12 Mean change
52
ITT population
Rimonabant 20mg
Cetilistat 120mg tid
% of Patients Completing Treatment who Lost >5% Body Weight
Cetilistat at 12 weeks
Xenical® at one year
(FDA Medical Review)
% of patients losing >5%
60
50
40
30
20
10
0
Placebo 60 mg
tid
120 mg 240 mg
tid
tid
Placebo Xenical
Cetilistat vs Xenical®: Frequency of GI Adverse Events
Frequency following 12 weeks treatment
Xenical
ATL-962
Placebo
25
20
15
10
5
Xenical® reference: FDA Medical Review
Liquid stools
Oily stool
Faecal
urgency
Faecal
incontinence
Oily spotting
0
Flatus with
discharge
Frequency (%)
30
Side Effects Of Anti-Obesity Products
Lipase Inhibitor Drugs
Xenical 60mg tid*
Oily Spotting
18.8%
Faecal Urgency
20.2%
Flatus with Discharge
18.9%
Xenical 120mg tid*
26.6%
22.1%
23.9%
ATL-962 Phase IIb**
2.2%
7.9%
1.8%
Hypertension
7.9%
Nausea
-
CNS
-
-
12.5%
?
Centrally Acting Drugs
Meridia
Acomplia
* European Public Assessment Report
** 3 month data
With obesity drugs : Efficacy is similar for all agents
: Side effect profile is everything!
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
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
Cetilistat:
Context 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.
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!