[ASC-media] Obesity

Niall Byrne niall at byc.com.au
Mon Mar 3 13:51:29 EST 2003

Half a kilo a week - early results for Australian obesity drug

Monday 3 March 2003

Trial results announced today confirm that the Australian-invented obesity
drug AOD9604 is safe. Participants in the one week long phase 2A trial also
lost an average of half a kilo. 

The next step will be a three month long weight loss trial with at least 250
participants - scheduled to start mid-year.

The drug is being developed by Australian biotech company Metabolic
Pharmaceuticals Ltd. 

"We're excited by the results," said Chris Belyea, CEO Metabolic
Pharmaceuticals Ltd. "It's the latest in a long series of positive trial

The drug enhances a natural hormonal process in our bodies that helps
control fat metabolism and is based on discoveries made by Dr Frank Ng and
his colleagues at Monash University.

"It's a completely different approach to that of our global competitors,
unique in that it replicates the natural fat reducing properties of growth
hormone," said Chris Belyea

Human growth hormone acts as a "fat controller", moderating fat metabolism.
The decline of human growth hormone levels as we age is one of the factors
responsible for middle age spread. 

But human growth hormone has many other roles in the body, such as bone
growth. The principle of AOD9604, already proven in animal studies, is to
mimic the natural fat reducing properties of human growth hormone without
producing any effects on blood sugar control or growth "Our drug is based on
a part of the natural human growth hormone protein so after each dose it
will go into the body, send out a molecular signal, naturally enhance fat
metabolism and then quickly disappear."

"Because we are using a natural chemical structure that mimics the body's
natural mechanism, we don't expect this drug to cause the side-effects that
have plagued previous weight-control drugs on the market," Dr Chris Belyea
said.  "If a weight loss of about 0.5 kg per week and the excellent safety
profile is confirmed over longer term dosing, AOD9604 will be substantially
more effective than existing obesity drugs.

The trial was a randomised, double-blind, placebo-controlled Phase 2A dose
escalation study to assess the safety of oral daily dosing of AOD9604 in 36
obese male volunteers. The study was designed with the primary end-point of
safety in mind. 

The key findings from the study were: 
* a positive outcome on safety and tolerability;
* weight loss trends met expectations and occurred in exactly the pattern
predicted from earlier studies;
* the optimum effective daily dose may be 10 mg or possibly lower;
* in the 10 mg dose group, the overall weight loss was 1.0 kg compared to
0.4 kg in the placebo group, and in the 20 older volunteers the weight loss
was 0.8 kg compared to a weight gain of 0.1 kg in the placebo group.

The trial was conducted at the Royal Adelaide Hospital. Dr Chris Belyea is
available for interview in Melbourne and the trial coordinator, Dr Gary
Wittert is available for interview in Adelaide. 

For photos, interviews and further information contact: 
Barbara Pesel, Pesel & Carr, phone: 0418 548 808
or Niall Byrne, phone 03 5253 1391. Also visit www.metabolic.com.au

Background - Metabolic and AOD9604

The Western world is facing an epidemic of obesity. 
The Australian Diabetes, Obesity & Lifestyle Report 2000, commissioned by
the Federal Government, reveals the prevalence of being overweight is 39.1%
and of obesity is 20.5%. This is more than double the rate observed in 1980.
The statistics related to overweight and obesity in the USA produced by the
National Institutes of Health (NIH) indicate much higher figures. The total
annual cost of overweight and obesity in the USA is $99.2 billion (direct
cost: $51.6 billion and indirect cost: $47.6 billion). The obese as a group
spend 77% more on health care, compared with 28% more by smokers. Health
risks associated with obesity include type 2 diabetes, hypertension, heart
disease, stroke, osteoarthritis, gallbladder disease and some forms of
cancer. The mortality rate associated with obesity is high. Obese
individuals have a 50-100% increased risk of death from all causes,
especially cardiovascular diseases. 
Obesity is a chronic health condition. Therefore, long-term use of
prescription medications is appropriate for some people to lose weight and
maintain weight loss. 
Currently most obesity prescriptions are either appetite suppressants
modifying the level of brain chemicals that regulate eating, or food
inhibitors working in the gastrointestinal tract to reduce fat absorption.
Both types of drugs have a very small effect and are not ideal for long-term
use. Safety controversies that surround appetite suppressant medication have
forced some of them off the market. The common side effects of food
inhibitors are cramping, gas and diarrhoea. 

Human growth hormone and AOD9604
Human growth hormone occurs naturally in the body and, as its name suggests,
causes growth. When administered to humans, growth hormone also causes body
fat reduction. This occurs by lipolysis (breakdown of fat into basic
chemical components), anti-lipogenesis (reduction of the rate of synthesis
of fat from its chemical components), and an increase in resting energy
expenditure. However, because growth hormone affects more than just fat
stores, it is not used as an anti-obesity drug. Major unwanted effects are
associated with bone, muscle and organ growth. Associate Professor Frank Ng
at Monash University and his co-workers have established that there is a
small region of the growth hormone molecule, less than one tenth of its
total size, denoted hGH 177-191, which appears to be responsible for its
specific effect on fat and appears not to have any effect on growth or on
insulin resistance. 
AOD9604 is a peptide variant of hGH 177-191. It has been demonstrated to
reduce body fat, neither affecting appetite nor producing any observed side
effects. The mechanism of action of the molecule is mainly in enhancing the
energy utilisation in body's tissues and reducing fat storage. The
physiological action is specific and likely to be safe. In all the trials
performed so far, AOD9604 has consistently shown that humans respond to
AOD9604 as expected, with excellent safety and tolerability. 

The trial design  
This was a randomised, double-blind, placebo-controlled Phase 2A dose
escalation study designed to assess the safety and tolerability of oral
daily dosing of AOD9604 in 36 obese male volunteers. Other key parameters
including body weight were also measured.  The volunteers ranged from
marginally obese (BMI = 30) to morbidly obese (BMI =47), and their age
ranged from 18 to 54. (BMI, or Body Mass Index, is a measure of obesity and
is weight in kg divided by the square of height in metres). 
The volunteers were closely monitored as residents in the CMAX clinical
trial unit based at the Royal Adelaide Hospital and were all required to eat
the same standard meals which were not calorie restricted.  At 9am each
morning for seven days, each volunteer swallowed capsules of AOD9604 or
placebo. The volunteers were randomised into four dose groups of 0
(placebo), 10, 30 or 60 mg AOD9604 daily. All volunteers completed all
aspects of the study.

Safety and tolerability
There were no clinically significant safety or tolerability concerns.  
The principle of AOD9604, already proven in animal studies, is to mimic the
natural fat reducing properties of human growth hormone without producing
any effects on blood sugar control or growth. As with previous studies there
was no evidence of effects on either blood sugar control or on markers of
The numbers of adverse events in the treated groups were similar to the
placebo group, except at the highest (60 mg) dose. At this dose, which is in
excess of the anticipated effective dose for weight reduction (see below),
there were a few occasions of abdominal discomfort of various kinds, mostly
shortly after dose. 

Weight loss
On average, there were consistent positive trends in weight loss measured at
end of the treatment week:
* the 10 mg and 30 mg groups lost more weight than the placebo group, with
the 10 mg group showing the best results;
* the weight loss effect was greater and more consistent in the 20 older
volunteers (aged 35 or older); 
* in the 10 mg dose group, the overall weight loss was 1.0 kg compared to
0.4 kg in the placebo group, and in the 20 older volunteers the weight loss
was 0.8 kg compared to a weight gain of 0.1 kg in the placebo group. 
This pattern of response to different doses occurs throughout Metabolic's
animal and in vitro data. In August 2002 they also reported the same trends
(10 and 30 mg active, 60 mg inactive) from a single dose oral human trial.
The age related pattern has also been noted before, in February 2002 when
they reported results of a single dose intravenous human study.

What's next?
Preparations are now under way for a Phase 2b three-month weight loss study
in at least 200 patients, scheduled to commence in mid-year. The design will
be determined with input from the US Food and Drug Administration. The main
aim will be to establish weight loss after three month's dosing and to
determine the best dose range. 
After Phase 2B, larger scale Phase 3 trials of about 2 years duration will
be conducted before the drug can be approved for sale.

The goal
The team's goal is a safer and more effective obesity treatment than
currently available drugs.  The anticipated absence of adverse side effects
commonly seen in current obesity drugs may lead to a high level of doctor
and patient acceptance. 

About Professor Frank Ng
Frank Man-Woon Ng (pronounced "ing") received his PhD in Biochemistry &
Molecular Biology at the University of Hull, England in 1966. He is
currently Associate Professor of Biochemistry & Molecular Biology at Monash
University, Melbourne, Victoria. He also has been a Visiting Professor at
the Shanghai Institute of Biochemistry, Academia Sinica, China for four
years and was a Visiting Foreign Scientist at the Diabetes Research Centre,
University of Virginia, Medical School, U.S.A. 
Professor Ng is a member of the Monash University Academic Board and a past
member of the Medical Faculty Board. He is President of the Chinese
Australian Academic Society (Vic.), a member of the Australian Diabetes
Society, Endocrine Society of Australia and the Australasian Society for the
Study of Obesity. He also has acted as a consultant to several
pharmaceutical companies and research laboratories. 
Professor Ng is the principal inventor of Metabolic's anti-obesity compounds
and led the scientific research into the AOD compounds. He is known
worldwide for his work in diabetes, obesity and endocrinology where most of
his research has centred on the human growth hormone. He is a Non-Executive
Director of and a consultant to Metabolic Pharmaceuticals Ltd. 
Dr Frank Ng, Associate Professor, Biochemistry and Molecular Biology
Tel: +613 9905 3777, fax: +613 9905 4699, email: frank.ng at med.monash.edu.au

About Chris Belyea
Chris Belyea is Managing Director of Metabolic Pharmaceuticals Ltd (ASX:
MBP), received his PhD in physics from the University of Melbourne in 1992
and is a registered patent attorney. He became the founding CEO of Metabolic
in 1998 when the company listed on the Australian Stock exchange to
commercialize AOD9604, after nurturing the project in collaboration with
Monash over two years from his previous role as Licensing and Projects
manager of Circadian Technologies. Dr Chris Belyea, Managing Director,
Metabolic Pharmaceuticals Ltd, Level 1, 10 Wallace Ave, Toorak Melbourne VIC
3142 Australia Phone +61 3 9826 0949, Fax +61 3 9824 0083, email:
info at metabolic.com.au  ASX code: MBP

Niall Byrne
Science Communication Consultant
Byrne Young Communication Pty Ltd
PO Box 199 Drysdale 3222 Australia
Ph +61 3 5253 1391, fax +61 3 9923 6008, mobile 0417 131 977
niall at byc.com.au www.byc.com.au

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