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PTK/ZK Inhibits All Known VEGF Receptors

CONFIRM 2 INTERIM ANALYSIS Results of an Interim Analysis of a Multinational Randomized, Double-Blind, Phase III Study in Patients With Previously Treated Metastatic Colorectal Cancer (mCRC) Receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or Placebo.

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PTK/ZK Inhibits All Known VEGF Receptors

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  1. CONFIRM 2 INTERIM ANALYSISResults of an Interim Analysis of a Multinational Randomized, Double-Blind, Phase III Study in Patients With Previously Treated Metastatic Colorectal Cancer (mCRC) Receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or Placebo C.-H. Koehne, E. Bajetta, E. Lin, E. Van Cutsem, J.R. Hecht, J.-Y. Douillard, M. Moore, C. Germond, D. Laurent, C. Jacques

  2. PTK/ZK Inhibits All Known VEGF Receptors VEGF-A VEGF-B PlGF VEGF-AVEGF-CVEGF-D VEGF-CVEGF-D Extracellular Endothelial Cell Intracellular PTK/ZK PTK/ZK PTK/ZK VEGFR-1/Flt-1 VEGFR-2/KDR VEGFR-3/Flt-4 Angiogenesis Angiogenesis Lymphangiogenesis Tumor metastasis • PTK/ZK also inhibits PDGFR-b and c-KIT

  3. CONFIRM 2 Study Design Stratification Factors: PS: 0, 1-2 LDH: ≤, >1.5 x ULN R A N D O M I Z E D • FOLFOX 4 + • PTK/ZK (n=426)1250 mg po qd Multinational randomized phase III trial in irinotecan-pretreated mCRC patients CONFIRM 2 855 patients • FOLFOX 4 + • Placebo (n=429)

  4. CONFIRM Study Design Stratification Factors: PS: 0, 1-2 LDH: ≤, >1.5 x ULN R A N D O M I Z E D CONFIRM 11168 patients 1st linemCRC • FOLFOX 4 + • PTK/ZK 1250 mg po qd CONFIRM 2 855 patients 2nd linemCRC • FOLFOX 4 + • Placebo

  5. CONFIRM 1: Progression Free Survival (ASCO 2005) High LDH Patients Overall Patients 100 100 HR = 0.88 (95% CI: 0.74, 1.03) P value = 0.118 HR = 0.60 (95% CI: 0.44, 0.82) P value = 0.001 75 75 50 Progression-Free Survival, % 50 Progression-Free Survival, % 25 25 FOLFOX4 + PTK/ZK FOLFOX4 + Placebo FOLFOX4 + PTK/ZK FOLFOX4 + Placebo 0 0 0 2 4 6 8 10 0 2 4 6 8 10 12 Time Since Randomization, mo Time Since Randomization, mo

  6. CONFIRM 2: Main Patient Eligibility Criteria • Patients with mCRC • Pretreatment for metastatic disease with irinotecan/fluoropyrimidine-based chemotherapy • Measurable disease per RECIST • WHO PS of 0-2 • Adequate hematological and organ function • No exclusions for prior coagulopathy or bleeding RECIST = Response Evaluation Criteria in Solid Tumors.

  7. CONFIRM 2: Study Objectives • Primary end point: Overall survival • Statistical hypothesis: One-year overall survival rate from 36% to 45% (HR 0.782, 90% power, 5% level of significance with 692 events) • Key secondary end points: • Overall survival in high LDH (> 1.5 x ULN) patients • Progression free survival* • Overall population • High LDH population (> 1.5 x ULN) • Overall response rate (RECIST) *Assessed by investigators following RECIST criteria.

  8. Patient Characteristics

  9. Patient Disposition *At time of data cut-off, patients are continuing study treatment.

  10. Safety and Tolerability

  11. Other Clinically Important Adverse Events

  12. Response Rate

  13. 100 100 12.1 moPTK/ZK vs 11.8 moPlaceboHR = 0.94 (95% CI:0.77, 1.14)P value = 0.51 75 75 Overall Survival, % 50 50 25 25 FOLFOX4 + PTK/ZK FOLFOX4 + Placebo 0 0 0 0 4 4 8 8 12 12 16 16 20 20 24 24 Time Since Randomization, mo Overall Survival*: Overall Population 426 429 373 377 239 234 115 119 48 56 14 14 0 5 PTK/ZK Placebo *Overall survival results based on interim analysis values; final data available end of 2006.

  14. Progression Free Survival: Overall Population 100 5.6 moPTK/ZK vs 4.1 mo Placebo HR = 0.83 (95% CI: 0.71, 0.98)P value = 0.026 75 75 Progression-Free Survival, % 50 25 FOLFOX4 + PTK/ZK FOLFOX4 + Placebo 0 0 4 8 12 16 20 Time since randomization, mo 0 0 426 429 194 182 49 38 10 6 2 2 PTK/ZK Placebo

  15. Progression Free Survival: High LDH Patients 100 5.6 moPTK/ZK vs 3.8 mo PlaceboHR = 0.61 (95% CI: 0.46, 0.80)P value = < 0.001 75 Progression-Free Survival, % 50 25 FOLFOX4 + PTK/ZK FOLFOX4 + Placebo 0 0 4 8 12 16 Time Since Randomization, mo PTK/ZK Placebo 124 126 68 48 18 8 5 2 2 0

  16. Overall Survival*: High LDH Patients 100 9.6 moPTK/ZK vs 7.5 mo Placebo HR = 0.78 (95% CI: 0.58, 1.05)P value = 0.105 75 Overall Survival, % 50 25 FOLFOX4 + PTK/ZK FOLFOX4 + Placebo 0 0 4 8 12 16 20 24 Time Since Randomization, mo 124 126 108 94 61 45 21 16 8 8 2 1 0 0 PTK/ZK Placebo *Overall survival results based on interim analysis values; final data available end of 2006.

  17. 0.83 CONFIRM 1* 0.026 Progression Free Survival by LDH Stratum: HR in CONFIRM 2 PFS by LDH Stratum:Hazard Ratio in CONFIRM 2 and 1 HR P value Overall Population 0.83 0.026 CONFIRM 2 High LDH Low LDH 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Favors PTK/ZK Favors Placebo *Investigator-based assessment of CONFIRM 1.

  18. Bulky/Hypoxic Tumors Boost HIF-1a Which Upregulates VEGF and LDH HIF-1astabilization HIF-1a/ARNT HRE LDH-A VEGF-AVEGFR-1 nucleus LDH-5 GLUT-1, -3 NOS Angiogenesis Anaerobic glycolysis EPO Erythropoiesis Adapted from Harris AL. Nature Rev Cancer. 2002;2:38-47.

  19. PTK/ZK Summary • CONFIRM 2 • Well-tolerated safety profile with anticipated antiangiogenic drug-related effects • No OS benefit for overall population based on interim analysis • PTK/ZK improved PFS for overall population (HR = 0.83, P= 0.026) • PTK/ZK significantly improved PFS in high LDH patients (HR = 0.61, P < 0.001) • PTK/ZK improved OS for patients with high LDH (HR = 0.78, P= 0.105) • Efficacy and safety results in overall population and high LDH patients are highly consistent between CONFIRM 1 and CONFIRM 2 • New studies in mCRC patients with high LDH are planned • Further development of PTK/ZK is ongoing in mCRC and additional tumor types

  20. Acknowledgments The patients and their families The investigators in over 200 medical centers worldwide The Novartis Pharmaceutical Corp, US and Schering AG, Germany CONFIRM team Related PTK/ZK ASCO presentations Major et al. #3529 CONFIRM 1/2 meta-analysis Azuma et al. #3530 Association of serum LDH with genes in the angiogenesis pathways in mCRC patients

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