discovering and developing pharmaceuticals obesity : the ‘new’ health issue overview of...
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Discovering and developing pharmaceuticals
Obesity : the ‘new’ health issue
Overview of therapeutics in the area
Dr Richard PalmerCEO 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
0
5
10
15
20
25
30
35
40
Russia
Scotla
nd
Poland
Germ
any
Czech
Rep
ublic
Yugos
lavia
Franc
e
Sweden
Englan
d
Portu
gal
Greec
eIta
ly
% o
verw
ieg
ht
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 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
2 – 10 kg weight loss
Oily, loose stools, anal leakage, fat soluble vitamins reduced
Only ONE phase 3 drug in development – CB1R antagonist Rimonabant
Obesity Targets
Central 5-HT2c agonists
CB1 antagonists
Appetite suppressant
Appetite suppressant
GI Tract Lipase inhibition
GLP-1/DPP-IV
Ghrelin
CCK agonist
PYY agonist
NPY antagonist
Reduced calorie intake
Satiety
Appetite suppressant
Appetite suppressant
Appetite suppressant
Appetite suppressant
Peripheral MC4R
3 adrenoceptors
DGAT1
Leptin
11 HSD-1
Acetyl CoA carboxylase inhibitor
Appetite suppressant
Metabolic activator
Triglyceride synthesis
Appetite/metabolism
Reduced cortisol
Lipid metabolism
Rimonabant (Acomplia™)
Endocanabinoid system
CB1 receptors : brain, adipocytes, liver
Rimonabant : inhibits food intake
reduces weight, waist circumference
improves insulin sensitivity
central vs. peripheral effects?
Weight loss from baseline
-1
1
3
5
7
9
3 months 12 months
Wei
ght
loss
(kg
)
Cetilistat placebo Cetilistat Xenical® placebo Xenical®
Acomplia placebo Acomplia Meridia placebo Meridia
Efficacy similar for all agents
Comparative Efficacy of Weight Loss Drugs
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
0
10
20
30
40
50
60
70
80
90
100
0 24 48 72 96 120 144 168
Time Point (h)
% A
dmin
iste
red
Dos
e
Urine Faeces Total
Cetilistat is poorly absorbed
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
Over view of Preliminary Unaudited ResultsPharmacodynamic Effects of Cetilistat and Orlistat (Xenical®)
Placebon = 24
Cetilistat n = 66
Orlistat n = 9
Adverse events(per volunteer)
2.88 2.77 7.33
[ATL-962] mg/tid
0 50 100 150 200 250 300 350
Faeca
l fat (g
/24Hr)
0
2
4
6
8
10
12
14
16
18
20
Orlistat120mg
[ATL-962] mg/tid
0 50 100 150 200 250 300 350
Faeca
l fat (g
/24Hr)
0
2
4
6
8
10
12
14
16
18
20
Orlistat120mg
[ATL-962] mg/tid
0 50 100 150 200 250 300 350
Faeca
l fat (g
/24Hr)
0
2
4
6
8
10
12
14
16
18
20
Orlistat120mg
Correlation of Faecal Fat Excretion and Episodes of Oily Stool
0
2
4
6
8
10
12
0 5 10 15 20 25
Faecal fat excretion (g/24h)
To
tal e
pis
od
es
of
oily
sto
ol Cetilistat
Orlistat
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
0
2
4
6
8
Placebo 60mg tid
120mgtid
240mgtid
Placebo 120mgtid
Weight loss
(kg)
Absolute Weight Loss
Cetilistat Xenical®
Ref: FDA Medical Review
p<0.002
Week 12 LS Mean change
p<0.0003P=0.005
Comparison of Cetilistat vs Xenical® over Time
Cetilistat week 12 Mean change
-7
-6
-5
-4
-3
-2
-1
0
0 12 24 36 52Weeks
Wei
ght
loss
(kg
)
Xenical Placebo Xenical 60mg tid Xenical 120mg tid Cetilistat/Placebo
Cetilistat 60mg tid Cetilistat 120mg tid Cetilistat 240 tid
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
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 12 24 36 52Weeks
We
igh
t lo
ss (
kg)
ITT populationRimonabant weight loss data from completers
% of Patients Completing Treatment who Lost >5% Body Weight
Xenical® at one year (FDA Medical Review)
Cetilistat at 12 weeks
0
10
20
30
40
50
60
Placebo 60 mgtid
120 mgtid
240 mgtid
Placebo Xenical
% o
f pa
tient
s lo
sing
>5
%
Cetilistat vs Xenical®: Frequency of GI Adverse Events
Xenical® reference: FDA Medical Review
Frequency following 12 weeks treatment
0
5
10
15
20
25
30F
latu
s w
ithd
isch
arg
e
Oily
sp
ott
ing
Fa
eca
lin
con
tine
nce
Fa
eca
lu
rge
ncy
Oily
sto
ol
Liq
uid
sto
ols
Fre
qu
en
cy (
%)
Xenical ATL-962 Placebo
Side Effects Of Anti-Obesity Products
With obesity drugs : Efficacy is similar for all agents: Side effect profile is everything!
Lipase Inhibitor Drugs
Oily Spotting Faecal Urgency Flatus with Discharge
Xenical 60mg tid* 18.8% 20.2% 18.9%
Xenical 120mg tid* 26.6% 22.1% 23.9%
ATL-962 Phase IIb** 2.2% 7.9% 1.8%
Centrally Acting DrugsHypertension Nausea CNS
Meridia 7.9% - -
Acomplia - 12.5% ?
* European Public Assessment Report** 3 month data
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
ContextContext
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
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!