1. A First-in-human, First-in-class, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients with Advanced Solid Tumors 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 Hoff Karmanos Cancer Institute, Wayne State University, Detroit, MI Johns Hopkins University, Baltimore, MD Translational Genomics (TGen), Scottsdale Clinical Research Institute, Scottsdale, AZ Genentech BioOncology, South San Francisco, CA Trial Sponsor: Genentech, Inc.

2. 2 Hedgehog Signaling Through PATCHED (PTCH) and SMOOTHENED (SMO) NormalNormal – Axial Patterning – Angiogenesis – Branching morphogenesis AbnormalAbnormal – Cancer – Growth abnormalities Inactive Receptor Ligand-dependent Activation PTCH/GLI1PTCH/GLI1 IGFIGF CyclinD1CyclinD1 Other GLI target genesOther GLI target genes GDC-0449 inhibits SMO GLI1 GDC-0449 GLI1 No Signal

3. 3 Developed by Genentech under a collaboration agreement with Curis. GDC-0449 Small molecule, oral inhibitor of SMOOTHENEDSmall molecule, oral inhibitor of SMOOTHENED –IC50 in Gli-Luciferase assay = ~ 3 nM –Preclinical pharmacokinetics favor once daily dosing GDC-0449 Cyclopamine

4. 4 GDC-0449 Phase 1 First-in-Human Study Primary objectivesPrimary objectives –Safety and tolerability in advanced solid tumor patients –Characterize PK profile Single oral doseSingle oral dose Continuous daily dosingContinuous daily dosing –Identification of a phase II dose Study designStudy design –3+3 dose escalation phase 1 study –Modified dose doubling until DLT or PK “futility” –Safety expansion and advanced basal cell carcinoma cohorts enrolled after escalation phase complete

5. 5 Description of Cohorts Cohort Dose Level N, Enrolled (N, completing safety assessment period*) Tumor Types 1 150 mg/day 7 (6) Pancreatic (2), BCC, Cholangiosarcoma, Colorectal, Mesothelioma, Renal 2 270 mg/day 9 (6) Pancreatic (2), Adenocystic carcinoma, BCC, Bladder, Carcinoid, Endometrial, SCLC, Melanoma 3 540 mg/day 3 (3) Adenocystic carcinoma, BCC, Mesothelioma *All patients discontinued prior to completing safety assessment period due to disease progression.

6. 6 Phase 1 Trial Schema … Day181522293643505764 Cohort 1 150 mg/day PK PD Cohorts 2 and 3 270 and 540 mg/day PK PD … … weeks Restaging every 8 weeks GDC-0449 oral dosing PK = Pharmacokinetics PD = Pharmacodynamics (skin punch biopsy and hair follicles)

7. 7 Single Dose Mean Plasma PK Profile of GDC-0449 Day of Study GDC-0449 Mean Plasma Concentration (uM) ± SD 150 mg 540 mg 270 mg

8. 8 GDC-0449 Mean Plasma Concentrations with Continuous Daily Dosing GDC-0449 Plasma Concentration (uM) ± SD Day of Study Predicted Minimum Efficacious Level (5 uM) GDC-0449 administration 150 mg 540 mg 270 mg PD

9. 9 GLI1 Expression in Surrogate Tissues 2-fold down- modulation Fold modulation Skin Punch Biopsies Hair Follicle Samples

10. 10 Drug-Related Adverse Events 150 mg N=7 270 mg N=9 540 mg N=3TotalN=19 AE (n)Gr 1-2Gr 3Gr 1-2Gr 3Gr 1-2 Dysgeusia1113 (15.8%) Hyponatremia22 (10.5%) Fatigue112 (10.5%) Alopecia11 (5.3%) Anorexia11 (5.3%) Acneiform dermatitis 11 (5.3%) Dyspepsia11 (5.3%) Nausea11 (5.3%) Skin exfoliation11 (5.3%) Weight loss11 (5.3%) As reported by 01 April 2008

11. 11 Metastatic and Locally Advanced Basal Cell Carcinoma Patients Baseline At 8 months Baseline At 2 months 84 yo with BCC Lesion Invasive into Auditory Canal 67 yo with BCC Metastatic to Lung, Liver, and Bone

12. 12 *Von Hoff, et al, AACR 2008, Abstract LB-138 Clinical Activity 19 patients enrolled have been evaluated19 patients enrolled have been evaluated –1 confirmed RECIST PR, BCC pt (150 mg qd), on study 487+ days –1 confirmed clinical PR, BCC pt (270 mg qd), on study 297+ days –2 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 days Results in a total of 9 BCC patients were reported at AACR 2008*Results in a total of 9 BCC patients were reported at AACR 2008* –6 of 9 (67%) confirmed PR –8 of 9 (89%) clinical benefit, with 2 SD of 120+ days

13. 13 Conclusions GDC-0449 has an unusual pharmacokinetic profileGDC-0449 has an unusual pharmacokinetic profile –High sustained micromolar plasma concentrations –Long terminal half-life Dose-limiting toxicities were not seen with GDC-0449Dose-limiting toxicities were not seen with GDC-0449 –Reversible grade 3 fatigue and asymptomatic hyponatremia reported beyond the DLT window Objective responses seen in patients with basal cell carcinomaObjective responses seen in patients with basal cell carcinoma Phase II studies using GDC-0449 at 150 mg once daily are ongoing and planned in first-line metastatic colorectal cancer and advanced BCCPhase II studies using GDC-0449 at 150 mg once daily are ongoing and planned in first-line metastatic colorectal cancer and advanced BCC