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Transcript of COMBINATORX SPEED DATING FOR MOLECULES BATIQUE Laura, MARICOURT Aurélie & PALADINI Bénédicte...
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