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  1. Xinlay™ (atrasentan) Oncologic Drugs Advisory Committee September 13, 2005

  2. Atrasentan • A potent selective ETA receptor antagonist • Orally bioavailable • Once-daily dosing Half-life (t½) = 25 hours

  3. Prostate Cancer Second Most Common Cancer in Men in the United States • >230,000 new cases of prostate cancer in 2005 • 30,000 men will die of prostate cancer • Most have advanced metastatic HRPC • 85% have osteoblastic bone metastases • 90% require opiates in the last month of life • Limited treatment options currently approved • Docetaxel is the standard of care for metastatic HRPC • Not all patients receive or are eligible

  4. Proposed Indication • Xinlay™ (atrasentan) is indicated for the treatment of men with hormone refractory prostate cancer with metastases to bone

  5. Atrasentan Development Program Initiated 1996 Atrasentan Clinical Trials Phase 1 Phase 1/2 Unique populations Phase 2/3 Double-blind, placebo-controlled (N = 2484) Investigator-sponsored IND studies M+ HRPC (N = 1228) Other PCa (Ongoing) Non-TTP M96-500(N = 131) TTP Endpoint M96-594 (N = 288) M00-211 (N = 809)

  6. Statistical Considerations • Studies M96-594 and M00-211 did not meet their primary endpoint • Study M00-211 IDMC recommended study stop for futility • Analysis of patients with bone metastases not protocol-specified

  7. Analyses of Patients With Bone Metastases • Consistent benefit in patients with bone metastases • Delays disease progression, attenuates biomarkers, and slows deterioration in quality of life • Across multiple measures in 2 studies • Strong scientific rationale based on emerging data • Role of the ET axis in PCa-osteoblast interaction • Study M00-211 is a large, placebo-controlled study • 690 of 809 (85%) patients have bone metastases • Large unmet need • 85% of patients with metastatic HRPC have bone metastases

  8. Agenda

  9. Consultants • David Cella, PhD; Professor of Psychology and Behavioral Science, Northwestern University • David Dearnaley, MD, FRCP, FRCR; Professor of UroOncology and Head of Urology, Royal Marsden Hospital and Institute of Cancer Research, London UK • Scott Emerson, MD, PhD; Professor of Biostatistics, University of Washington • Roberto M. Lang, MD; Professor of Medicine/Cardiologist, University of Chicago Hospitals • Daniel P. Petrylak, MD; Associate Professor of Medicine, Division of Hematology and Medical Oncology, Columbia University

  10. Unmet Need and Mechanistic Rationale Joel B. Nelson, MD Chairman of UrologyUniversity of Pittsburgh

  11. Incidence and Prevalence of Prostate Cancer 232,090 New casesin 2005 617,000aLocalizedPCa 383,000aAdvancedPCa 48,000a Hormonerefractory 30,000 Deaths in 2005 Treated with chemotherapyb (47%) • Not treated with chemotherapyb (53%) • -------------------------------- • Side effects/toxicity • No perceived benefit • Quality of life a 5-year prevalence: SEER 2005, NODB 2005 b Source: Oncology, Inc. Onco Track MAT June 2005

  12. Metastatic HRPC Is Predominantly a Disease in Bone • Bone is a common metastatic site • Occurs in over 85% of men • Classically osteoblastic • Intractable bone pain • Affects over 75% of patients • Leads to major declines in QOL • Main reason for hospitalization • 90% require opiates in month before death • Skeletal-related events • Pathological fractures • Spinal cord compression

  13. Treatment Remains Palliative • Reduction in SRE • Zoledronic acid • 38% ZA vs 49% placebo • Palliation of morbidity • Opiate analgesics • Focal radiation therapy • Radiopharmaceuticals • Mitoxantrone and prednisone

  14. Characteristics of Current Therapies • Intravenous • Toxicity • Inevitable failure Clear need for more treatment options

  15. Endothelins Act Via 2 Receptors ET-1 ET-2 ET-3 ETA ETB Vasoconstriction Mitogenesis Antiapoptosis Osteoblastic response Pain Nelson et al. Nat Rev Cancer. 2003;3:110.

  16. Rationale for Targeting ET Axis in Prostate Cancer • ET-1 is expressed in all stages of the disease • ET-1 clearance is decreased in HRPC • Osteoblasts express ETA at high density • 105 106 receptors per cell • ET-1/ETA activation induces an osteoblastic response • Interruption of ET axis by atrasentan inhibits bone formation in preclinical models

  17. Prostate Cancer – Bone InteractionA Vicious Cycle Prostate cancer cells Osteoblastic factors (ET-1) Osteolyticfactors Bone-derivedgrowthfactors ETA New bone Osteoblasts Osteoclasts Mineralized bone matrix

  18. mm2/bone New bone area Control Vehicle Atrasentan 1.5 1.0 0.5 ** ** 0.0 Vehicle 2 mg/kg 20 mg/kg mm2/bone Tumor area 4 New Bone 3 Cancer 2 1 * * Control 0 Atrasentan 2 mg/kg Vehicle 2 mg/kg 20 mg/kg Atrasentan 20 mg/kg Atrasentan Inhibits Osteoblastic Metastases in a Mouse Model Yin et al. PNAS. 2003;100:10954-10959. *P< .05; **P< .01

  19. Histomorphometric analysis of intra-tibial LuCaP 23.1 tumor area m2 7.0×10 7 6.0×10 7 5.0×10 7 4.0×10 7 3.0×10 7 * 2.0×10 7 * 1.0×10 7 0 Vehicle Atrasentan Zoledronic acid Atrasentan + zoledronic acid Atrasentan Blocks Prostate Cancer-Induced Osteoblastic Response in Bone Vehicle Atrasentan Zoledronic acid Atrasentan + zoledronic acid Mohammad K, et al. Skeletal Complications of Malignancy NIH 2005. *P< .01

  20. ET Axis and Atrasentan Clinical Development  Growing Focus on Bone Microenvironment Phase 1Atrasentan studies begin M96-594 First dose M00-211 First dose M00-211 Last dose Mar 2003 June 1996 June 2001 Feb 1998 Convergence ofclinical and basic science • Role of ET-1 in PCa • ? HRPC growth • ? Inhibits apoptosis • ? Osteoblastic • ? Pain Atrasentan inhibits ET-1induced bone formation in osteoblastic tumor model ET-1/ETA axis causal in osteoblastic bone metastases

  21. Xinlay™ (atrasentan)Efficacy Darryl J. Sleep, MD, FCS Oncology Global Project HeadAbbott Laboratories

  22. Atrasentan Randomized Controlled TrialsMetastatic Hormone Refractory Prostate Cancer Atrasentan 10 mg Atrasentan 2.5 mg M96-594 Placebo Screening Open-label atrasentanextension Atrasentan 10 mg M00-211 Placebo Randomization Disease progressionor study close

  23. Dose-Ranging Study M96-594 • 288 patients with asymptomatic metastatic HRPC • Primary endpoint: time to disease progression • Clinical • Radiographic Atrasentan 10 mg (n = 89) Open-label atrasentan extension Atrasentan 2.5 mg (n = 95) Screening Placebo (n = 104) Randomization Disease progressionor study close

  24. Time to Disease Progression Study M96-594 – ITT

  25. Change From Baseline to Final BAP and PSAStudy M96-594 – ITT BAP PSA ** Time from randomization (week) **P< .01 compared with placebo

  26. Study M00-211 • 809 patients with metastatic HRPC • Major entry criteria • Confirmed radiographic evidence of metastases • Independent radiologic review of all baseline scans • Confirmed medically or surgically castrate for ≥ 3 months • Rising PSA or PSA ≥ 20 ng/mL • No PCa-related pain requiring opiates • Chemotherapy-naïve • No prior or ongoing bisphosphonate therapy Atrasentan 10 mg (n = 408) Open-label atrasentan extension Screening Placebo (n = 401) Randomization Disease progressionor study close

  27. Baseline Characteristics BalancedStudy M00-211 – ITT

  28. Primary Endpoint Time to Disease ProgressionStudy M00-211 Time to first • Radiographic event • Progression by  2 new lesions on bone scan • Progression of extraskeletal metastases by modified RECIST criteria • Clinical event • Prostate cancer-related pain treated with • Any IV/IM/SQ opiates • Oral opiates or glucocorticoids for 10 of 14 consecutive days • Chemotherapy, radiotherapy • Skeletal-related event • Spinal cord compression • Pathological fracture • PCa progression event requiring intervention

  29. Endpoint Assessment and Confirmation • Scans scheduled every 12 weeks • Bone scans for all patients • CT or MRI for patients with baseline extraskeletal metastases • Unscheduled scans as clinically indicated • All scans independently assessed • All endpoints independently confirmed

  30. Time to Disease ProgressionStudy M00-211 – ITT Scheduled radiographic scans

  31. Survival Study M00-211 –ITT

  32. Metastatic Hormone Refractory Prostate Cancer Is a Disease of Bone • 85% of patients with M+ HRPC have bone metastases • Morbidity in HRPC is driven by bone metastases • Intractable pain • Skeletal events • Role of ET axis in osteoblastic bone metastases • Tumor-ET-1/osteoblast-ETA interaction in bone • ETA antagonism impacts bone metastases • 85% of patients in M00-211 had bone metastases • 690/809 randomized • Baseline characteristics balanced between groups

  33. Time to Disease Progression Study M00-211 – Patients With Bone Metastases

  34. Other Protocol-Specified Efficacy AnalysesStudy M00-211 • Mean change in bone alkaline phosphatase • Mean change in PSA • Quality of life

  35. Mean Change in Bone Alkaline Phosphatase Study M00-211 ITT Bone Metastases *** *** *** ** ** ** *** *** Time from randomization (week) Number of patients Atrasentan Placebo 346 369 334 335 309 308 364 374 304 308 292 278 270 253 320 312 **P< .01; ***P< .001

  36. Mean Change in PSA Study M00-211 ITT Bone Metastases * * * * *** ** ** ** Time from randomization (week) Number of patients Atrasentan Placebo 369 383 351 351 324 319 384 387 326 322 308 295 285 265 338 325 *P< .05; **P< .01; ***P< .001

  37. Atrasentan Has a Consistent Benefit in Quality of Life Compared to Placebo Study M00-211 ITT Bone Metastases Favors atrasentan Favors atrasentan FACT-P FACT-G PCS EORTC Global -5 -3 -1 0 1 -5 -3 -1 0 1 Mean treatment difference in change from baseline to final assessment (standardized 95% CI)

  38. Mean Change in Prostate Cancer SubscoreStudy M00-211 ITT Bone Metastases * * ** * Time from randomization (week) Number of patients Atrasentan Placebo 345 360 305 302 365 369 304 301 267 250 322 308 *P< .05; **P< .01

  39. Time to 50% Worsening in PCS Pain ScoreStudy M00-211 – Patients With Bone Metastases

  40. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases Favors atrasentan M00-211 Time to disease progression 0.2 0.4 0.6 0.8 1.0 Hazard ratio (95% CI)

  41. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone MetastasesAcross Multiple Measures and Studies Favors atrasentan M00-211 Time to disease progression Radiographic Clinical 0.2 0.4 0.6 0.8 1.0 Hazard ratio (95% CI)

  42. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone MetastasesAcross Multiple Measures and Studies Favors atrasentan M00-211 Time to disease progression Radiographic Clinical BAP progression PSA progression 0.2 0.4 0.6 0.8 1.0 Hazard ratio (95% CI)

  43. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone MetastasesAcross Multiple Measures and Studies Favors atrasentan M00-211 Time to disease progression Radiographic Clinical BAP progression PSA progression 50% decline in FACT-P pain score (>56 days) Opioid initiation (85 days) Adverse event of bone pain (40 days) 0.2 0.4 0.6 0.8 1.0 Hazard ratio (95% CI)

  44. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone MetastasesAcross Multiple Measures and Studies Favors atrasentan M00-211M96-594 Time to disease progression Radiographic Clinical BAP progression PSA progression 50% decline in FACT-P pain score (>56 days) Opioid initiation (85 days) Adverse event of bone pain (40 days) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Hazard ratio (95% CI)

  45. C Xinlay™ (atrasentan)Safety Gary Gordon, MD Oncology Vice PresidentAbbott Laboratories

  46. Atrasentan Safety Experience • 35 Abbott-sponsored studies • 1696 individuals received atrasentan (0.2 – 139.5 mg) • Healthy volunteers • Special populations • Prostate cancer patients • 1159 prostate cancer patients received atrasentan • 676 in phase 2/3 placebo-controlled studies • Mean long-term exposure greater than 270 days • 584 treated for longer than 6 months • 294 treated for longer than 1 year

  47. Atrasentan Is a Vasoactive Compound • Atrasentan is a targeted and potent ETA antagonist • Vasodilation • Fluid retention • Most adverse events were • Mild • Resolved

  48. Overview of Adverse EventsPhase 2/3 Placebo-Controlled Studies(Studies M96-500, M96-594, M00-211)

  49. Statistically Significant Adverse Events ≥ 10%Phase 2/3 Placebo-Controlled Studies *P < .05

  50. Cardiovascular Events • Arrhythmia • Heart failure • Adjudicator • John Teerlink, MD; Associate Professor of Medicine, University of California – San Francisco; Director, Heart Failure Clinic, Veterans Affairs Medical Center, San Francisco; Member of FDA Cardiovascular and Renal Drugs Advisory Committee • Myocardial infarction • Adjudicators • John Teerlink, MD • Michael Parmacek, MD; Chief, Division of Cardiovascular Medicine, Herbert C. Rorer Professor of Medical Sciences; University of Pennsylvania Medical Center