I ArQule 1. Pursuing treatments for biomarker-driven cancers and rare diseases June 2018

Transcription

1 I 1 Pursuing treatments for biomarker-driven cancers and rare diseases June 2018

2 FORWARD LOOKING STATEMENTS This presentation and other statements by contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act including, without limitation, statements with respect to current and proposed clinical trials with the Company s product candidates derazantinib (ARQ 087), miransertib (ARQ 092), ARQ 751, ARQ 761 and ARQ 531, financial operations and results, potential corporate partnerships as well as strategic objectives, business objectives, next steps, pipeline and other goals, projected inflection points, catalysts, market estimates and potentials, opportunities and other strategies. Forward-looking statements are typically identified by words such as believe, expect, anticipate, intend, outlook, position, goal 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 assumes no obligation to update them. Actual results may differ materially from forwardlooking statements or historical performance due to the factors discussed in this presentation and factors previously disclosed in 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. s product candidates are in various stages of development and are not available for sale or use outside of approved clinical trials. and the logo are registered trademarks of, Inc. 2

3 Experienced developer of novel kinase inhibitors Biomarker-driven discovery of precision medicines for cancer and rare diseases with potential for accelerated registration paths Four novel compounds in clinical development: Reversible BTK inhibitor that can overcome ibrutinib resistance fully owned Two AKT inhibitors for cancer and rare diseases fully owned FGFR inhibitor in a registrational trial for intrahepatic cholangiocarcinoma - partnered 3 I

4 Summary of Programs and Pipeline Goals Class Indications Current stage Target for next stage Western market potential (est.) ARQ 531 BTK inhibitor B-cell malignancies Phase 1a/b Registrational Large (and growing) blockbuster market potential MIRANSERTIB (ARQ 092) ONCOLOGY AKT inhibitor Endometrial cancer and other relevant solid tumors Phase 1b Phase 2/Registrational $500MM + in endometrial; blockbuster in other hormone sensitive tumors ARQ 751 Next generation AKT inhibitor Solid tumors Phase 1a Phase 1b Blockbuster potential in hormone sensitive tumors MIRANSERTIB (ARQ 092) RARE DISEASES AKT inhibitor Proteus syndrome PROS Phase 1/2 (Orphan and Rare Pediatric Disease Designation) Registrational Significant pricing leverage. Rare Pediatric Disease Voucher, if approved. DERAZANTINIB (ARQ 087) FGFR inhibitor icca (Intrahepatic cholangiocarcinoma) Registrational (Orphan Drug Designation) Conditional approval Partnered up to $400MM in regulatory and sales milestones plus royalties 4 I

5 Near-Term Catalysts ARQ 531 B-cell malignancies Miransertib Oncology ARQ 751 Oncology Miransertib Proteus/PROS Derazantinib icca 2018 Demonstration of clinical activity in B-cell malignancies and selection of Phase 1b dose (2H18) Announce expansion plan for endometrial program and other possible indications (4Q18) Demonstration of clinical activity in solid tumors with AKT/PI3K/PTEN genetic alterations and selection of Phase 2 dose (2H18) Publish case studies and results of the NIHsponsored Phase 1 trial in Proteus syndrome (2H18) Partnered with Roivant (2/2018) for greater China rights Initiate expansion phase of clinical trial in select tumor type(s) (4Q18) Commence registrational program in Proteus syndrome (2H18) Partnered with Basilea (4/2018) for global rights except Greater China 2019 Commence enrollment in Expansion cohort in select B-cell malignancy subgroup(s) (1Q19) Plan global registrational trial (2H19) Present data from Phase 1b expansion study in Endometrial cancer and announce plans for next stage of clinical testing Present data from Phase 1 trial and announce plans for next stage of clinical testing (1Q19) Announce clinical development plan and regulatory path in PROS (1H19) Basilea to pursue expanded development strategy Sinovant to initiate program in Greater China (1H19) 5I

6 ARQ 531 Reversible BTK inhibitor in B-cell malignancies 6

7 Targeting BTK in B-cell Malignancies B-CELL MALIGNANCIES CURRENT THERAPY & UNMET NEED ARQ 531 MARKET POTENTIAL B-Cell malignancies are a diverse group of diseases, including most non-hodgkin s lymphomas, some leukemias and myelomas, e.g. chronic lymphocytic leukemia (CLL) BTK is a component of the B-cell receptor (BCR) pathway BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion Ibrutinib and acalabrutinib are irreversible BTK inhibitors that covalently bind the catalytic site Long-term treatment with approved BTK inhibitors can lead to mutations, most notably C481S, which leads to resistance Reversible small molecule next generation BTK inhibitor targeting both WT and C481S-mutant BTK Potent, orally administered with predictable PK Currently in Phase 1 trial for B-cell malignancies Unique kinase profile, inhibits selected members of Trk, Src, Tec families More than 20,000 patients diagnosed with CLL in the US in % of CLL patients refractory to ibrutinib express the C481S mutation Potential to move into earlier lines of therapy and indications beyond CLL Potential market size: $1 billion + in CLL alone 7 I 1

8 ARQ 531 Addresses Treatment Resistant B-Cell Malignancies ARQ oral reversible inhibitor of both WT and C481S-mutant BTK ATP competitive inhibitor Non-covalent binding (reversible) Target patient population: 2 nd line B- cell malignancies, including CLL ARQ 531 Ibrutinib Covalent Interaction C481 C481 No interaction with C481 Binding mode of ibrutinib with BTK Binding mode of ARQ 531 with BTK 8 I

9 Vehicle 1 µm ARQ µm Ibrutinib Vehicle 1 µm ARQ µm Ibrutinib Vehicle 1 µm ARQ µm Ibrutinib ARQ 531 In Vitro Proof of Concept Both ARQ 531 and ibrutinib substantially decrease pbtk in wild type cells, but only ARQ 531 reduces pbtk in C481S BTK cells in vitro ARQ 531 inhibits Trk, Src, and Tec pathways providing potential expansion across multiple malignancies BTK Parental (BTK -/-) WT BTK C481S BTK pbtk(y551) Total BTK GAPDH 9 I IC 50 (nm) <1 nm 1-10 nm nm nm

10 ARQ 531 In Vivo Proof of Concept in a Mouse Model Comparative Survival Curves Compd. Vehicle Dose (QD), Cont. daily Median Survival 36 Days Ibrutinib 25 mg/kg 53 Days ARQ 531 ARQ mg/kg 75 mg/kg Not reached during treatment phase Not reached during treatment phase ARQ 531 is superior to ibrutinib in a TCL1 highly predictive transfer model of chronic lymphocytic leukemia (CLL), a B-cell malignancy 10 I

11 Phase 1a Dose Escalation for Refractory B-cell Malignancies Phase 1a Trial Key Objectives: Establish safety of ARQ 531, PK/PD measures and recommended Phase 2 dose Location: 2-4 sites in U.S. with the Ohio State University as the lead Design: 3+3 dose escalation Enrollment: B-cell malignancy patients refractory to any B- cell therapy, including but not limited to ibrutinib. IND cleared by FDA in April 2017 and 1 st patient dosed in July Target Population: Patients with relapsed and refractory CLL, Mantle cell, Waldenstrom s macroglobulinemia and B-cell non- Hodgkin s lymphoma ClinicalTrials.gov Identifier: NCT Planned dose escalation Planned Dose Escalation Cohort 7: 65 mg QD Cohort 6: 45 mg QD Cohort 5: 30 mg QD Cohort 4: 20 mg QD Cohort 3: 15 mg QD Cohort 2: 10 mg QD Cohort 1: 5 mg QD RP2D 11 I

12 Mean AUC-last (h*nm) Mean Half-time hours ARQ 531 Phase 1 Dose Escalation Interim Data (ASCO ) 1 st 3 cohorts of dose escalation (5, 10, 15mg) presented Low dose cohorts exhibited expected PK Well tolerated at all dose levels; no grade 3 AEs Dose proportional PK; half life supports once a day dosing Multiple demonstrations of dose-proportional target engagement (pbtk) and B-Cell function inhibition (CCL3) Expected exposure range of cohorts 4-7 Promising activity despite dosing below anticipated efficacy range Dose Proportional PK and Steady Half Life Promising Activity at Sub-Therapeutic Dosing Dose Diagnosis Prior Treatments Max Tumor Reduction Patient 1 5 mg Grade 3 FL 3 35% Patient 2 10 mg Grade 3 DLBCL 1 33% 12 I 0 Cohort 1 (5mg) Cohort 2 (10mg) AUC(h*nM) 1. Woyach J et al, EHA Congress 2018 t(1/2) H Cohort 3 (15mg) 0 Patient 3 15 mg CLL w/ C481S 5 (incl. ibrutinib + venetoclax) 29%

13 Phase1b Open Label, Multicenter, study of ARQ 531 in Patients with R/R B-cell malignancies Dose Expansion Key Objectives: To determine safety, tolerability and anti-cancer activity Dose Level: Recommended dose based on Phase 1a Enrollment: An additional patients; multiple cohorts (i.e., CLL patients with C481S-mutant) RP2D Phase 1b/II Expansion CLL NHL BTK C481S mutant Richter s syndrome DLBCL CNS Lymphoma FL WM MCL 13 I

14 Miransertib & ARQ 751 Targeted AKT inhibitors in oncology 14

15 Targeting AKT in Oncology CURRENT THERAPY & UNMET NEED MIRANSERTIB ARQ 751 MARKET POTENTIAL Currently no approved AKT inhibitors AKT inhibitors in development, either single agent or in combination, show promise in a molecularly-defined patient population, e.g., breast, prostate and endometrial Small molecule pan-akt inhibitor Potent, orally administered with predictable PK Differentiated mechanism of action relative to other AKT inhibitors Binds to the inactive form of AKT preventing membrane localization and activation as well as binding to active form of AKT with direct inhibition Orally administered, next generation small molecule AKT inhibitor with predictable PK Designed to be more potent and selective than miransertib with a wider therapeutic index 3-5% of all cancers have mutations in AKT pathway 1 PIK3CA mutations present in 32% colon, 27% brain, 25% gastric tumors, 37% endometrial, 31% breast and 2-3% prostate cancers 2,3,4 PTEN loss or mutation in up to 59% of stage IV cancers 5 15 I 1 Yi, KH and Lauring, J, Oncotarget, 7(4): , 2016; 2 Millis SZ et.al. JAMA Oncol. 2016;2(12): ; 3 Samuels, Y et al. Science, 304(5670):554, 2004; 4 Sun,X et al. Anticancer Research, 2009;5(29): ; 5 Alfieri R. Giovannetti E, et al. Frontiers in Oncology, 7(710), 2017

16 Sensitivity (mm) Sensitivity (mm) AKT Mutations Are Present in Multiple Solid Tumors 3-5% of all cancers have mutations in AKT pathway 1 PTEN loss or mutated in up to 59% of stage IV cancers 2 PIK3CA mutations present in 32% colon, 27% brain, 37% endometrial, 31% breast, 25% gastric tumors and 2-3% prostate cancers 3,4 53% (25/47) of cell lines with PIK3CA/PIK3R1 mutations are miransertib sensitive 1 73% (33/45) of cell lines with PIK3CA/PIK3R1 mutations are ARQ 751 sensitive 1 Strong correlation of anti-proliferative activity of miransertib and ARQ 751 with PIK3CA/ PIK3R1 mutations (47%) 25(53%) 12(37%) 33(73%) 126(76%) 39(24%) 101(58%) 74(42%) GI 50 = >1 mm ARQ 092-PIK3CA/PIK3R1 Mutant ARQ 751-PIK3CA/PIK3R1 Mutant ARQ 092-PIK3CA/PIK3R1 WT ARQ 751-PIK3CA/PIK3R1 WT GI50 = <1 mm (47%) 25(53%) 12(37%) 33(73%) 126(76%) 39(24%) (58%) 74(42%) PIK3CA/R1- mutant GI 50 = >1 mm ARQ 092-PIK3CA/PIK3R1 Mutant ARQ 751-PIK3CA/PIK3R1 Mutant ARQ 092-PIK3CA/PIK3R1 WT ARQ 751-PIK3CA/PIK3R1 WT PIK3CA/R1- Wild type 16 I 0.01 GI50 = <1 mm 1 Yi, KH and Lauring, J, Oncotarget, 7(4): , 2016; 2 Alfieri R. Giovannetti E, et al. Frontiers in Oncology, 7(710), 2017; 3 Samuels, Y et al. Science, 304(5670):554, 2004; 4 Sun,X et al. Anticancer Research, 2009;5(29):

17 Tumor volume (mm 3 ) Tumor Volume volume (mm 3 ) 3 ) Miransertib targets PI3K Pathway Alterations in Endometrial Cancer Miransertib is a highly selective allosteric AKT inhibitor Miransertib suppresses PIK3CA/AKT1 mutant dependent kinase signaling and is efficacious in endometrial tumor models Kinase domain Miransertib PH domain Miransertib (µm) pakt (T308) pakt (S473) Endometrial PIK3CA mutant AN3CA cells Miransertib mm Miransertib (µm) pakt(s473) pakt(s473) NIH-3T3 cells ppras40 (T246) β-actin AKT(pan) AKT(pan) Mouse xenograft model of AN3CA cell line AKT1-E17K mutant harboring endometrial PDX model Kinase IC 50 (nm) Fold difference against AKT1 AKT1 5 AKT AKT MARK MARK MARK DYRK IRAK Haspin Selectivity profiling tested against a panel of 303 kinases at 5 μm miransertib. Offtargets with >50% inhibition were measured for IC 50. Days post treatment Control 50 mg/kg 75 mg/kg 100 mg/kg Days Days post post treatment 17 I Yu et al., PLoS one, 2015 Lapierre et al., J. Med. Chem, 2016

18 Miransertib Trial Design & Next Steps Phase 1b trial in endometrial cancer with AKT and PI3K mutations Phase 1b Combination Trial Anastrozole Arm Key Objectives: Safety, PK profile and clinical activity in endometrial cancer Location: U.S. MSKCC, NY Design: Open-label, interventional treatment with anastrozole Dosing: Recommended Phase 2 dose 150 mg 5 days on 9 days off in combination with 1 mg daily of anastrozole Preliminary Results and Next Steps Signs of efficacy as a single agent Endometrial: 10% RR and 70% disease control rate in molecularly defined population Signs of activity in combination with anastrozole Endometrial 50% RR (best response) and 75% disease control rate in molecularly selected population Enrollment: Up to 25 patients Target Population: Patients with endometrial cancer with AKT and/or PI3K activating mutations ClinicalTrials.gov Identifier: NCT Next Steps: Publish data from completed Phase 1 single agent trial Expand anastrozole combination study in endometrial cancer Plan to initiate registrational study in I

19 Miransertib Phase 1b Interim Trial Results 1 Best % Change Tumor Size Interim data from Phase 1b trial of miransertib in combination with anastrozole in ER+ pts with endometrial or ovarian cancer harboring PIK3CA or AKT mutations Primary endpoint: safety and tolerability of miransertib and anastrozole combination therapy Secondary endpoint: PK, preliminary activity, determine Phase 2 dose Best % Change CA125 from Baseline Study Schema PK exposure in expected efficacious range Best tumor responses in serous endometrial cancer 19 I 1. Mekkler V et al, AACR Congress 2018 Continuation dose selected: 150mg miransertib + 1 mg anastrazole

20 Tumor volume (mm 3 ) Tumor Volume (mm3) Vehicle control ARQ 751 Second Generation AKT Inhibitor Targeting PI3K/AKT mutations ARQ 751 is a highly selective allosteric AKT inhibitor ARQ 751 demonstrates potent anti-tumor activity in PI3K/AKT driven tumors PH domain Potent inhibition of AKT and downstream signaling in AN3CA mouse xenografts Inhibition of phosphorylation of AKT1- E17K fused to GFP in NIH-3T3 cells Kinase domain ARQ 751 pakt(t308) pakt(s473) ARQ (mg/kg) pakt(s473) [ARQ 751] (nm) AKT ppras40 AKT(pan) PRAS40 Binding model based on the crystal structure of Miransertib/AKT Inhibition of tumor growth in AN3CA mouse xenografts Tumor growth inhibition in AKT1-E17K mutant harboring endometrial PDX model Untreated control 5 mg/kg 10 mg/kg 20 mg/kg 40 mg/kg 80 mg/kg 120 mg/kg Control 25 mg/kg 50 mg/kg 75 mg/kg Days post treatment Days post treatment 20 I >50% Inh <30-50% Inh

21 ARQ 751 Trial Design & Next Steps Phase 1a/1b trial in solid tumors with AKT, PI3K and PTEN mutations Phase 1a/1b Trial Key Objectives: Establish safety of ARQ 751, PK/PD measures, recommended Phase 2 dose and preliminary efficacy Location: MD Anderson Cancer Center, Houston TX Design: open-label, single group assignment dose escalation study Enrollment: 100 patients Target Population: patients with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTENnull or other known actionable PTEN mutations ClinicalTrials.gov Identifier: NCT Phase 2 Trial Key Objectives: Efficacy of ARQ 751 Dose Level: Recommended Phase 2 dose Enrollment: Molecularly defined patient population Next Steps: Complete and present Phase 1a trial with results in 2H 2018 Initiate Expansion cohort in 2H 2018 Proceed to Phase 2 trial 2H I

22 Miransertib AKT inhibitor in rare overgrowth diseases, including Proteus syndrome 22

23 Targeting AKT in Rare Overgrowth Diseases, Including Proteus Syndrome OVERGROWTH DISEASES CURRENT THERAPY & UNMET NEED MIRANSERTIB MARKET POTENTIAL Group of diseases characterized by excessive aberrant, asymmetric growth of bones, skin and other tissues Manifests in early childhood Proteus syndrome caused by mosaic mutation in AKT1 gene Other overgrowth diseases harbor PI3K mutations and are classified as PROS Currently no approved medicinal treatments for PROS or Proteus syndrome Standard of care relies on minimizing symptoms (e.g. physical therapy and surgery) Small molecule pan-akt inhibitor Potent, orally administered with predictable PK Different mechanism of action than other AKT inhibitors Completed Phase 1 trial for Proteus syndrome Significant pricing power in ultrarare indications Rare Pediatric Disease Voucher, if approved 23 I

24 A Mutation in AKT1 Causes Proteus Syndrome Somatic mosaic mutation in the AKT1 oncogene causes Proteus syndrome (PS) Non-inherited mutation arises randomly during early stages of development before birth Single point mutation in AKT1 gene causes tissue overgrowth characteristic of PS Mortality of 25% by age 22 Currently no approved treatments Clinical Manifestations of the Proteus syndrome in a 12-Year-Old Boy. Identification of underlying mutation allows for development of molecularly targeted treatments A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome Marjorie J. Lindhurst, Julie C. Sapp, Jamie K. Teer Leslie G. Biesecker 24 I

25 Miransertib First generation pan-akt inhibitor Potent, orally active, small molecule allosteric inhibitor of AKT Dual mechanisms of action 1. Binds inactive AKT: prevents membrane localization and activation 2. Binds membrane associated active AKT: direct inhibition 25 I Adapted from

26 Trial Design & Next Steps Phase 1/2 trials for Proteus syndrome and PROS NIH Sponsored Phase 1 Trial Key Objectives: Establish PK, safety and percent inhibition of p-akt Location: U.S. Design: 3+3 dose escalation, continuous dosing Enrollment: 6 patients (3 adult males in 1 st cohort, 3 children ages in 2 nd cohort) Target Population: Patients with Proteus syndrome Results: Inhibited AKT signaling in 5 out 6 patients Disease modification observed in cerebriform connective tissue nevus (CCTN) Improved pain scores and stabilized bone growth Safety profile acceptable Similar PK to miransertib in oncology Sponsored Phase 1/2 Expansion Trial Key Objectives: Externally validate (NIH) clinical proof of concept in Proteus syndrome and demonstrate clinical activity in PROS Location: U.S. & E.U. Design: Dose as determined in NIH trial (15-25 mg/m 2 ) Enrollment: up to 40 patients Target Population: Proteus and PROS; ages 2+ ClinicalTrials.gov Identifier: NCT Next Steps: Initiate global registrational program Seek regulatory feedback on path to approval Support Compassionate use program 26 I Compassionate use program in several countries

27 Derazantinib FGFR inhibitor in registrational icca trial 27

28 Targeting FGFR in Intrahepatic Cholangiocarcinoma (icca) icca CURRENT THERAPY & UNMET NEED DERAZANTINIB MARKET POTENTIAL Intrahepatic cholangiocarcinoma: cancer of the biliary tract Incidence of 1 in 100,000 in Western populations 1 Activating FGFR fusion mutation biomarker is present in 15-20% of cases 2 Surgical intervention is the only curative option: Only suitable in 30-40% patients Median disease free survival of ~26 months; 5 year survival rate of 20-40% Non-resectable: Fluoropyrimidinebased or gemcitabine-based chemotherapy, clinical trial, or supportive care 3 Chemotherapy shows ORR of <8% and median PFS of 2-3 months 4 Selective and potent fibroblast growth factor receptor (FGFR) inhibitor Expected to be active in tumors positive for FGFR fusion mutation biomarker Potent, orally administered Potential indications for FGFR driven cancers Currently in registrational trial for icca Partnered up to $400MM in regulatory and sales milestones plus royalties royalties 28 I 1 Antwi et. al. Annals of Hepatology March-April, Vol. 17 No. 2, 2018: ; 2 Based on data from the company s phase 1/2 clinical trial in icca; 3 From NCCN Guidelines Version ; 4 Lamarca et. al. Annals of Oncology, 25: , 2014

29 Trial Design & Next Steps Clinical trial for derazantinib as 2 nd line treatment for FGFR2 fusion icca patients Registrational Trial Key Objectives: Demonstrate efficacy of derazantinib as measured by objective response rate, progression free survival, overall survival, and duration of response. Safety of derazantinib as assessed by adverse events. Location: 16 sites, 8 in U.S. & 2 in Canada, 6 in Italy Design: Open-label single arm; trial designed with FDA and EMA feedback Enrollment: Estimated 100 participants, recruiting Target Population: 2 nd line patients with FGFR2 gene fusion positive inoperable or advanced icca ClinicalTrials.gov Identifier: NCT Preliminary Results and Next Steps Results from Phase 1/2 Trial: Achieved 21% response rate (3x rate observed with chemotherapy, 7.7 %1 ) Achieved 83% disease control rate Shows best-in-class safety profile with continuous oral QD dosing schedule* and low discontinuation rate due to AEs Patients still on treatment and overall duration of treatment will continue to improve Next Steps: Interim data readout from registrational trial expected in 2019 Potential to apply for Breakthrough Therapy designation following interim data readout Conditional approval pending the initiation of a confirmatory trial 29 I * Data as of September Lamarca et. al. Annals of Oncology, 25: , 2014

30 (NASDAQ: ARQL) Financial Profile Common Stock O/S as of June 5, 2018 ~95.6 M Market Cap as of June 5, 2018 market close $497.1 M Cash & Marketable Securities as of December 31, 2017 $48.0 M Net Use of Cash annual usage $27-29 M Projected Cash & Marketable Securities* at December 31, 2018 $40-42 M *Reflects impact of derazantinib licensing transactions with Basilea and Roivant. Cash to fund operating expenses into I

31 s Experienced Management Team PAOLO PUCCI Chief Executive Officer PETER S. LAWRENCE President & Chief Operating Officer BRIAN SCHWARTZ, MD Chief Medical Officer ROBERT J. WEISKOPF Chief Financial Officer Current management team has been leading for a decade. 31 I

32 Pursuing treatments for biomarkerdriven cancers and rare diseases. Thank You 32