SELECTIVELY KILLING CANCER CELLS Broad Spectrum, Targeted Approaches To Cancer Treatment
Safe Harbor The presentation made during this meeting and other statements by ArQule may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act with respect to clinical trials with the Company s product candidates, including ARQ 197, ARQ 501 and ARQ 171, the discovery of additional product candidates, competitive products, financial operations and results, and other future business objectives, opportunities and strategies. Forward-looking statements are typically identified by words such as believe, expect, anticipate, intend, outlook, position and similar expressions, or future or conditional verbs such as will, should, would, and could. Forwardlooking statements are subject to numerous assumptions, risks and uncertainties. Forward-looking statements speak only as of today, and ArQule assumes no obligation to update them. Actual results may differ materially from forward-looking statements or historical performance due to the factors discussed in this presentation and factors previously disclosed in ArQule s SEC reports. ArQule and the ArQule logo are registered trademarks of ArQule, Inc. 1
SELECTIVELY KILLING CANCER CELLS Company Overview
ArQule Selected R&D Portfolio Drug/Program Drug Target Partner Research 1 Pre-Clinical Development 2 Ph I 3 Ph II 3 Ph III 3 ARQ 501 E2F-1 Pathway Roche ARQ 197 c-met Inhibitor Kyowa 4 ARQ 171 E2F-1 Pathway Roche ARQ 761 E2F-1 Pathway Roche ARQ 350RP B-RAF Kinase Inhibitor ARQ 300RP Eg5 Inhibitor ARQ 250RP Hsp90 Inhibitor ARQ 700RP HDAC Inhibitor Portfolio Updated June 2007 Notes: 1 Pre-GLP toxicology testing 2 Post-initiation of GLP toxicology testing 3 Designation follows initiation of first patient enrollment and dosing 4 ArQule retains full worldwide commercial rights to ARQ 197 outside of Japan and other select Asian countries 3
SELECTIVELY KILLING CANCER CELLS ARQ 197 c-met Inhibitor
The Biology of c-met c-met c-met // HGF HGF network network Gab-1 / Grb-2 adaptors Ras-MAPK pathway PI3K-Akt pathway STAT-3 pathway Cell Proliferation Cell Motility Cell Invasion Cell Survival Cell Invasion If If dysregulated deregulated Branching Morphogenesis Cancer and Metastasis 5
Competitive Landscape: c-met Inhibitors Small molecule inhibitors Exelixis XL-880: c-met, VEGFR2, FLT3, PDGFR, Ron, Tie2; ATP competitive; Ph2 renal papillary, H&N, gastric planned Pfizer PF 02341066: c-met, ALK; ATP competitive; Ph 1 MethylGene MGCD 265: c-met, Ron, Tie2, VEGFR1-2-3; pre-glp tox, IND? Q4, 07 J&J JNJ38877605: c-met specific, ATP pocket binding; IND? End 2007 SGX523: c-met specific, binds to novel inactive conformation; 14 day tox initiated, IND? End 2007 Antibodies Amgen AMG-102: anti-hgf; Phase 1 Genentech one armed 5D5 : anti-c-met; GLP tox initiated 6
C-MET Expression in Various Cell Lines Cells Tissue origin Expression Constitutive levels of c-met activity of c-met NCI-H661 Lung (NSCLC) - na NCI-H446 Lung (SCLC) - na SK-MEL-28 Melanoma - na MCF-7 Breast ± ± MDA-MB-231 Breast + - DLD1 Colon ++ - HCT-116 Colon + - SW-480 Colon +++ - SW-620 Colon ++ - A549 Lung (NSCLC) +++ - NCI-H460 Lung (NSCLC) ++ - NCI-H441 Lung (NSCLC) ++++ ± PANC-1 Pancreas ++ - DU-145 Prostate ++ - PC-3 Prostate + - 769-P Kidney + - 786-O Kidney ++ - Caki-1 Kidney ++ - Caki-2 Kidney +++ - A498 Kidney +++ - ACHN Kidney ++++ - HeLa Cervix ++ - SK-UT-1 Uterus ++ - SK-OV-3 Ovary ++ - SK-LMS-1 Vulva +++ ++ PACA2 Pancreas ++ ++ HT-29 Colon +++ +++ VMRC-RCW Kidney ++++ ++++ MKN-45 Stomach ++++ ++++ 7
ARQ 197 Phase 1 Oral administration 2 dosing cohorts 39 patients in intermittent, or two weeks out of three 18 patients in continuous, or three weeks out of three Dose range 20mg 360mg total daily dose Maximum systemic exposure achieved at 240mg daily All doses give plasma exposure above in vitro IC50 for c-met inhibition No drug-related grade 3/4 adverse events Grade 1/2 events: fatigue, diarrhea, anemia, constipation, dry mouth 8
ARQ 197 Oral Dose Pharmacokinetics 20 mg BID 30 mg BID 40 mg BID 50 mg BID 70 mg BID In Vitro IC 50 9
Phase 1 Activity Data 35 Patients assessed in the intermittent schedule 2 patients withdrew prior to first tumor assessment; 2 patients not dosed Partial Response (PR): 3 Stable Disease (SD): 18 11/18 SD have shown some evidence of tumor shrinkage Overall response (PR/MR/SD): ITT: 56.8% (21/37) Evaluable: 60.0% (21/35) 10 patients assesses in the continuous cohort 7 of 10 stable at first assessment (7+ to 13+ weeks) 10
Response by Tumor Type (as of June 2007) Tumor type #pts Response (weeks on therapy) NSCLC 3 MR(21), SD(23), PD(5) Neuroendocrine 1 PR(33) Prostate 3 PR(35), PD(12), Withdrew consent (4) Pancreatic 2 SD(52+), PD(5) Renal 4 MR(40+),SD(34+),SD(21),PD(6) Thyroid 4 SD(34+), SD(26+), SD (21), SD(12) Testicular 1 PR(40+) AdenoCa?origin 2 MR(33), SD(19+) Ovarian 3 SD(10), PD(5), PD(6) Colon 6 SD(12),5xPD(5-9) PR=Partial Response; MR=Minor Response; PD=Progressive Disease; SD=Stable Disease 11
6 6 5 4 ARQ 197 Efficacy 12 7 7 6 6 6 6 6 6 9 9 9 10 11 12 6 18 19+ 20 21 60 52+ 50 40+ 36+ 36 40 34+ 34+ 34+ 34+ 33 32 29+ 26+ 30 23 23 20 10 0 Length of Time on Study (weeks) 007 020 001 022 027 028 030 032 006 008 036 038 014 034 005 026 039 016 029 004 021 010 024 025 031 017 018 002 003 011 012 015 019 033 035 009 037 Best Response Partial Response Stable Disease with Regression Stable Disease Progressive Disease
Summary Results From ASCO Broad and durable stable disease PRs observed in prostate, neuroendocrine and testicular cancer Long term, durable disease control in a range of tumor types Nearly 50% of patients stay on drug greater than 4 months Benign adverse event profile No dose limiting toxicity observed No drug-related grade 3/4 events Hints of positive quality of life benefit Signals of anti-metastatic effect which we intend to explore further Possible reduction in incidence of new metastases Do c-met inhibitors affect metastatic spread as well as primary lesions? 13
ARQ 197: Next Steps Current proposed Phase 2 clinical program Bioequivalence study in preparation for subsequent remaining Phase 2 program Fast-to-market: pediatric soft tissue sarcoma, gastric and advanced breast Proof of concept: prostate, pancreatic, NSCLC Identify possible combination regimens 14
ARQ 197: Kyowa Hakko Partnership Entered into April 27, 2007 Landmark Phase 1 deal with Japanese company Deal terms: $30 million upfront, $93 million in milestones, undisclosed sales milestones, royalties beginning mid-teens Territory: Japan, China (including Hong Kong), South Korea and Taiwan Preserves longer term strategic options, including increased partnering flexibility and enhanced ability to pursue independent development 15
SELECTIVELY KILLING CANCER CELLS ARQ 501 and ARQ 171 E2F1 Checkpoint Activators
ARQ 501: Roche Partnership Entered into April 1, 2004 Deal terms up to $276 million for E2F program Up to $33 million prior to option exercise Further payment due if positive option exercise Provides option to in-license E2F compounds on completion of ARQ 501 Leiomyosarcoma Phase 2 monotherapy ARQ 501 Pancreatic Phase 2 combination therapy ARQ 171 Monotherapy dose finding Phase 1 ArQule receives royalties, milestones and retains co-promotion rights if Roche exercises its option 17
Timeline to Roche Decision Final study reports for ARQ 501 Phase 2 program expected in 3Q 2007 Expected to complete recruitment in Phase 1 trial for ARQ 171 and recommend Phase 2 dose in 4Q 2007 Roche scientific review period Final decision by Roche expected in early 2008 18
Activated Checkpoint Therapy SM Differential Effects Forces apoptotic cell death in presence of irreparable DNA damage ARQ 501/ 171 E2F1 elevation Institutes DNA repair in presence of minor DNA damage Allows normal cell division in absence of DNA damage 19
Academic Validation Dual Induction of Apoptosis and Senescence in Cancer Cells by Chk2 Activation: Checkpoint Activation as a Strategy against Cancer Chang-Rung Chen, Wenxian Wang, Harry A. Rogoff, Xiaotong Li, William Mang, and Chiang J. Li July 15 th, 2005 20
SELECTIVELY KILLING CANCER CELLS ARQ 501 First Generation E2F1 Checkpoint Activator
Efficacy Positive Proof of Concept Phase 2 data: Pancreatic positive proof of concept in combination with gemcitabine ( >16% Response Rate vs. 8% for gemcitabine) Leiomyosarcoma positive proof of concept in monotherapy (17.5% Response Rate) Head and neck insufficient activity in monotherapy Phase 1 data: Evidence of broad activity Signs of activity in head and neck, pancreas, ovarian, colorectal, breast, adrenocortical carcinoma, melanoma 22
Summary of ARQ 501: Phase 2 Status Protocol Treated Assessed PR SD PD ARQ 501-221 (Leiomyosarcoma) 45 1 40 1 12 2 27 ARQ 501-208 (Head and neck) 81 3,4 41 1 17 23 ARQ 501-212 (Pancreatic) 93 5, 75 12 36 6 27 1 Includes 5 patients did not have post baseline tumor assessments (4 deaths, 1 withdrew consent) 2 Includes 6 patients with SD > 4 months 3 Includes 9 patients who did not have post baseline tumor assessments (deaths, SAE, withdrew consent) 4 Includes 31 patients whose baseline tumor evaluation is not yet entered into the database 5 Includes 18 patients who did not have post baseline tumor assessment (deaths, ADE, withdrew consent) 6 Includes 14 patients with minor response (14.3 27.0% tumor reduction) 23
ARQ 501 Safety Overview Reversible hemolytic anemia appears to be the dose limiting adverse event for ARQ 501 This may be reduced by: Second generation compound ARQ 171 or ARQ 761 Reformulation efforts to reduce cyclodextran excipient 24
ARQ 171: 2nd Generation E2F1 Activator Same mechanism as ARQ 501 Composition of matter IP expected Greater potency in preclinical tests Potential for wider therapeutic window Phase 1 initiated December 2006 Cohorts dosed successfully at 24-192 mg/m 2 384 mg/m 2 currently underway 25
ARQ 761 Recent discovery of new form of 501 which could provide Composition of matter IP Greatly improved formulation Potential for bioequivalence strategy 26
E2F Franchise Next Steps ArQule believes data to date is sufficient to justify a registration strategy Need to decide Which compound: 501/ 171/ 761 Which company: Roche or ArQule All necessary information estimated to be available by early 2008 decision 27
SELECTIVELY KILLING CANCER CELLS Financials & Milestones
Financial Highlights Cash at 3/31/07: $84 million Kyowa payment May, 2007 $27 million Follow-on offering June, 2007 >$50 million Net loss 2007 approx. $60-65 million Year end cash Dec, 2007 approx. >$110 million Market Cap June 15, 2007 approx. $340 million 29
Expected Upcoming Milestones Mid-2007 Initiate first Phase 2 study for ARQ 197 3Q 2007 Report data from Phase 2 program for ARQ 501 4Q 2007 Complete recruitment in Phase 1 trial for ARQ 171 and recommend Phase 2 dose 4Q 2007 4Q 2007 Early 2008 Submit E2F-1 activator program data package to Roche, initiating their scientific review Initiate toxicology testing with lead candidate from ARQ 350 research program Roche decision of further development of ARQ 501/171/761 30
Investment Highlights Potential best-in-class c-met inhibitor (ARQ 197) that has demonstrated expanded anti-cancer activity and was well-tolerated Series of novel oncology therapeutics (ARQ 501/171/761) utilizing proprietary DNA damage response MOAs Validating strategic partnerships with Roche and Kyowa Novel biology and proven chemistry to drive pipeline expansion Experienced management team Strong calendar of expected news flow over the next 12 months 31