Multi-Target Drugs for Cancer and Inflammation
Transcript of Multi-Target Drugs for Cancer and Inflammation
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Multi-Target Drugs for Cancer and Inflammation
November 2008NASDAQ: ENMD
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Forward-Looking Statements
Statements that are not descriptions of historical facts are
forward-looking and subject to risk and uncertainties.
Actual results may differ materially from those currently
anticipated due to a number of factors, including risks
relating to additional financing, early-stage product
development, clinical trials, and those set forth in the
Company’s Securities and Exchange Commission filings.
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Our Mission: Multi-Target Oncology Drugs
EntreMed is a clinical-stage pharmaceutical company developing
next generation multi-mechanism drugs to treat cancer and
inflammatory disorders by targeting disease cells directly and the
blood vessels that nourish them.
Rockville, Maryland and Toronto, OntarioResearch Facilities
Angiogenesis, Cell Cycle Regulation, Cell Signaling, and Inflammation
Technology Expertise
Phase 2 Oncology Development Stage
Oncology & InflammationTherapeutic Focus
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Business Model – Targeted, Multi-Mechanism Drugs
• Multiple Shots on Goal– Multiple drug candidates with multiple mechanisms of action – Risk mitigation via multiple early-stage clinical programs– Strong IP, retained commercial rights to all compounds
• Focused on important pathways and targets that can inhibit disease progression– Small molecule, orally-active, antiproliferative, antiangiogenic drugs– Expertise in angiogenesis, cell cycle regulation, cell signaling
• Create Value– Multi-product clinical pipeline – Execute partnering strategy
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Multiple Phase 1 and Phase 2 Partnering Opportunities
ClinicalCandidate Development
HypothesisGeneration
Risk
Cumulative InvestmentRisk
CumulativeInvestment
Pre‐ClinicalDevelopment
PhaseI
PhaseII
PhaseIII
Regis‐tration
GlobalLaunch
GlobalOptimization
Commercialization
LeadOptimization
Target Identificationand Validation
AssayDevelopment
LeadGeneration
Original Source: James Doroshaw, MD, National Cancer Institute Modified: ENMD November 2008
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Targeted Agents Will Drive the Growth in Oncology
Source: Oncology Market Size, Competition and Pricing, September 21, 2007
Oncology Market: Share Of Targeted Agents, 2000A-2015 (%)
37%27% 20% 16% 11%
22%
14%11%
8%6%
34%
27%
18%19%
18%
7%
33%51% 57% 65%
0%10%20%30%40%50%60%70%80%90%
100%
2000 2006 2010 2012 2015
Cytotoxics Hormonal Agents
Supportive Care Targeted Agents
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Focus on Tumor Cell and Angiogenic Inhibition
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Substantial Progress: All Programs in Clinical Development
• Multi-program clinical development pipeline
• MKC-1 Ph 2 Oncology• ENMD-1198 Ph 1 Oncology• ENMD-2076 Ph 1 Oncology• Panzem® Ph 1 Rheumatoid Arthritis (RA)
• Programs address high unmet medical needs
• Strong IP, retained commercial rights to all compounds
• Partnering discussions underway for ENMD-2076 and Panzem®
for RA
• Cash & short-term investments through 2009
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Target Interdiction is Key to Cancer Cell Inhibition
ProteinSynthesis
Akt
MKC-1
TORC2Complex
mTOR
GβL Rictor
TORC1ComplexmTOR
GβL Raptor
X
Angiogenesis, Proliferation,Metabolism
Translation
HIF-1α, STAT3, NFκB
Cell Kill, Apoptosis, Metabolic & Antiangiogenic Effects
Importin β
TFREs TFs
X
X
MKC-1
X
CellCycle
ENMD-2076
ENMD-2076
ENMD-1198
Mitosis
m&tRNA
SM/TFs
RTKs
TKs
XX
X
X
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Solid Clinical Pipeline: Multiple Product Opportunities
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MKC-1: Novel Phase 2 Cell Cycle Inhibitor
• Oral, antiproliferative, cell-cycle inhibitor; mTOR inhibitor, Importin β, HIF-1α targets
• Broad antitumor activity, alone and in combination
• Predictable toxicity (neutropenia, GI effects); no neuropathy, no abnormal cardiovascular effects
• Exclusive world-wide license from Roche
• Broad IP coverage through 2021, including composition-of-matter & formulation; substantial API inventory
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MKC-1 is a 2nd Generation mTOR Drug Candidate that Blocks the TORC2 Complex & Inhibits Akt Function
Cell Metabolism
Angiogenesis
VEGFsGrowth FactorSignaling
ProteinSynthesis
Cell Proliferation
EGFIGF
PI-3K
TSC2/1
RHEB
PTEN
TORC1Complex
mTORGβL
TORC2Complex
Raptor
mTOR
GβL Rictor
Nutrients
HIF-1α
Hypoxia
Akt
MKC-1
RapamycinRAD001
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MKC-1: Clinical Trials in Solid Tumors and Leukemia
INDICATION TRIAL TYPE SITE(S) N= Dosing
Metastatic Breast Cancer Phase 2 Multicenter Up to 60 Intermittent
Non-Small Cell Lung CancerPhase 1/2
(w/Alimta®)Multicenter Up to 60 Intermittent
Hematological Cancers Phase 1 Princess Margaret Hospital 30 Intermittent/
Continuous
Pancreatic Cancer Phase 2 Multicenter Up to 33 Intermittent/ Continuous
Ovarian/Endometrial Cancers Phase 2 Multicenter Up to 84 Intermittent
Solid Tumors Phase 1 University of Wisconsin Up to 24 Continuous
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MKC-1 Progress in Non-Small Cell Lung Cancer
• Trial Design: Phase 1/2, open label, in combination with pemetrexed(Alimta®) (Phase 1 dose escalation advanced solid tumors, Phase 2 non-small cell lung cancer)
• Dosing: Phase 1 escalating dose started with 75 mg/m2 BID for 14 days on, 7 days off, in combination with pemetrexed at standard dose
• Study Endpoints– Safety occurrence of treatment-emergent AEs– Efficacy (Phase 2) tumor response (according to RECIST)– Median progression free survival– Duration of response and time to response– Time to treatment failure– Median survival
• Primary endpoint (response) has been met
• Randomized Phase 2 in NSCLC (and RCC) under consideration
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ENMD-2076: Aurora A and Angiogenesis Inhibitor
• Orally active, selective-kinase inhibitor
• Unique combination of target activities: Aurora A & Angiogenic Kinases (VEGFR, FGFR, PDGFR); Growth Factor Kinases (Flt-3, Src, c-Kit)
• Tumor regression observed in multiple preclinical models
• Excellent efficacy as a single agent
• Combines well with other cancer drugs
• Excellent pharmaceutical properties
• Patents pending; > 600 analogs coveredAurora A
Key Regulator of Cell Division;Expression Linked to Decreased Survival
Aurora A
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Significant Tumor Regression Demonstrated with ENMD-2076 in Preclinical Leukemia Model
no treatment
vehicle alone
15 mg/kg
30 mg/kg
75 mg/kg
150 mg/kg
Tum
or V
olum
e (m
m3 )
Endpoint
0
200
400
600
800
1000
1200
1400
1600
20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Days following Tumor Challenge
Rx initiated
Rx changed
Free base
• MV4;11 Leukemia Tumor Model• Dose escalated to 150 mg/kg in 15 & 30 mg/kg cohorts
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Tumor Regression and Antiangiogenic Effects of ENMD-2076 in Preclinical Colon Carcinoma Models
Vehicle Control Day 28
ENMD-2076 po, qd (200 mg/kg) Day 28
HT29 Colon Carcinoma Xenograft
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• Ph 1 clinical study initiated 1Q08 – Dana-Farber and University of Colorado
• Ph 1 design and endpoints– 3 + 3 dose escalation with safety, PK
and clinical benefit endpoints– Daily dosing
• PD evaluation of soluble VEGFR2
• Cardiovascular monitoring
• Goal: determine MTD in solid tumor patients
• Clinical trial in hematological cancer planned for 2H08
Multicenter Clinical Trial Underway with ENMD-2076 in Advanced Cancer Patients
ENMD-2076 – Initial Phase 1 Comments & Observations
• Phase 1 clinical trial in patients with advanced solid tumors– Currently enrolling patients in 3rd cohort– Longest patient on study at 6 months of daily dosing
• Initial PK data suggest that T1/2 is higher than what was observed in animal studies
• Longer half life might lead to less than daily dosing/lower doses needed in humans
• Phase 1 results anticipated by mid-2009
2020
ENMD-1198: Oral, Multi-Mechanism Antimitotic Agent
• Novel drug targeting key transcription factors – HIF-1, STAT3 & NFκB
– HIF-1 has a central role in cell survival & proliferation; regulates > 80 genes
– Over-expression associated with tumor aggression & increased angiogenesis
• Antiproliferative & antiangiogenic activity against multiple tumor types, including resistant tumors
• Phase 1 study in advanced cancer patients nearing completion
– Reached dose-limiting toxicity– Cohort expansion to identify combination
therapies and target indications
• MOA indicates prostate cancer may be key indication; clinical development plan pending
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Joint in Rheumatoid Arthritis – Effects of 2ME2
Normal Joint
RheumatoidArthritis
2ME2
Pannus Formation
Cellular Infiltration
Cartilage Degradation
Bone Erosion
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Panzem® (2ME2) – An Oral, Small Molecule DMARD with Antiangiogenic Activity
• Dose-dependent inhibition in preclinical RA models (DMARD)– Cellular Infiltration– Pannus Formation– Cartilage Lesions– Bone Resorption
• Additive activity in combination with MTX
• Comparable activity to Enbrel® in preclinical RA models
• Orally-active, unique inhibition of targets distinguishes 2ME2 from other RA agents
• Broad IP position; composition-of-matter coverage through 2022
• $14 billion global market; >300 million cases worldwide– Oral, small molecule, unique mechanism– Potentially competitive with BRMs and other DMARDs
CH3
HO
H3CO
OH
2ME2
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Healthy Volunteer Study Complete: Clear Path Forward
• Study goals achieved
– Cross-over from oral liquid to dry powder formulation with equivalent PK
– Study used higher oncology dose
– Lower dose anticipated for RA indication
– Substantial safety history
• FDA review of results completed
• Clear development path forward– Drug-drug interaction (DDI) clinical study with methotrexate– Phase 2 following chronic animal toxicity study
• Active partnering effort underway
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Nine Months Ended September 30,
Year-End2008 2007 2007
Total revenues $ 3,501,307 $ 3,520,259 $ 7,395,651Research & development 16,629,127 18,089,240 23,739,392General & administrative 5,274,585 5,407,588 7,386,570Operating loss (19,314,476) (18,643,625) (22,411,121)
Acquired in-process R&D 2,000,000 0 0Net Loss (21,314,476) (18,643,625) (22,411,121)
Net loss per share attributable to common shareholders (basic) $ (0.26) $ (0.23) $ (0.28)
Weighted avg. number of shares outstanding (basic) 86,060,438 84,015,999 84,166,552Cash & short term investments $27,871,889 $ 50,644,261 $ 47,748,191
Good Financial Position: Emphasis on Tight Cash Management and Execution Against Milestones
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Key 2H08 & 1H09 Milestones: Moving Our Clinical Pipeline Forward
Initiate Phase 2 study in ovarian/endometrial cancers 1Q08Report results (Phase 2 metastatic breast cancer) 2Q08Initiate Phase 1 continuous dosing trial 2Q08Report Phase 1 and interim Phase 2 data (non-small cell lung cancer) 4Q08Initiate Phase 1 trial in solid tumors 1Q08Initiate Phase 1 trial in hematological tumors 4Q08Co-development alliance 1H09
Panzem® (2ME2) Complete healthy volunteer trial in rheumatoid arthritis 2H08Complete Phase 1 enrollment 4Q08Initiate expanded Phase 1 or Phase 2 trial 1H09Report interim data for Phase 1 1Q09
Status
MKC-1
ENMD-1198
ENMD-2076
Compound Goal Target
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Multi-Target Drugs for Cancer and Inflammation