Mansoor Saleh (1), Kyri Papadopoulos (2), Alireza Arabnia (1), Amita Patnaik (2),

Robin M. Stein (1), Federica Cattaneo (3), Giovanni Abbadessa (3),

Jonathan Greenberg (4), Steven Warren (4), and Anthony Tolcher(2)

(1) Georgia Cancer Specialist Affiliated with Northside Hospital Cancer Institute, Atlanta, GE, USA(2) South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio, TX, USA(3) ArQule, Inc., Woburn, MA, USA(4) Daiichi Sankyo, Edison, NJ, USA

First in Human Study with ARQ 092, a Novel Pan AKT-Inhibitor: Results from the Advanced Solid Tumors Cohorts

DISCLOSURES

Speaker Bureau for Novartis, Roche/Genentech, Bristol Myers Squibb

AKT Signal Transduction Is a Critical Node Serving a Variety of Cellular Functions Including Survival, Proliferation and Protein Synthesis

AKT SIGNALING PATHWAY IS A THERAPEUTIC TARGET IN ONCOLOGY

• AKT signal pathway is aberrantly dysregulatedin a wide range of tumor types

• Extensive molecular evidence validates thepathway as target in cancer

Vivanco I et al., Nat Rev Cancer, 2:489-501, 2002

Meric-Bernstam and Gonzalez-Angulo, J Clin Oncol 2009

Co-crystal X-Ray Structure, Biochemical and Anti-Proliferative Properties of ARQ 092ARQ 092 IS A NOVEL, ATP-INDEPENDENT, SELECTIVE PAN-AKT INHIBITOR

ARQ092 inhibits AKT in an ATP-independent manner and binds to the Pleckstrin Homology Domain, preventing ATP from being allocated

Biochemical Assay IC50 (nM)

In Vitro IC50 (µM)

AKT1 AKT2 AKT3A2780*Ovary

AN3-CA*Endom

LNCaP*Prostate

ZR-75-1*Breast

BT-474**Breast

2.9 9.3 17 0.73 0.62 0.91 4.2 1.3

8 12 65 3.85 0.55 1.18 4.07 1.54

ARQ 092

-

ATP

-

-

PHD

-

ATP pocketATP pocket

ARQ 0921

MK-2206 2

1Chan T. et al., AACR 2011, Abstract Number A2302Yan L. et al., AACR 2009: Abstract Number: DDT01-1

*PTEN deficiency ** PI3KCA mutation

Strong Antitumor Activity in the AN3-CA (PTEN-Deficient) Xenograft Model IN VIVO ACTIVITY OF ARQ 092

Days Post Implantation

Tum

or W

eigh

t (m

g)

8 hrARQ 092 100 mg/kg Q1Dx10

Vehicle

ARQ 092 150 mg/kg Q1Dx8

ARQ 092 50 mg/kg Q1Dx10

ARQ 092 200 mg/kg Q2Dx5

Chan T. et al., AACR 2011, Abstract A230

8 hr

8 hr8 hr

0 hr

0 hr

S473pAKT

Thr246pPRAS40

11 13 15 17 19 21 23

-15%

-55%-60%

-74%

0

500

1000

1500

2000

2500

Tumor sample ICH before and after single dose of ARQ 092 at 200 mg/kg

Vehicle

Endpoints and EligibilityARQ 092-101: FIRST IN HUMAN PHASE I STUDY

• Histologically/cytologically documented advanced/metastatic solid tumors in subjects who failed standard therapy

• ECOG PS ≤ 2• RECIST measurable disease

• Association between markers of the AKT signaling pathway, toxicity and clinical activity

• Changes in different pathways and potential combinations of interest

EXPLORATORY ENDPOINTS

KEY INCLUSION CRITERIA

Safety and tolerability in subjects with advanced

solid tumors

• Pharmacokinetic profile• Pharmacodynamic activity

(in blood and eventually in tumor) • MTD and RP2D• Preliminary evidence of activity

PRIMARY ENDPOINTS

SECONDARY ENDPOINTS

• History of Type 1 or 2 diabetes mellitus requiring regular medication (other than metformin)

• Hypercholesterolemia or hypertriglyceridemia > G2

• HbA1C >8%• LVEF < 50% by echocardiogram/MUGA scan• No previous treatment with AKT inhibitors • No cancer therapy within 4 weeks

(2 weeks for orally administered drugs)

• No major surgery or Rx tx within 4 weeks

KEY EXCLUSION CRITERIA

ARQ 092-101: STUDY DESIGN

• Open label • Cohorts 1-5: dose doubled• From cohort 6: modified Fibonacci

scheme (increase by 30% until RP2D) • 3+3* subjects per cohort (*if DLT)• Intra-subject dose escalation not allowed• Enrollment: November 2011 through

February 15th 2013, US

DOSE ESCALATION

Oral, once-daily ARQ 092, 28-day cycle

10 mg

QOD

10 mg QD

20 mg QD

40 mg QD

80 mg QD

60 mg QD

intermittent schedule

1,2 8 15,16 22 29 36 43 50 58 PK SAMPLING

TUMORASSESSMENT

DOSE

COHORT1 2 3 4 5 6 7

PD SCHEDULE

MTD IF ≤ 1 DLT OUT OF 6 TREATED SUBJECTS

• Standard DLT criteria•≥ G3 hyperglycemia -fasting blood glucose > 250 mg/dL or non-fasting > 500 mg/dL- requiring insulin (uncontrolled with metformin)

DLT if occurrence within the first cycle of:

Cycle 1: DLT window Cycle 2

ARQ 092-101: BASELINE SUBJECTS CHARACTERISTICS

All n=28

Median Age, yrs 62.0 (46-79)Male/Female, n (%) 9/16 (36/64)ECOG PS 0/1/2, n 10/13/2 (40/52/8)Median number of prior antineoplastic regimens (range) 4 (1-10)Patients with ≥ 3 prior regimens, n (%) 18 (72)Primary tumor type, n (%)

Uterine, n (%) 6 (21.4)Colon, n (%) 5 (17.8)NSCLC, n (%) 2 (7.1)Prostate, in (%) 2 (7.1)Bladder, n (%) 2 (7.1)Other*, i n (%) 11 (39.2)

*Includes meningioma, breast, sarcoma, melanoma, esophagus, ovary, head and neck, bronchial carcinoid, endocrine pancreas, neuroendocrine

Enrollment: November 2011- Ongoing, GCS (Atlanta) and START (San Antonio), 31 Subjects Screened, 28 Enrolled as of February 15th 2013

ARQ 092-101: TREATMENT-EMERGENT ADVERSE EVENTSDose-Specific Related and Unrelated AEs as of February 15th 2013

TEAEDOSE, mg/day Total

(n=28)Grades

10 QOD(n=4)

10(n=3)

20(n=3)

40(n=4)

60(n=7)

80(n=7)

FatigueAll (%) 2 (50.0) 1 (33.3) 2 (66.7) 1 (25.0) 2 (28.6) 4 (57.2) 14 (49.9)3-4 (%) 1 (25.0) 1 (14.3) 2 (7.1)

Decreased AppetiteAll (%) 2 (50.0) 1 (33.3) 2 (66.6) 3 (75.0) 1 (14.3) 3 (42.9) 12 (42.9)3-4 (%) 1 (14.3) 1 (3.6)

NauseaAll (%) 3 (100) 2 (66.6) 1 (25.0) 1 (14.3) 4 (57.1) 11 (39.3)3-4 (%) 1 (33.3) 1 (3.6)

DiarrheaAll (%) 2 (66.6) 2 (66.6) 1 (25.0) 1 (14.3) 2 (28.6) 8 (28.6)3-4 (%) 1 (33.3) 1 (33.3) 2 (7.1)

Weight DecreasedAll (%) 2 (50.0) 2 (66.6) 1 (33.3) 1 (25.0) 1 (14.3) 7 (25.0)3-4 (%) 1 (14.3) 1 (3.6)

HyperglycemiaAll (%) 2 (28.6) 4 (57.2) 6 (21.4)3-4 (%) 3 (42.9) 3 (10.7)

VomitingAll (%) 2 (66.6) 1 (25.0) 1 (14.3) 4 (14.3)3-4 (%) 1 (33.3) 1 (3.6)

Maculo-Papular RashAll (%) 3 (42.9) 3 (10.7)3-4 (%) 1 (14.3) 1 (3.6)

ARQ 092-101: DRUG-RELATED HYPERGLYCEMIA PRECEEDS RASH

#17 80 mgDiabetes Type II

Subject

G1 rash G2 rash G3 rash

Drugdosing

Drugholding

Med History

Daily Dose

#18 80 mg

G1 Intermittent

Hyperglycemia

#19 80 mg

#21 80 mg

#23 60 mgDiabetes Type II

100

150

200

250

300

0

50

100

150

200

40 mg

0

100

200

300

400

50

100

150

200

250

pre-visit wk 1 wk 2 wk 3 wk 4 wk 5 wk 7 wk 9

40 mg 20 mg

100

150

200

250

300

40 mg

Baseline

G3

G3

G2

G3

G2

G2

G3G2

G3

G2

G3

G3

DLT G3 Rash

DLT G3 Hyperglycemia requiring insulin

No Subject Discontinued Treatment Due to Rash

ARQ 092-101: DOSE-LIMITING TOXICITY

Daily Dose mg

Subjects Enrolled

n

DLT Recovery in 14 Days

Dose Reduction Tolerated

Reason for Discontinuation

80 mg QD

7

#15 G4 Congestive Heart Failure

(day 15)

NO NA DLT (off study wk 4)

#19 G3 Maculo-Papular

Rash (day 23)

YES (

40 mg QD (day 28)

PD (off study wk 24)

#21 G3 HyperglycemiaRequiring Insulin

(day 21)YES NA

InvestigatorDecision

(off study wk 5)

60 mg QD

7#24

G3 Increased AST(day 21)

YES .

40 mg QD (day 35)

Clinical Progression

(off study wk 8)

• MTD* for daily schedule was not formally declared*highest dose not causing DLT in >1 out of 6 patients during the first treatment cycle

• ARQ 092 has a manageable PK profile• Slow absorption, median Tmax range from 4-8 hrs for most subjects• Low clearance, mean half-life range from 19-53 hrs• Accumulation ratio (AUC C1Day15/ AUC C1Day1) range from 3-9• ARQ 092 exposure increased in an approximately dose-proportional fashion

ARQ 092-101: PHARMACOKINETIC PROFILE

0

200

400

600

800

1000

1200

1400

0 4 8 12 16 20 24

Time post- dose (hr)

1020406080

Dose (mg/day)

0

5000

10000

15000

20000

25000

30000

0 20 40 60 80

Dose (mg QD)

C1D15

Median

Mea

n A

UC

0-24

h(±

SD) (

h*nM

)

Mea

n Pl

asm

a Co

ncen

trat

ion

(±SD

)

Mean

C1D15

60

80

100

120

140

160

Subject Tumor typePRP pAKT

Baseline Day 15Decrease in PRP pAKT%

#17 Colon 23.8 11.6 -51.1#18 Uterine* 40.9 2.8 -93.3#19 Neuroendocrine** 24.3 2.1 -91.6#20 Colon 25.1 6.4 -74.7#21 Uterine₀ 24.5 4.9 -85.9#22 Uterine 24 8.6 -64.3#23 Uterine 10.2 3.3 -67.8

#24 Colon 12.1 5.6 -54.1

#26 Prostate 10.7 4.5 -57.9

ARQ 092-101: PHARMACODYNAMIC MARKERSP-AKT in Platelet Rich Plasma (PRP) Assay and Plasma Glucose Change

*On study > 6 months **On study for 6 months ₀ PTEN deletion

80 mg

Med

ian

Plas

ma

Glu

cose

Co

ncen

trat

ion

(mg/

dl)

Baseline

Week 3 (Day 21)

10mg QOD 10mg QD 20mg QD 40mg QD 60mg QD 80mg QD

60 mg

ARQ 092 PRELIMINARY ACTIVITY PROFILEEffect on Tumor Size in Evaluable Subjects

-30

-20

-10

0

10

20

30

40

50

60

70

80

Best

% c

hang

e fr

om b

asel

ine

Neuroendocrine EndometrialColonNSCLCBladderMelanoma EsophagusOvarian Sarcoma Meningioma

* Ongoing

#5 #4 #12 #20 #23 #11 #7 #22 #13 #2 #16 #6 #8 #19 #9 #10 #24 #3 #17 #18

**

n=20

ProgressionDisease

Stable Disease

°AKT1 mutation

°

ARQ 092-101: DURATION OF EXPOSURE (as of February 15th 2013)

Reason Off Study

• 28 subjects enrolled. 7 subjects on study ≥ 4 months; of them:- 4 subjects with long-term disease stabilization (≥ 6 months)- 1 subject on study for 13 months and ongoing

• 5 subjects ongoing (median 2 months)

0 8 16 24 32 40 48 56

Head and Neck Uterine

Prostate SNCLC Colon

UterineUterine

UterineColon

NeuroendocrineUterine

ColonMeningioma

Breast

Neck and headBladderOvarian

Sarcoma

NSCLCPancreas EndocrineBronchial Carcinoid

months

60mg QD

80mg QD

20mg QD

10mg QOD

*Congestive Heart Failure

*G3 Rash

PD

Clin ProgressPDPD

MD DecisionPDPDDeath AE: G3 Hyperglyc

AE: CHF

DeathPDPDPD

Clin Progress

Clin Progress

Dose Mg/Day

UterineEsophagus

Colon

MelanomaColon

BladderProstate

PDPDPD

PDPDPDPD

40mg QD

10mg QD

*G3 AST1 DLT

3 DLT

AKT1 mutation

*G3 Hyperglycemia; PTEN deletion

* DLTOngoingOff Study

2 4 6 8 10 12 14

ARQ 092-101: FIRST IN HUMAN STUDY IN ADVANCED SOLID TUMORS

• ARQ 092 has a safety profile consistent with that predicted by preclinical models

• Early hyperglycemia preceding rash might be a crucial differentiating feature of ARQ 092

• Drug exposure increases in a dose-dependent fashion

• Dose-dependent AKT pathway inhibition is obtained in peripheral blood

• MTD on a continuous daily schedule has not been formally declared

• Preliminary signals of single agent activity in patients with advanced solid tumors have beendocumented:- 4 heavily pretreated subjects experienced long-term (≥ 6 months) stable disease

• PK and clinical data support intermittent dosing schedules, currently planned in advancedsolid tumors and recurrent lymphoma

• Clinically valuable combinations with targeted agents in preclinical settings are warranted

ACKNOWLEDGEMENTS

Our heartfelt gratitude to the patients and their families

Georgia Cancer Specialists Affiliated with Northside Hospital Cancer Institute, Atlanta, GE, USA Alireza Arabnia, Mansoor Saleh, Robin M. SteinSouth Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio, TX, USA Elaine Golden, Kyri Papadopoulos, Amita Patnaik, Anthony TolcherArQule, Inc., Woburn, MA, USAGiovanni Abbadessa, Federica Cattaneo, Yinpu Chen, Beverly Fellows, Dora Ferrari, Maria Lamar, Ron Savage, Manish Tandon, Brian Schwartz, Yunxia Wang Daiichi Sankyo, Edison, NJ, USA Jonathan Greenberg, Jarema Kochan, Prasanna Kumar, Lori Varty, Steven WarrenCe3, Guilford, CT, USASusan Albert, Samira Ali