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COMBINATORX

SPEED DATING FOR MOLECULES

BATIQUE Laura,MARICOURT Aurélie& PALADINI Bénédicte

February, the 9th 2007

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

SUMMARY

Idea Organization chart Finance Research & development: cHTS Patent Pipeline Communication to stockholders conclusion

IDEA

summer 1999: group of young researchers:

History

disease: multifactorial process

No magic bullet

Multiple pathways

Brent Stockwell

Mike Foley

Alexy Borisy

Curtis Keith

« networked systems »

« Curious Liquid café »

Multiple pathways:

Screening for combinations: active small molecules

Look for syncretic drug

& synergistic drug through different pathways

To create a novel, strong & unexpected therapeutic effect

Traditional combinations : « art antérieur »

i.e. HIV & cancer treatment

« 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™)

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

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?

FOUNDERS

Foundersa group of young researchers

Alexis BORISY (Harvard University, independant industry consultant)

Mike FOLEY(Harvard University, researching the interface of chemistry and biology)

Brent STOCKWELL (Harvard University, assistant professor at Columbia University)

Curtis KEITH (Harvard University, McGill University)

MANAGEMENT TEAM

Management Team

Alexis BORISYPresident

Jan LESSEMChief Medical Officer

Curtis KEITHSenior vice president,

Research

Jason COLEGeneral Counsel

Lynn BAIRDQuality & Clinical

operations

Robert FORRESTERChief Financial Officer

Daniel GRAUCommercial Operations

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)

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

BOARD OF DIRECTORS

Board of Directors

Alexis BORISYPresident & CEO

Barbara DEPTULA Executive VP,

Shire Pharmaceuticals

Michael KAUFFMANNPresident and CEO

EPIX Pharmaceuticals

Patrick FORTUNEBoston Millenia Partners

Franck HAYDUDirector, Chaiman

of the Audit Committee

Richard ALDRICHManaging Director

Richard POPSCEO Alkernes

FINANCE

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)

Raising Funds

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

2004

September

Spinal Muscular Atrophy Foundation (SMA) potential milestones payment

Accelerate Brain Cancer Cure (ABC²) for Glioblastoma Multiforme (GBM)

December

Novartis: screening work: $500 000

2005

April

National Institute of Allergy and Infectious Disease (NIAID) $4,4million grant

block the adverse effects of anthrax toxin

July

Henkan Pharmaceutical: (taiwan)

$500 000 upfront potential $23million milestones payments

CRX-026 (exclusive & territorial license)

August

CHDI (Neurodegenerative Disease Foundation)

Huntington’s disease

Bio*One Capital: $2,5 million grant $17,5 million milestones payments

Infectious disease

October

Angiotech Pharmaceutical: $27million upfront $15million equity investment & potential milestones payments

medical devices and interventional medicines

January

2006

Fovea Pharmaceutical: $20 million in potential milestones payments

Ophtalmic disease

November

IPO Private placement

March

JuneApril

Cystic Fibrosis Foundation Therapeutics (CFFT):potential $ 13,8 million in Research

Cystic fibrosis (CF)

AdipoGenix:obesity

ANALYSE BOURSIERE

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

L’action

Entrée en bourse le 9 novembre 2005

Capitalisation boursière = 250 millions $

Cash position = 150 millions $

Yahoo finance

Comparaison avec l’indice des biotech

IPO : 9/11/05

Angiotech

Private placement

Fovéa

Adipogenix

CFFTYahoo finance

RESEARCH & DEVELOPMENT

COMBINATORX DISCOVERY PROCESS

Major Milestones for Development

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

Empiric multi-target discovery:

Phenotypic cellular models

Multicomponent therapeutics for networked systems; Curtis T. Keith, Alexis A. Borisy and Brent Stockwell; Nature reviews, drug discovery, january 2005

1) Stimulation of PBMC with LPS

production of TNF by several cell types

2) Monitoring production of TNF

screening in 384-well format: combinations of compounds that inhibit inflammatory response

3) Potential candidates therapeutics

treatment: psoriasis, RA, asthma…

i.e. Screening for inflammatory responses:

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

Perfect symetry?

A549, HCT 116, MRC 9

Tumoral cell lines

Each point = combination activity

Gathering of compounds by pharmacological target

CombinatorX_investors_presentation_2006.pdf

High density signal: pathways interaction

Potential synergy (red)

(blue: no synergy)

Potential « hit »?

CombinatorX_investors_presentation_2006.pdf

Dose-response Matrix

6 concentrations (including 0) for each compound

36 different wells of a microtiter plate

Aim: identification of « hits »

Interaction surface measured for each pair of compounds

Multiple combinations of # ratio of doses

3D inhibition surface

Comparison/reference model interaction surface

Standard mathematic model of additivity (Loewe, Bliss…)

to identify a synergy, an antagonism or a simple additivity

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)

Model excess surface score

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

Prioritizing & Optimizing Combinations

Evaluation:

chemical compatibility

compatibility: ADMET

Determination:

Combination Structure-Activity Relationship (CSAR):

Combination Mechanism-Activity relationship (CMAR):

Examples Inhibition of C.albicans proliferation

2 antifungal agents

No antifungal agent

1 antifungal agent

symetry

384-well plates

« cellular viability assay »: Alamar blue fluorescence

selection: 30 compounds

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

pentamidine = 0,03µM

phenazopyridine = 4,2µM

i.e: pentamidine-phenazopyridine : Dose-response matrix

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

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

PATENT

USPTO

PATENT

IDEA

DEVELOPPEMENT ET MISE AU POINT

D’UN PROCEDE

cHTS

Secret

Ex: formule du coca cola

Besoin de lever des fonds

Communications

Méthode dévoilée

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

DRUG’S PATENTS

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 1-600mgPrednisolone de 0.05 à 200 mg Formulation:IV,IM,VO,VV,VR,Vinh

PIPELINE

Introduction CRx-026: rescue CRx-102: success CRx-140: failure

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

CombinatoRx Pipeline: 2007

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

CRx-026

HTS result

In vitro, 100 000 combinations tested 600 interesting drugs 13 synergistic combinations identified and

confirmed

One of these combinations contains: Anti psychosis agent: Chlorpromazine Anti protozoal agent: Pentamidine

Birth CRx-026

CRx-026

Chlorpromazine Antipsychotic,

anxiolytic

Pentamidine Antimicrobial,

antiprotozoal (pneumocystosis, leshmaniasis, trypanosoma)

•Neither demontrates substancial activity at concentration

•Neither is currently used as an Anticancer drug

Studies (1)

Test in vitro: Percent inhibition of A 549

proliferation

Excess over Bliss additivism

Excess over HSA

(highest single 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

Studies (2)

Effect of chlorpromazine + pentamidine on the growth of A 549 in mice compared classical treatment

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

Mechanism of Action Anti proliferative activity approved

In vitro studies

Activity on a mitotic kinesin (hsEg5/KSP), tubulin and inhibition of PRL phosphatase

pentamidine chlorpromazine

Kinesin

It is a protein can move when it have ATP Function: Separate DNA when cellular division

Inhibition of KSP Blocks proper spindle function during mitosis

Mitotic kinesin is a molecular

essential for centrosome separation

Centrosome

Centrosome: Result

Figure 3: A. Inhibition of hsEg5/KSP ATPase activity in cell-free enzymatic assay (squares) and inhibition of proliferation of HCT116 colon cancer

cell line (triangles). B. Chlorpromazine caused the formation of monopolar spindle during mitosis (A549 cells). C. Chlorpromazine inhibits

centrosome separation but spares duplication (HCT116 cells). Green = alpha-tubulin; red =gamma-tubulin ; blue = DNA..

Discovery and clinical development of CRx-026, a syncretic and anti-mitotic agent with significant anti-cancer activity; Peter J. Elliott, Alexis A. Borisy,

Curtis T. Keith; march 2004; CombinatoRx.pdf

Pre-Clinical Profil (1)Synergy Activity

In vivo activity

Discovery and clinical development of CRx-026, a syncretic and anti-mitotic agent with significant anti-cancer activity; Peter J. Elliott, Alexis A. Borisy, Curtis T. Keith; march 2004; CombinatoRx.pdf

Pre-Clinical Profil (2)Compared classical treatment

Discovery and clinical development of CRx-026, a syncretic and anti-mitotic agent with significant anti-cancer activity; Peter J. Elliott, Alexis A. Borisy,

Curtis T. Keith; march 2004; CombinatoRx.pdf

Conclusion

Clinical evaluation: CRx-026 synergy with taxanes & vinca-alkaloids

CRx-102

CRx-102: Novel Oral Syncretic Drug Candidate

Very low dose of prednisolone (3mg): steroid Cardiovascular agent (inhibitor of PDE):

dipyridamole (200 or 400mg) Novel mechanism selectively amplifies steroid’s

desirable activities: A combination sciences dissociated agent

Dissociated Steroid Concept ?

GC therapy is highly effective at reducing inflammation but chronic use leads to undesirable side effects (osteoporosis, glaucoma, diabetes…)

A dissociated steroid could: clinical use steroid toxicities

Dipyridamole selective « amplifier » ??

CombinatorX_investors_presentation_2006.pdf

CRx-102: Mechanism of Action

« Transactivation » side effects

« Transrepression » anti-inflammatory effects

Dipyridamole: Action on «transrepression way »

Crx-102dipyridamole

PDEsAMP

cAMP

ACATP

PKA

A2A, A2B

Adenosine Reuptake

Steroid Immunomodulatory Effects

mRNA stability

prednisolone

PD

PD

GR

GR

PDGR

PDGR

+GRE

+GRE

AP-1NFkB

NFAT

CBP HAT

HDAC

CREB

cis-repression

trans-activation

Steroid Side Effect-Associated Genes

enhanced trans-repression inhibition of inflammation

CRx-102 Clinical Results to Date

highly positive studies

Generally well tolerated

Phase 2A

Extrait des JP Morgan, le 17/01/07, slide 16

Opportunities

The efficacy & safety profile of CRx-102 may result in a viable alternative for NSAIDS/COXIBs

Commercial Opportunities

Extrait des JP Morgan, le 17/01/07

CRx-140

CRx 140 : a novel oraly available syncretic agent

CRx 140 : one of seven product candidates

Indication : psoriasis

Cyclosporine has more side effects

Aim : increase effect of cyclosporine with another drug

Testing in phase II clinical trials

Psoriasis

Maladie chronique et généralement bénigne Lésions érythémato-squameuses Aussi fréquent pour les 2 sexes Évolution par poussées Étiologies inconnues Existe chez les jeunes sujets => psoriasis en goutte Divers traitements

Clinical trials Study design : multi-center, blinded, controlled,

patients with a severe psoriasis Index : PASI and PGA

PASI : Psoriasis Area and Severity IndexPGA : Physician Global Assessments

2 endpoints :Primary : PGASecondary : PASI

Results

Side effects

Conclusions

Phase IIa clinical results did not show statistical significance in pre-specified endpoints

Development discontinued as an oral product candidate for psoriasis

Resources focuses on other product candidates in portfolio

COMMUNICATION TO STOCKHOLDERS

CombinatoRx Pipeline: 2007

Extrait des JP Morgan, le 17/01/07

Pipeline 2006

Pipeline

Extrait des JP Morgan, le 17/01/07, slide 7

Failure in phase 2 clinical trials

Goals 2006 2005 = a year of validation :

Core Business Strategy Drug discovery approach Continued promise of cHTS technology from you, stockholders

2005 : collaborations Pipeline => oncology and inflammation :

CRx-102 : very encouraging CRx-140 : failure

Continue to fill our internal pipeline

Expect a mix of successes & failures;

Look forward to a continued flow of candidates in our pipeline

CombinatoRx, « from the president »

Real actions

New Partnerships :Fovea pharmaceuticalAdipoGenix Cystic Fibrosis Foundation Therapeutics

Private placement New failure : CRx-119 Developing 3 new molecules

Goals 2007

Extrait des JP Morgan, le 17/01/07, slide 9

JP Morgan

Extrait des JP Morgan, le 17/01/07, slide 7

Présentation attractive pour les investisseurs et

les futurs

CONCLUSION

Concept original Pipeline étendu Avenir prometteur

Attente de résultats cliniques concrets !! Balance Bénéfices/Risques

Merci de votre attention

BIBLIOGRAPHY

CombinatorX_investors_presentation_2006.pdf 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

Speed dating for molecules; Wendy Wolfson; Chemistry & Biology; elsevier; may 2006

Alexis Borisy; Charlie Schmidt, Portland, Maine; Nature biotechnology; may 2006

Screening for drug discovery: the leading question; Adam Smith; Technology Feature, Nature; july 2002

Multicomponent therapeutics for networked systems; Curtis T. Keith, Alexis A. Borisy and Brent Stockwell; Nature reviews, drug discovery, january 2005

Multi-target lead discovery for networked systems; Curtis T. Keith & Grant R. Zimmermann; Current drug discovery, Feature; september 2004

cHTS Systematic discovery of novel combination therapeutics; Grant R. Zimmermann, Margaret S. Lee, Joseph Léhar, Alexis A. Borisy, Curtis T. Keith; CombinatoRx_pdf; 2005

Systematic discovery of multicomponent therapeutics; Alexis A. Borisy, Peter J. Elliott, Nicole W. Hurst, Margaret S. Lee, Joseph Léhar, E. Royden Price, George Serbedzia, Grant R. Zimmermann, Michael A. Foley, Brent R. Stockwell, and Curtis T. Keith; PNAS; june 2003

CombinatoRx_investors_presentation CRx-102_november 2006.pdf Molecular Insights Into Steroid Dissociation of CRx-102, a Clinically

Active Immunomodulatory Agent; E. Royden Price, C. Fraser, P. Manivasakam, G. Nolan, B. Smith, J. Léhar, G. R. Zimmermann, C. T. Keith; november 2006; CombinatoRx.pdf

A phase II trial of a new anti-inflammatory combination drug, CRx-140, in patients with severe psoriasis; Alice Gottlieb, Yanzhen Zhang, Melissa Nichols, CRx-140 group at CombinatoRx, Incorporated and CRx-140 group of investigators UMDNJ & Robert Wood Johnson Med. Ctr., Nexx Brunswick, NJ and CombinatoRx; march 2006; CombinatoRx.pdf

Discovery and clinical development of CRx-026, a syncretic and anti-mitotic agent with significant anti-cancer activity; Peter J. Elliott, Margaret S. Lee, Mitchell Keegan, Yanzhen Zhang, M. James Nichols, Alexis A. Borisy, Curtis T. Keith; march 2004; CombinatoRx.pdf

CombinatoRx_ Annual Report 2005.pdf CombinatoRx_investors_presentation_april 2006.pdf HBA CombinatoRx presentation; september 2006.pdf JP Morgan, january 2007

www.combinatorx.com : www.combinatorx.com/pipeline/ http://www.combinatorx.com/overview/ http://www.combinatorx.com/discovery/ http://phx.corporate-ir.net/phoenix.zhtml?c=148036&p=irol-news

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