A First-in-human, First-in-class, Phase I Study A First-in-human, First-in-class, Phase I Study

of Systemic Hedgehog Pathway Antagonist, of Systemic Hedgehog Pathway Antagonist,

GDC-0449, in Patients with Advanced Solid TumorsGDC-0449, in Patients with Advanced Solid Tumors

P.M. LoRusso, C.M. Rudin, M.J. Borad, L. Vernillet, W.C. Darbonne, P.M. LoRusso, C.M. Rudin, M.J. Borad, L. Vernillet, W.C. Darbonne,

H. Mackey, J.F. DiMartino, F.J. de Sauvage, J.A. Low, D.D. Von HoffH. Mackey, J.F. DiMartino, F.J. de Sauvage, J.A. Low, D.D. Von Hoff

Karmanos Cancer Institute, Wayne State University, Detroit, MI Karmanos Cancer Institute, Wayne State University, Detroit, MI

Johns Hopkins University, Baltimore, MD Johns Hopkins University, Baltimore, MD

Translational Genomics (TGen), Scottsdale Clinical Research Institute, Scottsdale, AZTranslational Genomics (TGen), Scottsdale Clinical Research Institute, Scottsdale, AZ

Genentech BioOncology, South San Francisco, CAGenentech BioOncology, South San Francisco, CA

Trial Sponsor: Genentech, Inc.Trial Sponsor: Genentech, Inc.

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Hedgehog Signaling Through Hedgehog Signaling Through PATCHED (PTCH) and SMOOTHENED (SMO)PATCHED (PTCH) and SMOOTHENED (SMO)

• NormalNormal– Axial Patterning Axial Patterning – AngiogenesisAngiogenesis– Branching morphogenesisBranching morphogenesis

• AbnormalAbnormal– CancerCancer– Growth abnormalitiesGrowth abnormalities

Inactive ReceptorInactive Receptor Ligand-dependent ActivationLigand-dependent Activation

• PTCH/GLI1PTCH/GLI1• IGFIGF• CyclinD1CyclinD1• Other Other GLIGLI target target

genesgenes

GDC-0449 inhibits SMO

GLI1GLI1

GDC-0449

GLI1GLI1

NoSignal

3Developed by Genentech under a collaboration agreement with Curis.Developed by Genentech under a collaboration agreement with Curis.

GDC-0449GDC-0449

• Small molecule, Small molecule, oraloral inhibitor of SMOOTHENED inhibitor of SMOOTHENED– IC50 in IC50 in GliGli-Luciferase assay = ~ 3 nM -Luciferase assay = ~ 3 nM – Preclinical pharmacokinetics favor once daily dosingPreclinical pharmacokinetics favor once daily dosing

GDC-0449Cyclopamine

O

HN

H

H

HO

H

H

H

4

GDC-0449 Phase 1 First-in-Human StudyGDC-0449 Phase 1 First-in-Human Study

• Primary objectivesPrimary objectives– Safety and tolerability in advanced solid tumor patientsSafety and tolerability in advanced solid tumor patients– Characterize PK profile Characterize PK profile

• Single oral dose Single oral dose • Continuous daily dosingContinuous daily dosing

– Identification of a phase II doseIdentification of a phase II dose

• Study designStudy design– 3+3 dose escalation phase 1 study3+3 dose escalation phase 1 study– Modified dose doubling until DLT or PK “futility”Modified dose doubling until DLT or PK “futility”– Safety expansion and advanced basal cell carcinoma cohorts Safety expansion and advanced basal cell carcinoma cohorts

enrolled after escalation phase completeenrolled after escalation phase complete

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Description of CohortsDescription of Cohorts

CohortCohort Dose Dose LevelLevel

N, EnrolledN, Enrolled(N, completing safety (N, completing safety assessment period*)assessment period*)

Tumor TypesTumor Types

11150 150

mg/daymg/day 7 (6)7 (6)Pancreatic (2), BCC, Cholangiosarcoma, Colorectal, Mesothelioma, Renal

22270 270

mg/daymg/day 9 (6)9 (6)Pancreatic (2), Adenocystic carcinoma, BCC, Bladder, Carcinoid, Endometrial, SCLC, Melanoma

33540 540

mg/daymg/day 3 (3)3 (3) Adenocystic carcinoma, BCC, Mesothelioma

*All patients discontinued prior to completing safety assessment period due to disease progression.*All patients discontinued prior to completing safety assessment period due to disease progression.

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Phase 1 Trial SchemaPhase 1 Trial Schema

…Day 1 8 15 22 29 36 43 50 57 64

Cohort 1150 mg/day

PK

PD

Cohorts 2 and 3270 and 540 mg/day

PK

PD

…

…

Restaging every 8 weeksweeks

GDC-0449 oral dosing

PK = PharmacokineticsPK = PharmacokineticsPD = Pharmacodynamics (skin punch biopsy and hair follicles)PD = Pharmacodynamics (skin punch biopsy and hair follicles)

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Single Dose Mean Plasma Single Dose Mean Plasma PK Profile of GDC-0449PK Profile of GDC-0449

Day of Study

GD

C-0

449

Mea

n P

lasm

a C

once

ntra

tion

(uM

) ±

SD

150 mg

540 mg

270 mg

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GDC-0449 Mean Plasma Concentrations GDC-0449 Mean Plasma Concentrations with Continuous Daily Dosingwith Continuous Daily Dosing

GD

C-0

449

Pla

sma

Con

cent

ratio

n (u

M)

± S

D

Day of Study

Predicted Minimum Efficacious Level (5 uM)

GDC-0449 administrationGDC-0449 administration

150 mg

540 mg270 mg

PD

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GLI1GLI1 Expression in Surrogate Tissues Expression in Surrogate Tissues

2-fold down-modulation

Fol

d m

o du l

a tio

n

Skin Punch BiopsiesSkin Punch Biopsies

Hair Follicle SamplesHair Follicle Samples

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Drug-Related Adverse EventsDrug-Related Adverse Events

150 mg150 mgN=7N=7

270 mg270 mgN=9N=9

540 mg540 mgN=3N=3

TotalTotalN=19N=19

AE (n) Gr 1-2 Gr 3 Gr 1-2 Gr 3 Gr 1-2

Dysgeusia 1 1 1 3 (15.8%)

Hyponatremia 2 2 (10.5%)

Fatigue 1 1 2 (10.5%)

Alopecia 1 1 (5.3%)

Anorexia 1 1 (5.3%)

Acneiform dermatitis

1 1 (5.3%)

Dyspepsia 1 1 (5.3%)

Nausea 1 1 (5.3%)

Skin exfoliation 1 1 (5.3%)

Weight loss 1 1 (5.3%)

As reported by 01 April 2008

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Metastatic and Locally Advanced Metastatic and Locally Advanced Basal Cell Carcinoma PatientsBasal Cell Carcinoma Patients

BaselineBaseline At 8 monthsAt 8 months

BaselineBaseline At 2 monthsAt 2 months

84 yo with BCC Lesion Invasive into 84 yo with BCC Lesion Invasive into Auditory CanalAuditory Canal

67 yo with BCC Metastatic to Lung, Liver, and Bone67 yo with BCC Metastatic to Lung, Liver, and Bone

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*Von Hoff, et al, AACR 2008, Abstract LB-138

Clinical ActivityClinical Activity

• 19 patients enrolled have been evaluated19 patients enrolled have been evaluated– 1 confirmed RECIST PR, BCC pt1 confirmed RECIST PR, BCC pt (150 mg qd), on study 487+ days (150 mg qd), on study 487+ days– 1 confirmed clinical PR, BCC pt1 confirmed clinical PR, BCC pt (270 mg qd), on study 297+ days (270 mg qd), on study 297+ days– 2 adenocystic carcinomas with SD2 adenocystic carcinomas with SD

• Salivary gland with lung mets (270 mg qd), 179 daysSalivary gland with lung mets (270 mg qd), 179 days• Sinus with local invasion (540 mg qd), 95 daysSinus with local invasion (540 mg qd), 95 days

• Duration on study (Cutoff date is 23 May 2008)Duration on study (Cutoff date is 23 May 2008)– Range from 11 days to 487+ days, median 50 daysRange from 11 days to 487+ days, median 50 days

• Results in a total of 9 Results in a total of 9 BCCBCC patients were reported at AACR 2008* patients were reported at AACR 2008*– 6 of 9 (67%) confirmed PR6 of 9 (67%) confirmed PR– 8 of 9 (89%) clinical benefit, with 2 SD of 120+ days8 of 9 (89%) clinical benefit, with 2 SD of 120+ days

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ConclusionsConclusions

• GDC-0449 has an unusual GDC-0449 has an unusual pharmacokinetic profilepharmacokinetic profile– High sustained micromolar plasma concentrations High sustained micromolar plasma concentrations – Long terminal half-lifeLong terminal half-life

• Dose-limiting toxicitiesDose-limiting toxicities were not seen with GDC-0449 were not seen with GDC-0449– Reversible grade 3 fatigue and asymptomatic hyponatremia reported Reversible grade 3 fatigue and asymptomatic hyponatremia reported

beyond the DLT windowbeyond the DLT window

• Objective responsesObjective responses seen in patients with basal cell carcinoma seen in patients with basal cell carcinoma

• Phase II studies using GDC-0449 at Phase II studies using GDC-0449 at 150 mg once daily150 mg once daily are are ongoing and planned in first-line metastatic colorectal cancer and ongoing and planned in first-line metastatic colorectal cancer and advanced BCCadvanced BCC