COMBINATORX

1. February, the 9th 2007 COMBINATORX SPEED DATING FOR MOLECULES BATIQUE Laura, MARICOURT Aurélie & PALADINI Bénédicte

2. Safe Harbor • This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques de Lille • The opinions expressed are our own and not necessarily those of Combinatorx

3. SUMMARY • Idea • Organization chart • Finance • Research & development: cHTS • Patent • Pipeline • Communication to stockholders • conclusion

4. IDEA

5. History • summer 1999: group of young researchers: • Brent Stockwell • Mike Foley • Alexy Borisy • Curtis Keith « Curious Liquid café » • disease: multifactorial process • No magic bullet • Multiple pathways « networked systems »

6. Multiple pathways:

7. Traditional combinations : « art antérieur » • i.e. HIV & cancer treatment Screening for combinations: active small molecules Look for syncretic drug & synergistic drug through different pathways To create a novel, strong & unexpected therapeutic effect

8. « Logistical nightmare »: • - library of 100 000 compounds •  100 billion paired combinations •  screening them: $10 billion/50 000 years!!! Focus exclusively on FDA-approved drugs with expired patents  2 000 compounds  2 million paired combinations • How? • HIGH THROUGHPUT SCREENING (cHTS™)

9. Interests: Pre-approved Compounds • Bypassing time-consuming synthesis stage • Available data: • - pharmacology/toxicology • - dosing • - formulation • - safety and kinetic studies Lessen development time, cost and risks Higher degree of success

10. Risks • Why low doses of therapeutics that have nothing to do with a disease have an effect on the disease process? •  metabolism issue? • Why doctors wouldn’t prescribe 2 drugs independently, instead of the combined cocktail? •  Adjust formulation • Regulatory risks: •  negative synergistic effects?

11. FOUNDERS

12. Foundersa group of young researchers • Alexis BORISY(Harvard University, independant industry consultant) • MikeFOLEY(Harvard University, researching the interface of chemistry and biology) • Brent STOCKWELL(Harvard University, assistant professor at Columbia University) • Curtis KEITH(Harvard University, McGill University)

13. MANAGEMENT TEAM

14. Management Team Alexis BORISY President Robert FORRESTER Chief Financial Officer Jan LESSEM Chief Medical Officer Lynn BAIRD Quality & Clinical operations Daniel GRAU Commercial Operations Jason COLE General Counsel Curtis KEITH Senior vice president, Research

15. Scientific Advisors • Mike FOLEY • Brent STOCKWELL • Gary BORISY (professor of cell and molecular biology at Northwertern University Medical School) • Peter ELLIOTT( B.S. at London University, Cambridge University ) • Todd GOLUD(expert in medecine, cancer biology and pharmacogenomics , Harvard, University of Chicago) • Joanna HOROBIN ( over 20 years of industry experience) • Josh LEDERBERG (Nobel Laureate, 82)

16. Scientific/Technical Backgrounds • CombinatoRx Research group: • - 45 employees in Research: • approximately one third hold advanced degrees • - Matrix organizational structure • - Discovery Biology, In vivo Pharmacology, Formulations… • Valuable Expertise: • - Cell based assay development • - High Throughput screening • - Commercial insight

17. BOARD OF DIRECTORS

18. Board of Directors Alexis BORISY President & CEO Richard ALDRICH Managing Director Richard POPS CEO Alkernes Barbara DEPTULA Executive VP, Shire Pharmaceuticals Patrick FORTUNE Boston Millenia Partners Franck HAYDU Director, Chaiman of the Audit Committee Michael KAUFFMANN President and CEO EPIX Pharmaceuticals

19. FINANCE

20. Raising Funds • 1990s: Beginning of High Throughput screening • Founded in March 2000 • Business Angel Investor: Jacob Goldfield: $ 2,5million • Raised a total of $ 180 million, since 2000: • $ 90 million: - Boston Millenia Partners • - Canaan Ventures Partners • - Flagship Ventures • $ 44,3 million: IPO (november 2005) • $ 48 million: private placement (march 2006)

21. New Partnerships • Leverage the business with partners : •  gains 50-90% rights to next product candidates •  retains 100% rigthts to existing clinical programs CombinatorX_investors_presentation_2006.pdf

22. 2004 2005 September December April July Spinal Muscular Atrophy Foundation (SMA) potential milestones payment Novartis: screening work: $500 000 National Institute of Allergy and Infectious Disease (NIAID) $4,4million grant block the adverse effects of anthrax toxin Henkan Pharmaceutical: (taiwan) $500 000 upfront potential $23million milestones payments CRX-026 (exclusive & territorial license) Accelerate Brain Cancer Cure (ABC²) for Glioblastoma Multiforme (GBM)

23. IPO Private placement 2006 November March August October January April June CHDI (Neurodegenerative Disease Foundation)  Huntington’s disease AdipoGenix:obesity Angiotech Pharmaceutical: $27million upfront $15million equity investment & potential milestones payments medical devices and interventional medicines Cystic Fibrosis Foundation Therapeutics (CFFT):potential $ 13,8 million in Research Cystic fibrosis (CF) Fovea Pharmaceutical: $20 million in potential milestones payments Ophtalmic disease Bio*One Capital: $2,5 million grant $17,5 million milestones payments Infectious disease

24. ANALYSE BOURSIERE

25. Identity card of compagny • Name : combinatoRx, Incorporated • Symbol : CRXX • CEO : Alexis Borisy • Description : a biopharmaceutical compagny focused on developing new medecines built from synergistic combinations of approved drugs • Information industry : drugs - biotechnology Les échos

26. L’action Entrée en bourse le 9 novembre 2005 Capitalisation boursière = 250 millions $ Cash position = 150 millions $ Yahoo finance

27. Comparaison avec l’indice des biotech Private placement Adipogenix Angiotech Fovéa CFFT IPO : 9/11/05 Yahoo finance

28. RESEARCH & DEVELOPMENT COMBINATORX DISCOVERY PROCESS

29. Major Milestones for Development

30. Cell-based phenotypic assay • Multi-target drug discovery • Action on multiple pathways • The only solution: screening of the whole cell • Much more complex than biochemical screening • « disease-modifying targets » • Cells preserve the essential elements of the disease network

31. Empiric multi-target discovery: Phenotypic cellular models i.e. Screening for inflammatory responses: • Stimulation of PBMC with LPS • production of TNF by several cell types • Monitoring production of TNF • screening in 384-well format: combinations of compounds that inhibit inflammatory response • 3) Potential candidates therapeutics • treatment: psoriasis, RA, asthma… Multicomponent therapeutics for networked systems; Curtis T. Keith, Alexis A. Borisy and Brent Stockwell; Nature reviews, drug discovery, january 2005

32. High Throughput Screening: cHTS • Screening pairwise combinations Demand informatic tools (automated robotic screening) & Laboratory Information Management System (LIMS) • Partition: • active compounds: tested through dose-ratio interaction surfaces • inactive compounds: tested in synergistic pairs at a single high concentration

33. Each point = combination activity • Gathering of compounds by pharmacological target Perfect symetry? A549, HCT 116, MRC 9 Tumoral cell lines CombinatorX_investors_presentation_2006.pdf

34. High density signal: pathways interaction  Potential synergy (red) (blue: no synergy)  Potential « hit »? CombinatorX_investors_presentation_2006.pdf

35. Dose-response Matrix • 6 concentrations (including 0) for each compound • 36 different wells of a microtiter plate • Aim: identification of « hits » Multiple combinations of # ratio of doses Interaction surface measured for each pair of compounds 3D inhibition surface

36. Comparison/reference model interaction surface • Standard mathematic model of additivity (Loewe, Bliss…) • to identify a synergy, an antagonism or a simple additivity Model excess surface  score • Overall shape of the interaction surface: information: • how the compounds act on pathways • how the targets for the compounds are related to each other (network connectivity)

37. Analyzing a collection of scores • synergy scores • « synergy profile » of each agent • to emphasize relationships between pathways • grid: axes sorted by molecular mechanism for each agent, grouped by pathway Multi-target therapeutics: when the whole is greater than the sum of the parts; Grant R. Zimmermann, Joseph Léhar and Curtis T. Keith; elsevier, drug discovery today, january 2007

38. Prioritizing & Optimizing Combinations • Evaluation: • chemical compatibility • compatibility: ADMET • Determination: • Combination Structure-Activity Relationship (CSAR): • Combination Mechanism-Activity relationship (CMAR):

39. Examples • Inhibition of C.albicans proliferation • 384-well plates • « cellular viability assay »: Alamar blue fluorescence • selection: 30 compounds symetry • 2 antifungal agents • No antifungal agent • 1 antifungal agent Systematic discovery of multicomponent therapeutics; Alexis A. Borisy, Joseph Léhar, E. Royden Price, Grant R. Zimmermann, Michael A. Foley, Brent R. Stockwell, and Curtis T. Keith; PNAS; june 2003

40. i.e: pentamidine-phenazopyridine : Dose-response matrix pentamidine = 0,03µM phenazopyridine = 4,2µM Systematic discovery of multicomponent therapeutics; Alexis A. Borisy, Joseph Léhar, E. Royden Price, Grant R. Zimmermann, Michael A. Foley, Brent R. Stockwell, and Curtis T. Keith; PNAS; june 2003

41. Anthrax Antitoxin Program • NIAID: $4,4million grant • Biodefense • Therapeutic goals: • Block toxic effects of exposure to anthrax (Bacillus anthracis and its toxin) • status: preclinical CombinatorX_investors_presentation_2006.pdf

42. PATENT USPTO

43. PATENT IDEA DEVELOPPEMENT ET MISE AU POINT D’UN PROCEDE cHTS Besoin de lever des fonds Communications Méthode dévoilée Secret Ex: formule du coca cola

44. Protection de la Méthode • Revendication: • Screening de 2 molécules • Synergique • Robotisation • Associations • Conséquences: • Nouvelle • Innovante • Application industrielle • Publication de demande de brevet en 2002 BREVET

45. Revendications: Description du mécanisme d’action Description des cibles Résultats: Combinaisons inattendues Applicables industriellement Non prévisible pour l’homme de l’art Brevets délivrés: 6 brevets délivrés Ex: Pentamidine + Chlorpromazine ex: Amoxapine+Prednisolone Principes et mécanismes des maladies inflammatoires Inhibition imp de TNF Pas activité aux concentrations Utilisation pour inh/réduire inflammation Composition: Amoxapine de 1-600mg Prednisolone de 0.05 à 200 mg Formulation: IV,IM,VO,VV,VR,Vinh DRUG’S PATENTS

46. PIPELINE Introduction CRx-026: rescue CRx-102: success CRx-140: failure

47. Introduction • Disease areas: • Immuno-inflammatory • Oncology • Metabolic disease • Neurodegenerative disease • Infectious disease • Portfolio: • 8 product candidates (phase 2 clinical trials) • multiple preclinical candidates in metabolic disease

48. CombinatoRx Pipeline: 2007

49. Product Strategy • Target product profile: • single pill/ synergistic/ New medical benefit/ Novel & non obvious patterns of activity/ customized, synergy-based formulation: Non substituable • CombinatoRx Advantage: Discovery to Phase 2: Focusing on rapidly building a product pipeline and  drug development risk

50. CRx-026