Transcript combinatorx

February, the 9th 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 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
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 »
Multiple pathways:
 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 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
Founders
a 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 BORISY
President
Robert FORRESTER
Chief Financial Officer
Jan LESSEM
Lynn BAIRD
Daniel GRAU
Chief Medical Officer
Quality & Clinical
operations
Commercial Operations
Jason COLE
General Counsel
Curtis KEITH
Senior vice president,
Research
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 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
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)
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
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)
$4,4million
grant
block the
adverse effects
of anthrax toxin
Henkan
Pharmaceutical:
(taiwan)
$500 000 upfront
potential
$23million
milestones
payments
CRX-026
(exclusive &
territorial license)
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
Angiotech
Pharmaceutical:
$27million upfront
$15million equity
investment &
potential
milestones
payments
medical devices
and interventional
medicines
March
January
April
June
AdipoGenix:
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
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
Private placement
Angiotech
Adipogenix
Fovéa
IPO : 9/11/05
CFFT
Yahoo 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
i.e. Screening for inflammatory responses:
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…
Multicomponent therapeutics for networked systems; Curtis T. Keith, Alexis A. Borisy and Brent Stockwell; Nature reviews, drug discovery, january 2005
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
 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
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
3D inhibition surface
Multiple
combinations of #
ratio of doses
 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)
 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
 384-well plates
 « cellular viability assay »:
Alamar blue fluorescence
symetry
 selection: 30 compounds
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
 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
 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
Besoin de lever des fonds
Secret
Ex: formule du coca cola
Communications
Méthode dévoilée
Protection de la Méthode

Revendication:
Screening de 2 molécules
 Synergique
 Robotisation
 Associations


Conséquences:
Nouvelle
 Innovante
 Application industrielle


BREVET
Publication de demande de brevet en 2002
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 1-600mg
Prednisolone 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
pentamidine
chlorpromazine
Activity on a mitotic kinesin (hsEg5/KSP),
tubulin and inhibition of PRL phosphatase
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
Crx-102
prednisolone dipyridamole
GR
PD
A2A, A2B
mRNA
stability
ATP
GR
PD
PKA
+GRE
trans-activation
GR
PD
+GRE
cis-repression
Steroid Side EffectAssociated Genes
GR
PD
Adenosine
Reuptake
AC
cAMP
AMP
PDEs
NFkB
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 2A
 highly positive studies
 Generally well tolerated
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 Index
 PGA : Physician Global Assessments
2 endpoints :
 Primary : PGA
 Secondary : PASI
Results
Side effects
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
CombinatoRx Pipeline: 200
Pipeline
Pipeline
Extrait des JP Morgan, le 17/01/07
2006
Pipeline
Failure in phase 2 clinical trials
Extrait des JP Morgan, le 17/01/07, slide 7
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
pharmaceutical
 AdipoGenix
 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
Présentation attractive
pour les investisseurs et
les futurs
Extrait des JP Morgan, le 17/01/07, slide 7
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, CRx140, 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