RESEARCH IS TO SEE WHAT EVERYONE HAS SEEN AND TO THINK WHAT NOBODY HAS THOUGHT. "Albert Szent-Gyoergyi, nobel priz

1. RESEARCH IS TO SEE WHAT EVERYONE HAS SEEN AND TO THINK WHAT NOBODY HAS THOUGHT. "Albert Szent-Gyoergyi, nobel prize 1937.

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

3. The Company • Created by Dr Itzik HAROSH in January 2000 • Strong team of 2 researchers, advisors in medicinal chemistry and pharmacology • 4 patents giving a strong IP position • Several biotech collaborations • Acollaboration with INRA (France) • SP7 ADIBET, France, UK, Spain, Finland • Member of the Genopole at Evry, France

4. Advisory board Prof. M. Radman, Hôpital Necker, Paris, France; specialist in genetics and evolution; member of the "Académie 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 Rhône-Poulenc Rorer. Prof. D. Bensimon, Ecole Normale Supérieure, 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, Hôpital Necker-Enfants Malades, France, Expert in, and major contributor to, the obesity field; member of the "Académie des Sciences de l'Institut de France".

5. Mission ObeTherapy applies a highly innovative strategy for the development of medications for obesity: We look for « lean genes » or « energy expenditure genes » in the lean phenotype

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

7. Obesity Type II diabete Absorption Metabolism Carbohydrate Proteins Lipids Lipids Carbohydrates  Acetyl-CoA Acetyl-CoA ATP Metabolic Pathways Involved In Obesity Appetite/Satiety (CNS)

8. Researchers from the Monell Center have for the first time attempted to count the number of genes that contribute to obesity and body weight. The findings suggest that more than 6,000 genes—about 25 percent of the genome—help determine an individual’s body weight. BODY WEIGHT INFLUENCED BY THOUSANDS OF GENES Danielle Reed et al. BMC Genet. 2008

9. Genes linked or associated with obesity - Single gene 7 - Mendelian disorders 41 - Associated 90 - Linkage 322 - Total 460 http://obesitygene.pbrc.edu

10. PL (xenical) Targets for obesity treatment past and present in R&D Fat and Carb. metabolisms Energy thermogenesis Appetite Satiety Others NPY Orexin PTP-1B AGRP MG Axokine CNTF OB DB CCK POMC MCH Tubby CART Agouty FAT GLP-1 MC4R PYY (3-36) UCP1 UCP2 UCP3 PKA-IIb -Adrenergic R -Adrenergic R ACC-2 Adiponectin (Famoxin) PTP1B S6K1 PPAR-g SREBP1 C/EBPs FATPs MTP GLT1 GLT2 SIRT1 H1 receptors PRMD16 BMP-7 CB1 (rimonabant) Abandonned and retracted 5-HT receptors Serotonin (Meridia)

11. Why did we evolve to be obese? Is obesity an advantage? No, obesity is not an advantage

12. Darwin's grand idea of evolution by natural selection

13. The thrifty genome theory (James Neel, 1962 Am. J. Hum. Genet.) • During thousand of years of evolution, when food was scarce, long periods of famine have selected individuals having an efficient organism for food absorption and energy metabolism. • When food supply increased the thrifty genotype became a liability rather than an asset. • 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.

14. ObeTherapy’s strategy Focus on « Lean Genes » or « Energy Expenditure Genes » as Potential Targets for the Treatment of Obesity and Type II diabetes

15. From a Particular case (Lean phenotype) General obesity

16. Our first target: Blocking protein absorption

17. Question: Doesn’t blocking protein absorption cause a loss of muscle tissue and a decrease in body strenght?

18. Answer:NOWe consume more than twice the amount of protein necessary for our daily activities, as recommended by:U.S. Food and Drug Administration Center for Food Safety and Applied NutritionA Food Labeling Guide, September, 1994 (Editorial revisions June, 1999)

19. Meat consumption in USA In 1997, the average American consumed: 44 kg of beef 31 kg of pork total = 123 kg of meat 48 kg of poultry This consumption is equivalent to 92 g of protein per day which correspond to 184% of the USDA recommended daily allowance. And that does not take in account all the other protein sources: eggs, cheese etc… Source: USDA, 1998

20. Daily requirement Source: U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition A Food Labeling Guide, September, 1994 (Editorial revisions June, 1999)

21. Our protein absorption inhibition target is: •Associated with the lean phenotype in humans • Tissue specific • Non redundant • Peripheral target (intestine)

22. MW heterozygote heterozygote homozygote homozygote homozygote homozygote homozygote First results of KO mice for protein absorption target Litter of KO mice Homozygote pup is in green circle From all 12 litters obtained, all homozygote pups (29%) died between 1 to 10 days old

23. Lead compounds at nanomolar range inhibition OBE1999 OBE2000 IC50=33nM IC50=68nM OBE2002 OBE2001 IC50=34nM IC50=7nM

24. Effect of OBE lead on protein absorption

25. Effect of OBE lead on triglycerides absorption

26. Effect of OBE lead on weight of treated mice Drug administration 3h before night phase Drug administration1h before night phase

27. Summary • We have a gene target which is tissue specific (intestine) • Non redundant • Peripheral target (intestine) • The gene associated with a lean phenotype (genotype-phenotype associations) • Drugable (enzyme) • Active small molecules in vivo • No visible side effect • Validation by knock-out of the gene target

28. (obesity) EINSTEIN’S “MIRACLE YEAR”PublishedWorksin1905atage26: 3. Equivalence of Mass and Energy . The Photoelectric Effect, used Planck’s Quantum Hypothesis. Special Theory of Relativity.

29. Our second target: Blocking lipid absorption

30. Why lipids? Because, mass per mass, lipids contain seven times as much energy as proteins or carbohydrates

31. OBETHERAPY Target: The Gateway Chylomicrons VLDL/LDL Bile HDL Liver Metabolism Adipocytes Storage Absorption Lipids must be absorbed by the intestine in order to be stored as body fat. OBETHERAPY CAN TOTALLY OR PARTIALLY BLOCK THE INTESTINAL ABSORPTION OF LIPIDS.

32. INTESTINE LIVER apoB gene * * CAA CAA UAA AAAn UAA AAAn mRNA * * UAA C UAA AAAn Stop codon COOH H2N COOH H2N ApoB48 ApoB100 protein VLDL Chylomicrons ApoB, One Gene-Two Proteins Transcription Apobec-1, Editing Translation Chylomicron formation depends on ApoB48, an Apobec-1-dependent isoform of ApoB

33. ObeTherapy has identified several compounds that are active at the high micromolar level against this target. These compounds are currently being optimized.

34. SOME FACTS • 4 PATENTS: • First ObeTherapy’s target on lipids (issued EU and US) • Second ObeTherapy’s target on proteins (PCT application) • Biochemical in vitro assay: (issued F & US) • List of hit compounds (PCT) • OTHER MARKET FOR OBETHRAPY TECHNOLOGY: • DYSLIPIDEMIA • TYPE II DIABETES • ATHEROSCLEROSIS

35. RESEARCH TIME TABLE 2 to 3 years 2 to 3 years 2 to 3 years Phase II studies Target identification Target selection Target validation Drug Screening or RDD Lead optimiz. Phase I studies Preclinical studies Protein absorption inhibitor Lipid absorption inhibitor

36. Advantage of ObeTherapy compared to other Biotechs:- ObeTherapy function as a low cost company.- Very lean structure (6 polyvalent scientists). - Minimum overhead- Very low burn rate - Very flexible structure - Subcontracting to CRO companies the chemistry, in vivo and preclinical study, therefore every investment goes directly to the development.

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