RESEARCH IS TO SEE WHAT EVERYONE HAS SEEN AND TO THINK WHAT NOBODY HAS THOUGHT.

"Albert Szent-Gyoergyi, nobel prize 1937.

Lean genes allow you to eat without gaining weight Nature did it, ObeTherapy can reproduce it.

The Company
Created by Dr Itzik HAROSH in January 2000 Strong team of 6 researchers 5 patents giving a full scientific protection One industry contract with Zambon Group SpA (Milan, Italy) Several biotech collaborations One academic collaboration with INRA (France) Member of the Genopole at Evry, France

Core Team
Itzik HAROSH, PhD, Chairman and Chief Scientist
Officer (CSO)

Georges GAUDRIAULT, PhD, Scientific Director Sandrine BRAUD, PhD, Project Leader Vladimir CHARRON, Engineer David SENAC, Engineer Christelle MOUGIN, Laboratory Manager

Advisory board
Prof. M. Radman, Hpital Necker, Paris, France; specialist in genetics and evolution;
member of the "Acadmie des Sciences de l'Institut de France".

Prof. A. Levy, The Weizmann Institute of Science, Rehovot, Israel; specialist in

biotechnology and genetics.

Prof. T. Baasov, Chemistry Faculty Technion, Haifa, Israel; specialist in medicinal chemistry
and chemical synthesis.

Prof. B. Peault, McGowan Institute for Regenerative Medicine, Pittsburgh, USA; specialist in
cellular models and biotechnology, pioneer of Systemix.

Dr Y. Champey, former Senior Vice President and Executive Medical Director at RhnePoulenc Rorer.

Prof. D. Bensimon, Ecole Normale Suprieure, Paris, France; specialist in biophysics of

DNA and proteins.

Prof. M. Rubinstein, Weizmann Institute, Israel; Geneticist, Expert in the obesity field. Prof. D. Ricquier, PhD, Director of CEREMOD/CNRS Unit 9078, Hpital Necker-Enfants
Malades, France, Expert in the obesity field in which he is a major contributor; member of the "Acadmie des Sciences de l'Institut de France".
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PRIMARY MARKET: OBESITY

Source: Farrigan C, Nat Rev Drug Discov, 1, 257

Mission

With a completely innovative strategy, Obetherapy aims to develop medication for obesity. By looking for lean genes or expenditure genes in lean phenotype

What is Obesity ? Obesity = imbalance between food intake and energy expenditure
Energy expenditure
(metabolism& physical activity)

Food intake

Metabolic Pathways Involved In Obesity

Appetite/Satiety (CNS)

Absorption

Type II diabete

Obesity

Metabolism
Carbohydrates Carbohydrate Proteins Lipids Lipids

Acetyl-CoA Acetyl-CoA
ATP
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Genes linked or associated with obesity

- Single gene - Mendelian disorders - Associated - Linkage - Total

7 41 90 322 460

http://obesitygene.pbrc.edu
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Targets for obesity treatment currently in research and development Energy Appetit NPY Orexin PTP-1B AGRP MG Axokine CNTF Canabinoid
(Rimonabant)

Satiety OB DB CCK POMC MCH Tubby CART Agouty FAT GLP-1 MC4R MC4R PYY (3-36)

homeostasis

Fat metabolism PPAR- SREBP1 C/EBPs FATPs Fat Absorption PL (Orlistat) MTP

UCP1 UCP2 UCP3 PKA-IIb

-Adrenergic R -Adrenergic R
ACC-2 Adiponectin
(Famoxin)

PTP1B S6K1
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Why did we evolve to be obese? Is obesity an advantage?

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Natural selection Darwin's grand idea of evolution by natural selection

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Natural selection Darwin's grand idea of evolution by natural selection

Is this an advantage?
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The thrifty genome theory

(James Neel, 1962 Am. J.Hum. Genet.)

During thousand of years of evolution, when food

was scare, long periods of famine have selected individuals having an efficient organism for food absorption and energy metabolism. become a liability rather than an asset.

When food supply increased the thrifty genotype On the other hand, individuals with low efficiency
for food absorption and energy metabolism became rare.

This explains why we are, in the vast majority, very

efficient for food absorption and energy metabolism.
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Obetherapy strategy

Using the Lean Genes or Expenditure genes as Potential Targets for the Treatment of Obesity and Type II diabetes
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Research & Development Process

Target Identification and Validation Hit Identification
Structure Activity Relationship

Improved Leads

Lead Optimization

Medicinal Chemistry

Preclinical Development Clinical Development Registration Launch Selection of a Drug Candidate

Target n1 Target n2
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Our first target:

Blocking the lipids absorption

in collaboration with Zambon Group SpA

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OBETHERAPY Target: The Gateway

Liver

Metabolism
VLDL/LDL Bile

Chylomicrons

Adipocytes

HDL

Intestine

Storage

Absorption

Lipids are transported by chylomicrons (from intestine to liver) and by VLDL/LDL/HDL (from liver to target tissue). OBETHERAPY CAN STOP TOTALLY OR PARTIALLY THE PROCESS. 19

Validation of our first target

Transgenic (F1)

Control (F1)

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Status on target n 1 Development collaboration signed in 2004 with Zambon Group SpA. Zambon Group SpA was founded in Vicenza in 1906. It operates in Europe, South America and Asia. It employs 2,300 employees in 16 countries and has consolidated sales in the region around 500m. Some scientific data: High throughput screening using ObeTherapys proprietary technology was conducted late 2004. HIT identification milestone was reached in April 2005. Lead identification milestone was reached in October 2005. Next milestone will characterize the Candidate Drug to enter preclinical mid 2007.
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SOME FACTS
5 PATENTS: First ObeTherapys target on lipids (issued EU and US)
Second ObeTherapys target on proteins (PCT application) Biochemical in vitro assay: (issued F & US) List of hit compounds (PCT) Cellular HTS (PCT)

2 PATENTS IN PREPARATION WITH ZAMBON GROUP SpA

OTHER MARKET FOR OBETHRAPY TECHNOLOGY: DYSLIPIDEMIA TYPE II DIABETES ATHEROSCLEROSIS

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Investment opportunities
ObeTherapy is looking to raise 3 million euros for the next 2 years.
(i) Coinvest with Zambon and share risk on the development of the first program. (ii) Bring the second program to preclinical stage.
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Lean genes allow you to eat without gaining weight... Nature did it, ObeTherapy can reproduce it.