Скачать презентацию February the 9 th 2007 COMBINATORX SPEED DATING Скачать презентацию February the 9 th 2007 COMBINATORX SPEED DATING

f4b51e875cb3425a2df8d8f9acf3f7b6.ppt

  • Количество слайдов: 90

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

Safe Harbor This is an independent study performed by students from the Faculté des 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 n n n n Idea Organization chart Finance Research & development: c. HTS SUMMARY n n n n Idea Organization chart Finance Research & development: c. HTS Patent Pipeline Communication to stockholders conclusion

IDEA IDEA

 History § summer 1999: group of young researchers: üBrent Stockwell üMike Foley üAlexy History § summer 1999: group of young researchers: üBrent Stockwell üMike Foley üAlexy Borisy üCurtis Keith « Curious Liquid café » § disease: multifactorial process § No magic bullet § Multiple pathways « networked systems »

Multiple pathways: Multiple pathways:

§ Traditional combinations : « art antérieur » § i. e. HIV & cancer § 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

§ « Logistical nightmare » : - library of 100 000 compounds 100 billion § « 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 (c. HTS™)

 Interests: Pre-approved Compounds § Bypassing time-consuming synthesis stage § Available data: - pharmacology/toxicology 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 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 FOUNDERS

Founders a group of young researchers n Alexis BORISY (Harvard University, independant industry consultant) Founders a group of young researchers n Alexis BORISY (Harvard University, independant industry consultant) n Mike FOLEY(Harvard University, researching the interface of chemistry and biology) n Brent STOCKWELL (Harvard University, assistant professor at Columbia University) n Curtis KEITH (Harvard University, Mc. Gill University)

MANAGEMENT TEAM MANAGEMENT TEAM

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

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

Scientific/Technical Backgrounds § Combinato. Rx Research group: - 45 employees in Research: approximately one Scientific/Technical Backgrounds § Combinato. Rx 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

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

FINANCE FINANCE

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

 New Partnerships § Leverage the business with partners : gains 50 -90% rights New Partnerships § Leverage the business with partners : gains 50 -90% rights to next product candidates retains 100% rigthts to existing clinical programs Combinator. X_investors_presentation_2006. pdf

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

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

ANALYSE BOURSIERE ANALYSE BOURSIERE

Identity card of compagny n n n Name : combinato. Rx, Incorporated Symbol : Identity card of compagny n n n Name : combinato. Rx, 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 $ 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 Private placement Angiotech Adipogenix Fovéa IPO : 9/11/05 CFFT Comparaison avec l’indice des biotech Private placement Angiotech Adipogenix Fovéa IPO : 9/11/05 CFFT Yahoo finance

RESEARCH & DEVELOPMENT COMBINATORX DISCOVERY PROCESS RESEARCH & DEVELOPMENT COMBINATORX DISCOVERY PROCESS

Major Milestones for Development Major Milestones for Development

Cell-based phenotypic assay n n n Multi-target drug discovery Action on multiple pathways The Cell-based phenotypic assay n n n 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

Ø Empiric multi-target discovery: Phenotypic cellular models i. e. Screening for inflammatory responses: 1) Ø Empiric multi-target discovery: Phenotypic cellular models i. e. Screening for inflammatory responses: 1) Stimulation of PBMC with LPS q production of TNF by several cell types 2) Monitoring production of TNF q screening in 384 -well format: combinations of compounds that inhibit inflammatory response 3) Potential candidates therapeutics q treatment: psoriasis, RA, asthma… Multicomponent therapeutics for networked systems; Curtis T. Keith, Alexis A. Borisy and Brent Stockwell; Nature reviews, drug discovery, january 2005

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

§ Each point = combination activity § Gathering of compounds by pharmacological target Perfect § Each point = combination activity § Gathering of compounds by pharmacological target Perfect symetry? A 549, HCT 116, MRC 9 Tumoral cell lines Combinator. X_investors_presentation_2006. pdf

High density signal: pathways interaction Potential synergy (red) (blue: no synergy) Potential « hit High density signal: pathways interaction Potential synergy (red) (blue: no synergy) Potential « hit » ? Combinator. X_investors_presentation_2006. pdf

Ø Dose-response Matrix § 6 concentrations (including 0) for each compound § 36 different Ø 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 3 D inhibition surface Multiple combinations of # ratio of doses

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

Ø Analyzing a collection of scores ü synergy scores ü « synergy profile » Ø Analyzing a collection of scores ü synergy scores ü « synergy profile » of each agent ü to emphasize relationships between pathways ü 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 Ø Evaluation: § chemical compatibility § compatibility: ADMET Ø Prioritizing & Optimizing Combinations Ø Evaluation: § chemical compatibility § compatibility: ADMET Ø Determination: § Combination Structure-Activity Relationship (CSAR): § Combination Mechanism-Activity relationship (CMAR):

Examples Ø Inhibition of C. albicans proliferation § 384 -well plates § « cellular Examples Ø Inhibition of C. albicans proliferation § 384 -well plates § « cellular viability assay » : Alamar blue fluorescence symetry § selection: 30 compounds ü 2 antifungal agents üNo antifungal agent ü 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

§ i. e: pentamidine-phenazopyridine : Dose-response matrix pentamidine = 0, 03µM phenazopyridine = 4, § 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

Ø Anthrax Antitoxin Program § NIAID: $4, 4 million grant § Biodefense § Therapeutic Ø Anthrax Antitoxin Program § NIAID: $4, 4 million grant § Biodefense § Therapeutic goals: ü Block toxic effects of exposure to anthrax (Bacillus anthracis and its toxin) § status: preclinical Combinator. X_investors_presentation_2006. pdf

PATENT USPTO PATENT USPTO

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

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

DRUG’S PATENTS n Revendications: ¨ ¨ n Résultats: ¨ ¨ ¨ n Description du DRUG’S PATENTS n Revendications: ¨ ¨ n Résultats: ¨ ¨ ¨ n Description du mécanisme d’action Description des cibles Combinaisons inattendues Applicables industriellement Non prévisible pour l’homme de l’art Brevets délivrés: ¨ ¨ 6 brevets délivrés Ex: Pentamidine + Chlorpromazine ex: Amoxapine+Prednisolone Ø Principes et mécanismes des maladies inflammatoires Ø Ø Inhibition imp de TNF Pas activité aux concentrations Utilisation pour inh/réduire inflammation Ø Composition: Amoxapine de 1 -600 mg Prednisolone de 0. 05 à 200 mg Ø Formulation: IV, IM, VO, VV, VR, Vinh Ø

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

 Introduction § Disease areas: üImmuno-inflammatory üOncology üMetabolic disease üNeurodegenerative disease üInfectious disease § Introduction § Disease areas: üImmuno-inflammatory üOncology üMetabolic disease üNeurodegenerative disease üInfectious disease § Portfolio: ü 8 product candidates (phase 2 clinical trials) ümultiple preclinical candidates in metabolic disease

Combinato. Rx Pipeline: 2007 Combinato. Rx Pipeline: 2007

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

CRx-026 CRx-026

HTS result n n n In vitro, 100 000 combinations tested 600 interesting drugs HTS result n n n In vitro, 100 000 combinations tested 600 interesting drugs 13 synergistic combinations identified and confirmed One of these combinations contains: Ø Ø Anti psychosis agent: Chlorpromazine Anti protozoal agent: Pentamidine Birth CRx-026

CRx-026 Chlorpromazine q Antipsychotic, anxiolytic Pentamidine q Antimicrobial, antiprotozoal (pneumocystosis, leshmaniasis, trypanosoma) • Neither CRx-026 Chlorpromazine q Antipsychotic, anxiolytic Pentamidine q Antimicrobial, antiprotozoal (pneumocystosis, leshmaniasis, trypanosoma) • Neither demontrates substancial activity at concentration • Neither is currently used as an Anticancer drug

Studies (1) Test in vitro: n Percent inhibition of A 549 proliferation n Excess Studies (1) Test in vitro: n Percent inhibition of A 549 proliferation n Excess over Bliss additivism n 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) n Effect of chlorpromazine + pentamidine on the growth of A 549 Studies (2) n 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 pentamidine chlorpromazine Activity on Mechanism of Action Anti proliferative activity approved In vitro studies pentamidine chlorpromazine Activity on a mitotic kinesin (hs. Eg 5/KSP), tubulin and inhibition of PRL phosphatase

Kinesin n n It is a protein can move when it have ATP Function: Kinesin n n 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

Centrosome: Result Figure 3: A. Inhibition of hs. Eg 5/KSP ATPase activity in cell-free Centrosome: Result Figure 3: A. Inhibition of hs. Eg 5/KSP ATPase activity in cell-free enzymatic assay (squares) and inhibition of proliferation of HCT 116 colon cancer cell line (triangles). B. Chlorpromazine caused the formation of monopolar spindle during mitosis (A 549 cells). C. Chlorpromazine inhibits centrosome separation but spares duplication (HCT 116 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; Combinato. Rx. pdf

Pre-Clinical Profil (1) Synergy Activity In vivo activity Discovery and clinical development of CRx-026, 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; Combinato. Rx. pdf

Pre-Clinical Profil (2) Compared classical treatment Discovery and clinical development of CRx-026, a syncretic 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; Combinato. Rx. pdf

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

CRx-102 CRx-102

CRx-102: Novel Oral Syncretic Drug Candidate Very low dose of prednisolone (3 mg): steroid CRx-102: Novel Oral Syncretic Drug Candidate Very low dose of prednisolone (3 mg): steroid n Cardiovascular agent (inhibitor of PDE): dipyridamole (200 or 400 mg) n Novel mechanism selectively amplifies steroid’s desirable activities: q A combination sciences dissociated agent n

Ø Dissociated Steroid Concept ? n GC therapy is highly effective at reducing inflammation Ø Dissociated Steroid Concept ? n GC therapy is highly effective at reducing inflammation but chronic use leads to undesirable side effects (osteoporosis, glaucoma, diabetes…) A dissociated steroid could: q clinical use q steroid toxicities n Dipyridamole selective « amplifier » ? ? n Combinator. X_investors_presentation_2006. pdf

Ø CRx-102: Mechanism of Action Crx-102 prednisolone dipyridamole GR PD A 2 A, A Ø CRx-102: Mechanism of Action Crx-102 prednisolone dipyridamole GR PD A 2 A, A 2 B m. RNA stability ATP GR PD PKA +GRE trans-activation GR PD +GRE cis-repression Steroid Side Effect. Associated Genes GR PD Adenosine Reuptake AC c. AMP PDEs NFk. B NFAT AP-1 CBP CREB HAT HDAC enhanced trans-repression inhibition of inflammation Steroid Immunomodulatory Effects § « Transactivation » side effects § « Transrepression » anti-inflammatory effects § Dipyridamole: Action on «transrepression way »

CRx-102 Clinical Results to Date Phase 2 A highly positive studies Generally well tolerated CRx-102 Clinical Results to Date Phase 2 A highly positive studies Generally well tolerated Extrait des JP Morgan, le 17/01/07, slide 16

Opportunities n The efficacy & safety profile of CRx-102 may result in a viable Opportunities n 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 Commercial Opportunities Extrait des JP Morgan, le 17/01/07

CRx-140 CRx-140

CRx 140 : a novel oraly available syncretic agent § CRx 140 : one 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 n n n n Maladie chronique et généralement bénigne Lésions érythémato-squameuses Aussi fréquent Psoriasis n n n n 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 n n n Study design : multi-center, blinded, controlled, patients with a Clinical trials n n n Study design : multi-center, blinded, controlled, patients with a severe psoriasis Index : PASI and PGA ü PASI : Psoriasis Area and Severity Index ü PGA : Physician Global Assessments 2 endpoints : ü Primary : PGA ü Secondary : PASI

Results Results

Side effects Side effects

Conclusions § Phase IIa clinical results did not show statistical significance in prespecified endpoints Conclusions § Phase IIa clinical results did not show statistical significance in prespecified endpoints § Development discontinued as an oral product candidate for psoriasis § Resources focuses on other product candidates in portfolio

COMMUNICATION TO STOCKHOLDERS COMMUNICATION TO STOCKHOLDERS

Combinato. Rx Pipeline: 200 Pipeline 2006 Extrait des JP Morgan, le 17/01/07 Combinato. Rx Pipeline: 200 Pipeline 2006 Extrait des JP Morgan, le 17/01/07

Pipeline Failure in phase 2 clinical trials Extrait des JP Morgan, le 17/01/07, slide Pipeline Failure in phase 2 clinical trials Extrait des JP Morgan, le 17/01/07, slide 7

Goals 2006 n 2005 = a year of validation : Core Business Strategy ¨ Goals 2006 n 2005 = a year of validation : Core Business Strategy ¨ Drug discovery approach ¨ Continued promise of c. HTS technology ¨ from you, stockholders ¨ n 2005 : collaborations Pipeline => oncology and inflammation : n CRx-102 : very encouraging ¨ CRx-140 : failure Continue to fill our internal pipeline n ¨ Expect a mix of successes & failures; Look forward to a continued flow of candidates in our pipeline Combinato. Rx, « from the president »

Real actions n New Partnerships : ¨ Fovea pharmaceutical ¨ Adipo. Genix ¨ Cystic Real actions n New Partnerships : ¨ Fovea pharmaceutical ¨ Adipo. Genix ¨ Cystic Fibrosis Foundation Therapeutics Private placement n New failure : CRx-119 n Developing 3 new molecules n

Goals 2007 Extrait des JP Morgan, le 17/01/07, slide 9 Goals 2007 Extrait des JP Morgan, le 17/01/07, slide 9

JP Morgan Présentation attractive pour les investisseurs et les futurs Extrait des JP Morgan, JP Morgan Présentation attractive pour les investisseurs et les futurs Extrait des JP Morgan, le 17/01/07, slide 7

CONCLUSION CONCLUSION

§ § § Concept original Pipeline étendu Avenir prometteur § Attente de résultats cliniques § § § Concept original Pipeline étendu Avenir prometteur § Attente de résultats cliniques concrets !! § Balance Bénéfices/Risques

Merci de votre attention Merci de votre attention

BIBLIOGRAPHY BIBLIOGRAPHY

n n n n Combinator. X_investors_presentation_2006. pdf Multi-target therapeutics: when the whole is greater n n n n Combinator. X_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

n n n c. HTS Systematic discovery of novel combination therapeutics; Grant R. Zimmermann, n n n c. HTS Systematic discovery of novel combination therapeutics; Grant R. Zimmermann, Margaret S. Lee, Joseph Léhar, Alexis A. Borisy, Curtis T. Keith; Combinato. Rx_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 Combinato. Rx_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; Combinato. Rx. 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 Combinato. Rx, Incorporated and CRx-140 group of investigators UMDNJ & Robert Wood Johnson Med. Ctr. , Nexx Brunswick, NJ and Combinato. Rx; march 2006; Combinato. Rx. pdf

n n n Ø Ø Discovery and clinical development of CRx-026, a syncretic and n n n Ø Ø 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; Combinato. Rx. pdf Combinato. Rx_ Annual Report 2005. pdf Combinato. Rx_investors_presentation_april 2006. pdf HBA Combinato. Rx 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