Investor Presentation February 2016

Transcription

1 Investor Presentation February 2016

2 Safe Harbor This presentation 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 tivantinib (ARQ 197), ARQ 092, ARQ 087, ARQ 761 and ARQ 751, competitive products, financial operations and results, corporate partnerships and other future business objectives, opportunities and strategies. Forwardlooking 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. Forward-looking 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. See discussion of Risk Factors in the Company s Annual Report on Form 10-K as filed with the SEC. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this presentation. ArQule s product candidates are in various stages of development and are not available for sale or use outside of approved clinical trials. ArQule and the ArQule logo are registered trademarks of ArQule, Inc. 2

3 Who We Are Clinical-stage biopharmaceutical company focused on small molecules for precision medicine Multiple programs in biomarker-defined oncology and rare disease indications Pivotal phase 3 trial for lead compound tivantinib approaching completion Multiple phase 1/2 trials on-going with three proprietary compounds Phase 1 trial in Proteus syndrome (rare disease) in collaboration with NIH ARQ 751, next-generation AKT inhibitor, to enter the clinic in 2016 Experienced team managing a cost effective organization 3

4 Pipeline of Products Pre-Clinical Phase 1a/1b Phase 2 Phase 3 Collaborator Regulatory Designation Tivantinib C-MET ARQ 087 FGFR ARQ 092 AKT ARQ 751 AKT ARQ 761 NQO1 METIV-HCC Trial (West) Fully Accrued JET-HCC Trial (Japan) Intrahepatic Cholangiocarcinoma (icca) Solid Tumors Solid Tumors/lymphoma/ endometrial cancer Proteus syndrome Other Rare Diseases Cancer/ Rare Diseases Solid Tumors/Pancreatic Cancer SPA Orphan Drug Designation Orphan Drug Designation Orphan Drug Designation 4

5 Pipeline Clinical Trials Overview Tivantinib, small molecule c-met inhibitor, in Phase 3 trials Pivotal Phase 3 clinical development program in 2 nd line hepatocellular carcinoma (HCC), METhigh patients only, with companion diagnostic ARQ 087, small molecule FGFR inhibitor, in Phase 1b/2 trial Phase 2 in intrahepatic cholangiocarcinoma (icca) Phase 1b in adrenocortical and other tumors harboring FGFR translocations, amplification/mutations ARQ 092, small molecule AKT inhibitor, in Phase 1b trial for oncology and Phase 1 for Proteus syndrome Phase 1b in endometrial cancer, lymphoma and other tumors harboring either AKT or PI3K mutations Phase 1 collaboration with the NIH in the orphan/rare disease, Proteus syndrome, in patients harboring the AKT1 mutation ARQ 761, NQO1 inhibitor, in Phase 1/2 trial Phase 1/2 trial in pancreatic cancer recruiting patients with high levels of NQO1; partnership with UT Southwestern Medical Center 5

6 Significant 2015 Milestones Q1 Q2 Q3 Q4 ARQ 087 progressed to a biomarker-driven phase 2 trial in intrahepatic cholangiocarcinoma with FGFR2 translocations based on data from phase 1 trial Initiated move to new facility resulting in annualized savings of ~$5 million Established research and development collaboration with Beryllium Development Corporation to streamline R&D process ARQ 087 phase 1 data presented at ASCO showing efficacy in cancers with FGFR translocations Tivantinib biomarker data presented at ILCA from hepatocellular carcinoma phase 2 trial showing MET is a prognostic and predictive biomarker ARQ 092 preliminary phase 1b oncology data presented at ESMO demonstrating efficacy in AKT1 mutations; fully enrolled lymphoma and endometrial cohorts of the phase 1b trial Increased year-end cash guidance to between $37 and $39 million ARQ 092 and ARQ 751 manuscript published in PLOS ARQ 092 and ARQ 087 received FDA orphan drug designation for Proteus syndrome and cholangiocarcinoma, respectively ARQ 092 enrolled first patient in phase 1 trial in Proteus syndrome Tivantinib accrual completed for METIV-HCC pivotal phase 3 trial in HCC 6

7 2015 Key Data Presentations AACR ASCO ESMO GI ILCA ESMO ECC ARQ 087 Determination of FGF 19, 21 and 23 protein levels in a phase 1 clinical trial of ARQ 087, an oral pan-fgfr inhibitor [Abstract CT319] Combinations of ARQ 087 with chemotherapeutic agents are safe and show a striking antitumor activity in different xenograft models [Abstract 3500] Tivantinib A Randomized Phase II Trial of the MET inhibitor Tivantinib + Cetuximab Versus Cetuximab alone in Patients with Recurrent/Metastatic Head and Neck Cancer [Abstract 6060] ARQ 087 Phase 1, first-in-human study of ARQ 087, an oral pan-fibroblast Growth Factor Receptor (FGFR) inhibitor, in patients (pts) with advanced solid tumors [Abstract 2545] Tivantinib Phase II Study of Tivantinib (ARQ 197) in Combination with Cetuximab in EGFR inhibitorresistant, MET-High, KRAS Wild-Type Metastatic Colorectal Cancer [Abstract O-008] Tivantinib Tivantinib in Pretreated Hepatocellular Carcinoma (HCC): Tumor and Plasma Biomarker Analysis from the Randomized Controlled Phase 2 Trial (RCT) ARQ [Abstract O-029] ARQ 092 Determination of FGF 19, 21 and 23 protein levels in a phase 1 clinical trial of ARQ 087, an oral pan-fgfr inhibitor [Abstract 338] 7

8 2015 Key Data Presentations PLOS AACR- NCI- EORTC Scientific Research ARQ 092 Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric Inhibitor, ARQ 092 [PLoS ONE 10(10): e doi: /journal.pone ] Tivantinib Tivantinib in Combination with Erlotinib vs Erlotinib Alone for EGFR Mutant NSCLC: Subgroup Results from the Phase 3 MARQUEE Study [Abstract B194] ARQ 087 In FGFR2 Driven Tumors, Preclinical Pharmacokinetics (PK), Pharmacodynamics (PD), and Efficacy Translate into Clinical Activity of ARQ 087 [Abstract B151] Combo ARQ 087/ARQ 092 ARQ 092 Enhances the Efficacy of Paclitaxel, Lapatinib, Trastuzumab, Trametinib, and ARQ 087 both in Cancer Cell Lines and Mouse Xenograft Cancer Models [Abstract B185] ARQ 092 and ARQ 751 Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma [Abstract B111] Association of AKT1E17K and PIK3CAH1047R Mutations with Efficacy of ARQ 092 In Vitro, In Vivo and in Patients [Abstract B181] Targeting PI3K Pathway Dependent Endometrial Tumors with Allosteric Inhibitors, ARQ 092 and ARQ 751 [Abstract B183] ARQ 092 Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome [Scientific Reports DOI: /srep17162] 8

9 2016 Goals PROPRIETARY PIPELINE ARQ 092 AKT Inhibitor Complete phase 1b trial in oncology make decisions on next steps Analyze preliminary phase 1 data in Proteus syndrome make decisions on next steps Explore opportunities in other rare over-growth diseases ARQ 087 FGFR Inhibitor Complete phase 2 trial in intrahepatic cholangiocarcinoma make decisions on next steps Complete phase 1b in oncology make decisions on next steps ARQ 751 next-generation AKT inhibitor Initiate phase 1 trial in oncology with AKT1 and PI3K mutations PARTNERED PIPELINE Tivantinib Compete METIV-HCC planned interim analysis to occur by early Q2 16 9

10 Tivantinib in HCC Snapshot Tivantinib is a class leading investigational oral inhibitor of the MET receptor tyrosine kinase currently in phase 3 clinical development in two biomarkerdefined trials for second-line treatment of hepatocellular carcinoma (HCC) in a MET-high population METIV-HCC trial being conducted in the West (U.S., Europe, South America, and rest of world), partnered with and co-funded with Daiichi Sankyo¹; this trial is fully accrued JET-HCC trial being conducted in Asia (Japan and select Asian countries), partnered with and funded by Kyowa Hakko² Previous studies support drug activity in MET-high patients In NSCLC (non-small cell lung cancer) a pre-defined sub-analysis from phase 3 trial, MARQUEE In HCC (hepatocellular carcinoma) a successful randomized double blind phase 2 trial In CRC (colorectal cancer) Stage 1 data from a phase 2 investigator-initiated trial In HCC, phase 3 METIV-HCC trial preliminary analysis of baseline MET status Granted Orphan Drug Status for HCC by the FDA and EMA Composition of Matter patent protection through 2030 ¹ Development and Commercialization partnership with Daiichi Sankyo for U.S., Europe, South America, and rest of world. ² Development and Commercialization partnership with Kyowa Hakko for Japan, and select Asian countries. 10

11 Tivantinib Milestones in HCC Phase 1 EXPLORATORY December 2008 Trial initiated January 2010 Preliminary trial results presented at ASCO GI October 2010 Final trial results presented at ESMO Phase 2 PROOF OF CONCEPT September 2010 January 2012 June 2012 January 2013 Trial initiated Trial meet primary endpoints Trial results presented at ASCO Trial results published in Lancet Phase 3 REGISTRATION January 2013 METIV-HCC (second-line HCC) initiated September 2013 Dosage change implemented November 2015 Exercised co-commercialization option in U.S. with Daiichi Sankyo December 2015 Completed accrual Early Q Expect planned interim analysis to take place 11

12 Liver Cancer Facts 782,000 cases diagnosed annually 6 th most common cancer worldwide Liver Cancer A Worldwide Disease 746,000 deaths annually 2 nd most common cause of cancer related death About 90% of all liver cancers are HCC Most cases diagnosed >75 years old Risks include age, cirrhosis, hepatitis A and B and smoking Five Year Survival Rate is 12% Early stages generally do not show symptoms Source: World Cancer Research Fund International/American Institute for Cancer Research. Continuous Update Project Report: Diet, Nutrition, Physical Activity and Liver Cancer Available at: wcrf.org/sites/default/files/liver-cancer-2015-report.pdf 12

13 About Liver Cancer Liver cancer is the abnormal and uncontrolled growth of cells within the liver that disrupt normal liver function. It is typically defined as either primary liver cancer, which starts in the liver, or secondary liver cancer, and spreads to the liver from another part of the body such as the pancreas, colon, stomach, breast or lung. There are four types of primary liver cancer: 1. Hepatocellular carcinoma (HCC): The most common type of liver cancer, HCC starts in the hepatocyte cells of the liver and can have different growth patterns. It can start as a single tumor that grows larger, and only late in the disease does it spread to other parts of the liver. Other times, it can start as many small cancer nodules throughout the liver, which is usually seen in people with cirrhosis. 2. Intrahepatic cholangiocarcinoma (icca): This type of liver cancer (bile duct cancer) starts in the bile ducts (the tubes that carry bile to the gallbladder) within the liver. 3. Angiosarcoma and hemagiosarcoma: These are rare types that start in the blood vessels of the liver. 4. Hepatoblastoma: A very rare type of cancer that develops in children under four years of age. 13

14 HCC High Unmet Need Limited Treatment Options for HCC Current treatment options¹ Surgery Tumor ablation Embolization therapy Radiation treatment Targeted therapy 1 st line therapy - sorafenib is the only approved systemic agent Need for 2 nd line therapy No standard of care exists at this time for 2 nd line therapy Several phase 3 studies in 2 nd line HCC failed brivanib, everolimus, and ramucirumab Tivantinib is the only drug in a biomarker-driven phase 3 trial for HCC ¹ American Cancer Society. Liver Cancer Overview. 14

15 The Role of MET in HCC Amplification and overexpression of the MET pathway is associated with poor outcomes in many cancers, including HCC In cancer cells, MET is dysregulated continuously thus playing a role in cancer cell growth, survival, angiogenesis, invasion and metastasis HGF/MET signaling plays a role in liver regeneration [1] and MET expression is reported to be increased in some HCC tumors [2-4] MET overexpression by IHC correlates with poor prognostic features and poor outcomes [6-8] HGF overexpression and subsequent autocrine MET activation can induce tumor growth in transgenic in vivo models [5] Elevated plasma HGF associated with decreased benefit from sorafenib in SHARP study [9] 1. Borowiak M, et al. Proc Natl Acad Sci U S A. 2004;101: Kiss A, et al. Clin Cancer Res. 1997;3: Selden C, et al. J Hepatol. 1994;21: Tavian D, et al. Int J Cancer. 2000;87: Horiguchi N, et al. Oncogene. 2002;21: Ueki T, et al. Hepatology. 1997;25: Wu FS, et al. Chin J Surg. 2006;44: Santoro A, et al. Lancet Oncol. 2013;14: Llovet JM, et al. Clin Cancer Res. 2012;18:

16 Phase 2 HCC MET Data Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study Volume 14, Issue 1, Pages 55-63, January 2013 MET-high Patients Placebo controlled, double blind in patients with advanced HCC and Child-Pugh cirrhosis who progressed or were unable to tolerate first-line systemic therapy 2:1 randomization to receive tivantinib or placebo until disease progression; 37 MET-high patients In the MET-high sub group, median time to progression (TTP) was 2.7 months (95% CI ) in the tivantinib group compared with 1.4 months (95% CI ) in the placebo group (HR 0.43, 95% CI ; p=0.03) Median overall survival was 7.2 months (95% CI ) for patients with MET-high tumours who received tivantinib versus 3.8 months (95% CI ) for patients who received placebo (HR 0.38, 95% CI ; p=0.01) 16

17 Tumor H-Score Tumor H-Score METIV-HCC vs. Phase 2 Baseline Phase 2 HCC Baseline Tumor MET Status 1 Phase 3 METIV-HCC Preliminary Baseline Tumor MET Status* 1 H-Score Median Min Max MET-High Patients MET-Low Patients * Data are preliminary, from non-cleaned database, from biopsied patients regardless of enrollment status ¹ Rimassa, L. et al Gastrointestinal Cancers Symposium. Abstr #197. H-Score Median Min Max MET-High Patients MET-Low Patients Similar patient tumor MET-high population for phase 2 trial and phase 3 METIV-HCC trial 17

18 MET Status After Sorafenib Phase 2 HCC Baseline Tumor MET Status 1 MET-High Samples (rate) Tested samples (N=77) 37 (48%) Phase 3 METIV-HCC Preliminary Baseline tumor MET Status* 1 MET-High Samples (rate) Tested samples (N=1138) 576 (51%) Samples with available biopsy data (N=72) 36 (50%) Samples with available biopsy date (N=925) 527 (57%) Tumor samples taken before sorafenib (N=55) 22 (40%) Tumor samples taken before sorafenib (N=438) 173 (39%) Tumor samples taken after sorafenib (N=17) 14 (82%) Tumor samples taken after sorafenib (N=487) 354 (73%) In both the phase 2 trial and the phase 3 METIV-HCC trials the rate of tumor MET-high patients was higher after sorafenib treatment * Data are preliminary, from non-cleaned database, from biopsied patients regardless of enrollment status ¹ Rimassa, L. et al Gastrointestinal Cancers Symposium. Abstr #

19 Phase 3 MARQUEE MET Data MET-High NSCLC Phase 3 trial of 1,048 patients, selected by non-squamous cell histology previously receiving one to two systemic treatments, tivantinib in combination with erlotinib versus erlotinib plus placebo Trial was discontinued for futility at planned interim analysis in Q In the intent to treat (ITT) population overall survival (8.5 vs 7.8 months, HR = 0.98, 95% CI = 0.84;1.15) improved but was not significant while improvement in progression free survival (3.6 vs 1.9 months, HR = 0.74, CI 0.64;0.85) demonstrated significance Approximately 500 patients were able to be analyzed for MET status per protocol; of these, 211 patients where confirmed as being MET-high of which 104 and 107 patients, respectively, where enrolled in the tivantinib and the placebo arms of the trial¹. A pre-specified exploratory analysis indicated improved median overall survival (9.3 vs 5.9 months, HR = 0.70, 95% CI = 0.49;1.01) and progression-free survival (3.7 vs 1.9 months, HR = 0.72, 95% CI = 0.52;0.98) in patients with high MET expression¹ ¹ Scagliotti, G. et al. ESMO

20 Phase 2 CRC MET Data Progression Free Survival Months Overall Survival Months Investigator-initiated (two stage) Phase 2 single-arm study evaluating tivantinib in combination with cextuximab in EGFR-inhibitor resistant, MET-high, KRAS wild-type colorectal cancer patients failing at least one systemic therapy 21 patients enrolled in Stage 1 with the primary end point of overall survival Stage 1 results 1 patient experienced a complete response (CR) 2 patients experienced durable confirmed partial responses (PRs) Stable disease was observed in 8 patients, including 2 short duration PRs, for an overall Disease Control Rate of (CR + PR + SD) 52.4% The trial has continued to Stage 2 and is expected to be completed by year-end 2015 ¹ Rimassa, L. et al. ESMO 17 th Annual World Congress on Gastrointestinal Cancer Abstr #O-DD8. 20

21 Tivantinib Phase 3 Trial Design METIV-HCC (West)¹ (NCT ) MET-high patients receiving tivantinib in advanced HCC Patients with MET-high (assessed by IHC) inoperable locally advanced metastatic HCC treated with 1 prior systemic therapy (sorafenib) Companion diagnostic Conducted under FDA SPA Stratification Factors Vascular invasion Extra-hepatic spread AFP (< or > 200 ng/ml) Endpoints 1 o : OS Tivantinib 120 mg tablet BID* 2 : PFS, safety ~200 pts Placebo ~100 pts 3 : ORR, DCR, TTP, PD, PK, biomarkers *Dose reduced from 240 mg tablet twice daily (BID) to 120 mg tablet BID following observation of higher incidence of neutropenia. DMC safety analysis of reduced dose cleared the trial to proceed. PK analysis of DMC-determined cohort demonstrated that 120 mg tablet BID has comparable exposure to 240 mg capsule as per the Phase 2 trial data. R A N D O M I Z E D ¹ Development and Commercialization partnership with Daiichi Sankyo for U.S., Europe, South America, and rest of world. 21

22 METIV-HCC Interim Analysis Trial Design Primary Endpoint Overall Survival (OS) > 257 events required Median OS assumptions 7.7 months in treatment arm 5.0 months in placebo arm Hazard ratio = 0.65 Interim Analysis Triggered with ~ 154 OS events DMC to review and determine: Efficacy stop No futility stop Continue trial Minimal alpha spend Anticipated by early Q2 16 Enrollment Completed 22

23 Tivantinib Financials Daiichi Sankyo Partnership¹ Costs of development are shared 50/50; however, Daiichi is responsible for all phase 3 costs and ArQule reimburses only if milestones and royalties are realized ArQule has received a total of $100 million in upfront and milestone payments from Daiichi and currently owes $59 million for its share of the phase 3 trial Potential for up to an additional approximated $500 million in development and sales milestones Upon commercialization, ArQule will receive tiered, double-digit royalties, starting at 20%, on net sales of tivantinib and has a co-commercialization option in the U.S. Daiichi pays all costs of commercialization, including costs of an ArQule salesforce Kyowa Hakko Kirin Partnership² All development and commercial costs are borne by KHK ArQule has received a total of $48 million in upfront and milestone payments from KHK Potential for up to an additional $75 million in regulatory milestones plus undisclosed sales milestones Upon commercialization, ArQule will receive tiered royalties in the mid-teen to low-twenty percent range on net sales of tivantinib ¹ Development and Commercialization partnership with Daiichi Sankyo for U.S., Europe, South America, and rest of world. ² Development and Commercialization partnership with Kyowa Hakko for Japan, and select Asian countries. 23

24 Proprietary Pipeline Pre-Clinical Phase 1a/1b Phase 2 Phase 3 ARQ 087 FGFR ARQ 092 AKT ARQ 751 AKT ARQ 761 NQ01 Intrahepatic Cholangiocarcinoma (icca) Solid Tumors Solid Tumors/lymphoma/ endometrial cancer Proteus syndrome Other Rare Diseases Cancer/ Rare Diseases Solid Tumors/Pancreatic Cancer 24

25 Proprietary AKT Program Therapeutic Area Pre-Clinical Phase 1a/1b Phase 2 Phase 3 ARQ 092 AKT Oncology Rare Diseases Solid Tumors fully enrolled Lymphoma fully enrolled Endometrial cancer Proteus syndrome Other Rare Diseases ARQ 751 AKT Oncology Rare Diseases Cancer Rare Diseases Pursuing a multiple AKT inhibitor strategy to address a broader range of therapeutic needs 25

26 ARQ 092 and AKT1 Mutation ARQ 092 suppresses the AKT pathway via two modes of action 1) By binding to the inactive form of AKT, ARQ 092 prevents membrane localization and full AKT activation 2) ARQ 092 also directly inhibits the membrane associated active form of AKT Potential dual mechanism of action 26

27 AKT1 Mutation Publications Publications support AKT1 as a target in oncology and Proteus syndrome Sources: N Engl J Med : , August 18, Nature. 448: , July, 26, PLoS ONE 10(10): e doi: /journal.pone Scientific Reports DOI: /srep

28 ARQ 092- Selective AKT Inhibitor ARQ 092 is an orally available, selective, pan-akt inhibitor that demonstrates potent inhibition with IC 50 values in the low nanomolar range for AKT1, 2, and 3 Kinase profiling showed that ARQ 092 is highly selective with IC 50 values below 1 µm for only five other kinases; moreover ARQ 092 was much more potent against AKT1 (26 to 162 fold) in comparison to those other kinases 28

29 ARQ Inhibits AKT1-E17K ARQ 092 inhibits p-akt(s473) phosphorylation in both mutant AKT1-E17K and the wild-type form of AKT 29

30 ARQ Potential Inhibitor PIK and AKT mutations are possible predictive biomarkers for ARQ 092 Inhibition of tumor growth and downstream signaling in vivo in tumors with dysregulated PI3K/AKT pathway In vivo activity in models with AKT1-E17K and PIK3CA mutations PIK3CA Mutation AKT1-E17K Mutation 30

31 ARQ 092 Oncology Phase 1a Phase 1a completed with 82 patients treated in three dosing schedules Recommended phase 2 dose established for continuous (60 milligrams daily), intermittent (200 milligrams daily every other week) and weekly dosing (600 milligrams once a week) schedules Generally well tolerated with hyperglycemia, rash, mild liver function impairment and stomatitis as more frequent adverse events Safety profile differentiated from other AKT inhibitors in the clinic; hyperglycemia precedes rash Pharmacodynamics show correlation between blood sugar, insulin and drug levels Efficacy: PR observed in patient with small lymphocytic lymphoma (SLL) with a PI3K mutation and minor responses seen in breast and endometrial cancers 31

32 ARQ 092 Patient PR Phase 1a Baseline 4 Months Subject was a 70-year-old white male with chronic lymphocytic leukemia /small lymphocytic lymphoma and PIK3CA and PIK3R1 mutations, diagnosed in 2002, received 5 lines of prior therapy The patient s tumors had 49% and 53% reductions after 8 and 16 weeks on study treatment, and progressed after 32 weeks on study treatment 32

33 ARQ 092 Oncology Phase 1b Three cohorts: Lymphoma (fully enrolled) Endometrial tumors (fully enrolled) AKT (AKT1 E17K) and PI3K (PIK3CA H1047R) activating mutations in solid tumors Dosing: 200 milligrams daily every other week for solid tumors and 600 milligrams once a week for lymphomas Preliminary efficacy: Lymphoma (n=8): 2 PRs observed in heavily pretreated Follicular lymphoma (1 with AKT1 E17K mutation and one unknown) Endometrial (n=10): 2 PRs observed (1 with PIK3CA H1047R mutation and one AKT1 E17K mutation) AKT1 E17K mutation and PIK3CA H1047R (n=9): 1 PR in breast cancer and 1 MR in a parotid gland tumor Continue to enroll patients in AKT and PI3K activating mutations in solid tumors 33

34 Total Oncology PRs for ARQ 092 ARQ 092 Phase 1a Trial Disease Mutation Best ORR Dose Escalating Trial (n=82) ARQ 092 Phase 1b Trial (3 Expansion Cohorts) Lymphoma Cohort (n=8, fully enrolled) Lymphoma Cohort (n=8, fully enrolled) Endometrial Cohort (n=10, fully enrolled) AKT and PI3K Mutation Cohort (n=9 evaluable) Endometrial Cohort (n=10, fully enrolled) Small Lymphocytic Lymphoma PR = Partial Response defined as at least 30% shrinkage in tumor PIK3CA+PIK 3R1 Disease Mutation Best ORR Duration on trx (weeks) PR 32 Duration on trx (weeks) Follicular Lymphoma AKT1 E17K PR 17 Follicular Lymphoma Unknown PR 60+ Endometrial PIK3CA H1047R PR 30 Breast AKT1 E17K PR 12 Endometrial AKT1 E17K PR 8 Continuing to enroll patients in P1b trial while assessing next steps 34

35 ARQ 092 Patient PR Phase 1b Baseline Week 8 Subject was a 46 years old Caucasian female with breast cancer (ER+, PR+, Her2-) diagnosed in 2002 She had received 5 lines of prior systemic therapies; her tumor had AKT1 E17K mutation PR was observed after 8 weeks on study treatment; the patient was taken off study due to increased ascites although her target lesions were stable at that time 35

36 About Proteus Syndrome According to the patient advocacy and support group, the Proteus Syndrome Foundation ( the condition was named for Proteus, the Greek god who could transform his shape Patients experience changes in the shapes of certain body structures over time, including abnormal, often asymmetric, massive growth (overgrowth) of the skeleton, skin, adipose tissue and central nervous system out of proportion to the rest of the body which may appear normal 36

37 Proteus Syndrome Patients Proteus syndrome is a rare disorder and an orphan disease (incidence <1 in 1 million people worldwide) Only a few hundred individuals have been reported in medical literature Approximately 50 patients are being actively followed by the NIH in a longitudinal study with the total patient population estimated to be 100 to 200 in the U.S. Patient registries are available in some European countries where advocacy groups are also active Although patients may have minimal or no manifestations at birth, the disease develops and becomes apparent in early childhood (6-18 months) and rapidly progresses with intense growth in the first 10 years of life Very few patients reach adulthood Causes of death for Proteus syndrome patients are bullous lung degeneration, deep vein thrombosis, pulmonary embolism and more rarely cancer Currently the only available therapeutic intervention for Proteus syndrome is surgery, which is problematic and characterized by poor wound healing; symptomatic removal of lesions does not arrest continued overgrowth 37

38 AKT Pathway: Proteus Syndrome A landmark discovery by researchers from the National Human Genome Research Institute led by Dr. Biesecker demonstrated that a somatic mutation in the AKT1 oncogene, which carries the set of instructions to produce the AKT1 kinase, causes Proteus Syndrome Somatic mutations do not occur in germ cells (sperm and egg), and the genetic change leading to Proteus Syndrome is therefore not inherited but arises randomly during the early stages of development before birth A point mutation a single-letter misspelling in the DNA of the genetic code in the AKT 1 gene activates the tissue growth characteristic of Proteus Syndrome As cells continue to grow and divide, some cells will have the mutation and others will not; this mixture of cells with and without a genetic mutation is known as mosaicism ¹ ¹ N Engl J Med : , August 18,

39 ARQ 092 Proteus Syndrome Early in the development of ARQ 092, ArQule was contacted by the NIH team headed by Dr. L. G. Biesecker to explore the drug potential in Proteus syndrome Based on the subsequent preclinical work, Dr. Biesecker and his NIH team concluded: ARQ 092 targets the constitutive activation of AKT1 that is caused by the p.glu17lys activating mutation and the p.h1047r mutation of PROS This effect can be demonstrated in cell lines derived from patients with these disorders and in tissue from biopsies The effect of ARQ 092 on PS is distinct from that of everolimus, supporting an approach of specifically targeting that mutation, as opposed to the pathway more generally Human trials are warranted to test the efficacy of ARQ 092 and a Phase 1 trial is ongoing Sources: N Engl J Med : , August 18, 2010.; Biesecker, L.G. et al. ASHG

40 ARQ 092 Proteus Trial Design On-going NIH sponsored Phase 1 study A 3+3 Phase 1 dose escalation design Continuous dosing based on preclinical and oncology clinical data Safety and percent inhibition of pakt will be analyzed after completion of each dose level prior to determining the need for a dose escalation to the next dose level Objectives Safety and tolerability Tissue pakt inhibition and ARQ 092 concentration Change in Proteus syndrome symptoms Imaging Photography Quality of life and patient reported physical functioning Phase 1 trial enrolling first cohort enrolled Orphan drug designation granted by FDA 40

41 ARQ 092 Other Rare Diseases Currently exploring opportunities for ARQ 092 in other rare diseases with dysregulation of the PI3K/AKT pathway Cloves syndrome Cloves - (Congenital, Lipomatous, Overgrowth Vascular malformations, Epidermal nevi and spine/skeletal anomalies and/or Scoliosis Only treatment option is surgery Cowden syndrome A disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers Only treatment is regular screening of tumors for cancer 41

42 PI3K/AKT/mTOR in Rare Diseases CLOVES/PROS PI3K Cowden syndrome PHTS PTEN Shp2 deficient (PTPN11 Y297C ) AKT Proteus syndrome LEOPARD syndrome mtor 42

43 ARQ Next-Generation AKT ARQ 751 is an orally available small molecule, next generation AKT inhibitor Diversified portfolio of AKT inhibitors might provide us the opportunity to best address oncology and rare diseases Plan to begin clinical trials in first half of 2016 in oncology Pre-clinical profile for ARQ 751 defines a highly potent and highly selective molecule 43

44 ARQ 087 Potent FGFR Inhibitor Multi-kinase inhibitor that potently inhibits FGFR with demonstrated efficacy in FGFR2 amplified tumors Clean ADME profile, good oral bioavailability and drug-like properties Clinical responses observed in intrahepatic cholangiocarcinoma (icca) patients with FGFR2 fusions Phase 2 patient selection strategy for icca that may provide rapid path to approval Biochemical IC 50 (µm) In Vitro PD (p-fgfr) EC 50 (µm) FGFR1* FGFR2* FGFR3* FGFR3 (K560E)* FGFR3 (K560M)* FGFR4* Kato-III SNU K i (µm) FGFR1 FGFR ARQ 087 FGFR inhibition profile *Data generated using kinase assays at Carna Biosciences Experiments done using active forms of kinases 44

45 ARQ 087 Phase 1 Phase 1a completed, 60 patients treated, recommended dose established as 300 mg daily Safety profile differentiated from other FGFR inhibitors, no renal toxicities so far Preliminary single agent activity: confirmed stable disease > 16 weeks in 10 of 57 subjects in dose expansion cohorts, including two adrenocortical tumors Increased FGFR levels identified as a potential surrogate marker, evaluation of other biomarkers ongoing Treated 12 icca patients (5 FGFR2 fusions, 1 unknown mutation, and 6 non FGFR mutations) and observed positive activity in all five FGFR2 fusions Initiated phase 1b portion with a patient selection strategy, at the recommended phase 2 dose, defined to provide rapid POC; currently focusing on adrenocortical tumors and those with FGFR fusions, amplification and mutations Phase 1b portion of the trial ongoing; one partial response observed in advanced bladder cancer with FGFR2 aberration 45

46 ARQ 087 FGFR Responses Trial Cancer Type FGFR Status # of Prior Therapies Treatment Duration Best Response/ Change in Tumor Size Phase 1a icca Not Tested 1 9 weeks SD/+16% Phase 1a icca FGFR2 KIAA weeks PR/-32% Phase 1a icca FGFR2 BICC weeks PR/-35% Phase 1a icca FGFR2 BICC1 2 8 weeks SD/+16%* Phase 1a icca FGFR2 TACC1 2 8 weeks SD/0%* Phase 1a icca FGFR2 CCDC weeks MR/-28% Phase 2 portion icca FISH positive 1 Ongoing MR/-18% Phase 1b Bladder FGFR2 Genetic Alteration 3 ongoing PR/-38% * Target lesion stable but new lesions detected PR = Partial Response defined as 30% shrinkage in tumor; MR = Minor Response defined as 15-30% shrinkage in tumor; SD = Stable disease Phase 2 for icca enrolling patients with FGFR alterations 46

47 ARQ 087 icca Patient in P1a 1 st Scan 2 nd Scan 3 rd Scan Patient in phase 1a trial with intrahepatic cholangiocarcinoma (icca) FGFR2 BICC1 translocation, treatment-naïve Partial Response: C3D1 35% tumor shrinkage after two cycles of treatment 47

48 ARQ 087 icca Patient in P1a 1 st Scan 2 nd Scan Patient in phase 1a trial with intrahepatic cholangiocarcinoma (icca) that spread to the lung Patient with FGFR2 CCDC6 translocation, having received one prior treatment Minor Response: C3D1 28% tumor shrinkage after two cycles of treatment 48

49 ARQ 087 Phase 2 for icca Objectives Further explore positive responses observed in Intrahepatic Cholangiocarcinoma (icca) FGFR2 fusions in phase 1a portion of the trial and potential expedited path forward Determine Overall Response rate and response duration in icca with FGFR2 fusions Design A cohort of up to 20 (icca) patients with known fusions will be enrolled Secondary endpoints Tumor marker changes, safety and pharmacokinetics in this population Progression Free Survival FGFR-related markers Orphan drug designation granted by FDA 49

50 ARQ 761 NQO1 Inhibitor ARQ 761 is an NQO1 inhibitor with the potential to enhance the effect of chemotherapy and other cancer therapies NQO1 is over-expressed in many cancers ~90% of pancreatic and NSCLC cancers: fold ~60% of breast, prostate and colon cancers: 5-20 fold NQO1 as a key target in rapid, selective tumor cell death More than 50+ peer-reviewed publications supporting all aspects of mechanism NQO1 over-expression within the tumor drives rapid H ² O ² production via bioamplification Normal detoxification function of NQO1 is hijacked into futile redox cycle, amplifying drug concentration 100x in 2 minutes Normal cells unaffected due to little NQO1 expression are protected by high catalase levels, which scavenge H ² O ² 50

51 ARQ 761 Clinical Trials Collaboration with the University of Texas Southwestern Medical Center where trials are funded by our partner ARQ 761 is an intravenously administered prodrug of β-lapachone Activity has been demonstrated in vitro and vivo testing against a wide range of tumors Phase 1a testing with ARQ 761 identified anti-cancer activity as measured by tumor responses occurring exclusively in a portion of the patient population with high levels of NQO1 Phase 1b cohorts are focusing on patients with high levels of NQO1 in solid tumors Began recruiting in a Phase 1/2 trial in pancreatic cancer in combination with chemotherapy 51

52 Financial Profile Cash Balance Cash and marketable securities at December 31, 2015 $38.7 Mil 2016 Guidance Net use of cash Projected cash balance end of 2016* $23-25 Mil $29-31 Mil Shares Outstanding* ~71 Mil * Assumes completion of recent registered direct offering of common stock 52