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  • not go down the whole list. Just summarize the events were infrequent and looking at any of the categories, there was no difference between atrasentan and placebo.
  • PPT

    1. 1. Xinlay™ (atrasentan) Oncologic Drugs Advisory Committee September 13, 2005
    2. 2. Atrasentan <ul><li>A potent selective ET A receptor antagonist </li></ul><ul><li>Orally bioavailable </li></ul><ul><li>Once-daily dosing Half-life (t ½ ) = 25 hours </li></ul>
    3. 3. Prostate Cancer Second Most Common Cancer in Men in the United States <ul><li>>230,000 new cases of prostate cancer in 2005 </li></ul><ul><ul><li>30,000 men will die of prostate cancer </li></ul></ul><ul><ul><li>Most have advanced metastatic HRPC </li></ul></ul><ul><ul><li>85% have osteoblastic bone metastases </li></ul></ul><ul><ul><li>90% require opiates in the last month of life </li></ul></ul><ul><li>Limited treatment options currently approved </li></ul><ul><ul><li>Docetaxel is the standard of care for metastatic HRPC </li></ul></ul><ul><ul><li>Not all patients receive or are eligible </li></ul></ul>
    4. 4. Proposed Indication <ul><li>Xinlay™ (atrasentan) is indicated for the treatment of men with hormone refractory prostate cancer with metastases to bone </li></ul>
    5. 5. Atrasentan Development Program Initiated 1996 Other PCa (Ongoing) Phase 1 Investigator-sponsored IND studies Phase 1/2 Unique populations M+ HRPC (N = 1228) Phase 2/3 Double-blind, placebo-controlled (N = 2484) Atrasentan Clinical Trials TTP Endpoint M96-594 (N = 288) M00-211 (N = 809) Non-TTP M96-500 (N = 131)
    6. 6. Statistical Considerations <ul><li>Studies M96-594 and M00-211 did not meet their primary endpoint </li></ul><ul><ul><li>Study M00-211 IDMC recommended study stop for futility </li></ul></ul><ul><li>Analysis of patients with bone metastases not protocol-specified </li></ul>
    7. 7. Analyses of Patients With Bone Metastases <ul><li>Consistent benefit in patients with bone metastases </li></ul><ul><ul><li>Delays disease progression, attenuates biomarkers, and slows deterioration in quality of life </li></ul></ul><ul><ul><li>Across multiple measures in 2 studies </li></ul></ul><ul><li>Strong scientific rationale based on emerging data </li></ul><ul><ul><li>Role of the ET axis in PCa-osteoblast interaction </li></ul></ul><ul><li>Study M00-211 is a large, placebo-controlled study </li></ul><ul><ul><li>690 of 809 (85%) patients have bone metastases </li></ul></ul><ul><li>Large unmet need </li></ul><ul><ul><li>85% of patients with metastatic HRPC have bone metastases </li></ul></ul>
    8. 8. Agenda Michael A. Carducci, MD Associate Professor in Oncology and Urology Johns Hopkins University Place in Therapy Gary Gordon, MD Oncology Vice President Abbott Laboratories Safety Darryl J. Sleep, MD, FCS Oncology Global Project Head Abbott Laboratories Efficacy Joel B. Nelson, MD Chairman of Urology University of Pittsburgh Unmet Need and Mechanistic Rationale
    9. 9. Consultants <ul><li>David Cella, PhD; Professor of Psychology and Behavioral Science, Northwestern University </li></ul><ul><li>David Dearnaley, MD, FRCP, FRCR; Professor of UroOncology and Head of Urology, Royal Marsden Hospital and Institute of Cancer Research, London UK </li></ul><ul><li>Scott Emerson, MD, PhD; Professor of Biostatistics, University of Washington </li></ul><ul><li>Roberto M. Lang, MD; Professor of Medicine/Cardiologist, University of Chicago Hospitals </li></ul><ul><li>Daniel P. Petrylak, MD; Associate Professor of Medicine, Division of Hematology and Medical Oncology, Columbia University </li></ul>
    10. 10. Unmet Need and Mechanistic Rationale Joel B. Nelson, MD Chairman of Urology University of Pittsburgh
    11. 11. Incidence and Prevalence of Prostate Cancer Treated with chemotherapy b (47%) <ul><li>Not treated with chemotherapy b (53%) </li></ul><ul><li>-------------------------------- </li></ul><ul><li>Side effects/toxicity </li></ul><ul><li>No perceived benefit </li></ul><ul><li>Quality of life </li></ul>a 5-year prevalence: SEER 2005, NODB 2005 b Source: Oncology, Inc. Onco Track MAT June 2005 617,000 a Localized PCa 232,090 New cases in 2005 383,000 a Advanced PCa 30,000 Deaths in 2005 48,000 a Hormone refractory
    12. 12. Metastatic HRPC Is Predominantly a Disease in Bone <ul><li>Bone is a common metastatic site </li></ul><ul><ul><li>Occurs in over 85% of men </li></ul></ul><ul><ul><li>Classically osteoblastic </li></ul></ul><ul><li>Intractable bone pain </li></ul><ul><ul><li>Affects over 75% of patients </li></ul></ul><ul><ul><li>Leads to major declines in QOL </li></ul></ul><ul><ul><li>Main reason for hospitalization </li></ul></ul><ul><ul><li>90% require opiates in month before death </li></ul></ul><ul><li>Skeletal-related events </li></ul><ul><ul><li>Pathological fractures </li></ul></ul><ul><ul><li>Spinal cord compression </li></ul></ul>
    13. 13. Treatment Remains Palliative <ul><li>Reduction in SRE </li></ul><ul><ul><li>Zoledronic acid </li></ul></ul><ul><ul><ul><li>38% ZA vs 49% placebo </li></ul></ul></ul><ul><li>Palliation of morbidity </li></ul><ul><ul><li>Opiate analgesics </li></ul></ul><ul><ul><li>Focal radiation therapy </li></ul></ul><ul><ul><li>Radiopharmaceuticals </li></ul></ul><ul><ul><li>Mitoxantrone and prednisone </li></ul></ul>
    14. 14. Characteristics of Current Therapies <ul><li>Intravenous </li></ul><ul><li>Toxicity </li></ul><ul><li>Inevitable failure </li></ul>Clear need for more treatment options 41 32 – 79 Neutropenia 17 – 41 26 – 61 Gastrointestinal 15 8.7 – 15 Dyspnea Docetaxel Mitoxantrone Any Grade % 9.6   5 MI/Ischemia Any Grade % Adverse Event 5 – 22 Decreased LVEF 2 CHF
    15. 15. Endothelins Act Via 2 Receptors ET-1 ET B Vasoconstriction Mitogenesis Antiapoptosis Osteoblastic response Pain Nelson et al. Nat Rev Cancer. 2003;3:110. ET-2 ET-3 ET A
    16. 16. Rationale for Targeting ET Axis in Prostate Cancer <ul><li>ET-1 is expressed in all stages of the disease </li></ul><ul><li>ET-1 clearance is decreased in HRPC </li></ul><ul><li>Osteoblasts express ET A at high density </li></ul><ul><ul><li>10 5  10 6 receptors per cell </li></ul></ul><ul><li>ET-1/ET A activation induces an osteoblastic response </li></ul><ul><li>Interruption of ET axis by atrasentan inhibits bone formation in preclinical models </li></ul>
    17. 17. Prostate Cancer – Bone Interaction A Vicious Cycle Osteoblastic factors (ET-1) Bone-derived growth factors New bone Prostate cancer cells Osteoclasts Mineralized bone matrix Osteoblasts Osteolytic factors ET A
    18. 18. Atrasentan Inhibits Osteoblastic Metastases in a Mouse Model Yin et al. PNAS . 2003;100:10954-10959. * P < .05; ** P < .01 Control New Bone Cancer Vehicle Atrasentan Vehicle 2 mg/kg 20 mg/kg 0 1 2 3 4 * * Tumor area mm 2 /bone mm 2 /bone New bone area Vehicle 2 mg/kg 20 mg/kg ** 0.0 0.5 1.0 1.5 ** Control Atrasentan 2 mg/kg Atrasentan 20 mg/kg
    19. 19. Atrasentan Blocks Prostate Cancer-Induced Osteoblastic Response in Bone Mohammad K, et al. Skeletal Complications of Malignancy NIH 2005. Vehicle Atrasentan Zoledronic acid Atrasentan + zoledronic acid * P < .01 0 1.0×10 7 2.0×10 7 3.0×10 7 4.0×10 7 5.0×10 7 6.0×10 7 7.0×10 7 Histomorphometric analysis of intra-tibial LuCaP 23.1 tumor area Vehicle Atrasentan Zoledronic acid Atrasentan + zoledronic acid  m 2 * *
    20. 20. ET Axis and Atrasentan Clinical Development  Growing Focus on Bone Microenvironment Phase 1 Atrasentan studies begin M00-211 First dose M96-594 First dose <ul><li>Role of ET-1 in PCa </li></ul><ul><li>? HRPC growth </li></ul><ul><li>? Inhibits apoptosis </li></ul><ul><li>? Osteoblastic </li></ul><ul><li>? Pain </li></ul>Atrasentan inhibits ET-1  induced bone formation in osteoblastic tumor model ET-1/ET A axis causal in osteoblastic bone metastases M00-211 Last dose Convergence of clinical and basic science June 1996 Feb 1998 June 2001 Mar 2003 2003 2002 2001 2000 1999 1998 1997 1996 1995
    21. 21. Xinlay™ (atrasentan) Efficacy Darryl J. Sleep, MD, FCS Oncology Global Project Head Abbott Laboratories
    22. 22. Atrasentan Randomized Controlled Trials Metastatic Hormone Refractory Prostate Cancer Atrasentan 10 mg Placebo Atrasentan 2.5 mg M96-594 Randomization Disease progression or study close Open-label atrasentan extension Screening M00-211 Atrasentan 10 mg Placebo
    23. 23. Dose-Ranging Study M96-594 <ul><li>288 patients with asymptomatic metastatic HRPC </li></ul><ul><li>Primary endpoint: time to disease progression </li></ul><ul><ul><li>Clinical </li></ul></ul><ul><ul><li>Radiographic </li></ul></ul>Open-label atrasentan extension Atrasentan 10 mg (n = 89) Placebo (n = 104) Atrasentan 2.5 mg (n = 95) Screening Randomization Disease progression or study close
    24. 24. Time to Disease Progression Study M96-594 – ITT 10 mg vs placebo HR = 0.769 (95% CI = 0.545, 1.085) P = .132
    25. 25. Change From Baseline to Final BAP and PSA Study M96-594 – ITT BAP ** P < .01 compared with placebo ** PSA Time from randomization (week)
    26. 26. Study M00-211 <ul><li>809 patients with metastatic HRPC </li></ul><ul><li>Major entry criteria </li></ul><ul><ul><li>Confirmed radiographic evidence of metastases </li></ul></ul><ul><ul><ul><li>Independent radiologic review of all baseline scans </li></ul></ul></ul><ul><ul><li>Confirmed medically or surgically castrate for ≥ 3 months </li></ul></ul><ul><ul><li>Rising PSA or PSA ≥ 20 ng/mL </li></ul></ul><ul><ul><li>No PCa-related pain requiring opiates </li></ul></ul><ul><ul><li>Chemotherapy-naïve </li></ul></ul><ul><ul><li>No prior or ongoing bisphosphonate therapy </li></ul></ul>Randomization Disease progression or study close Atrasentan 10 mg (n = 408) Placebo (n = 401) Open-label atrasentan extension Screening
    27. 27. Baseline Characteristics Balanced Study M00-211 – ITT 88 87 Karnofsky score ≥ 90, % 81 (54 – 177) 83 (47 – 154) Weight, kg Median (range) Atrasentan 10 mg n = 408 Placebo n = 401 186 (97 – 1318) 188 (108 – 2365) LDH, IU/L 110 (36 – 5482) 112 (41 – 3774) Total ALP, IU/L 26 (2 – 1904) 25 (2 – 1599) BAP, ng/mL 70 ( 2 – 5784) 80 ( 2 – 5425) PSA, ng/mL 13 ( 9 – 17) 13 ( 9 – 18) Hgb, g/dL 73 (45 – 93) 72 (45 – 92) Age, y
    28. 28. Primary Endpoint  Time to Disease Progression Study M00-211 <ul><li>Time to first </li></ul><ul><li>Radiographic event </li></ul><ul><ul><li>Progression by  2 new lesions on bone scan </li></ul></ul><ul><ul><li>Progression of extraskeletal metastases by modified RECIST criteria </li></ul></ul><ul><li>Clinical event </li></ul><ul><ul><li>Prostate cancer-related pain treated with </li></ul></ul><ul><ul><ul><li>Any IV/IM/SQ opiates </li></ul></ul></ul><ul><ul><ul><li>Oral opiates or glucocorticoids for 10 of 14 consecutive days </li></ul></ul></ul><ul><ul><ul><li>Chemotherapy, radiotherapy </li></ul></ul></ul><ul><ul><li>Skeletal-related event </li></ul></ul><ul><ul><ul><li>Spinal cord compression </li></ul></ul></ul><ul><ul><ul><li>Pathological fracture </li></ul></ul></ul><ul><ul><li>PCa progression event requiring intervention </li></ul></ul>
    29. 29. Endpoint Assessment and Confirmation <ul><li>Scans scheduled every 12 weeks </li></ul><ul><ul><li>Bone scans for all patients </li></ul></ul><ul><ul><li>CT or MRI for patients with baseline extraskeletal metastases </li></ul></ul><ul><ul><li>Unscheduled scans as clinically indicated </li></ul></ul><ul><li>All scans independently assessed </li></ul><ul><li>All endpoints independently confirmed </li></ul>
    30. 30. Time to Disease Progression Study M00-211 – ITT Scheduled radiographic scans P (G 1,1 ) = .136 HR = 0.885 (95% CI = 0.755 – 1.037)
    31. 31. Survival Study M00-211 – ITT P (G 1,1 ) = .313 HR = 0.935 (95% CI = 0.796 – 1.100)
    32. 32. Metastatic Hormone Refractory Prostate Cancer Is a Disease of Bone <ul><li>85% of patients with M+ HRPC have bone metastases </li></ul><ul><ul><li>Morbidity in HRPC is driven by bone metastases </li></ul></ul><ul><ul><ul><li>Intractable pain </li></ul></ul></ul><ul><ul><ul><li>Skeletal events </li></ul></ul></ul><ul><li>Role of ET axis in osteoblastic bone metastases </li></ul><ul><ul><li>Tumor-ET-1/osteoblast-ET A interaction in bone </li></ul></ul><ul><ul><li>ET A antagonism impacts bone metastases </li></ul></ul><ul><li>85% of patients in M00-211 had bone metastases </li></ul><ul><ul><li>690/809 randomized </li></ul></ul><ul><ul><li>Baseline characteristics balanced between groups </li></ul></ul>
    33. 33. Time to Disease Progression Study M00-211 – Patients With Bone Metastases HR = 0.813 (95% CI = 0.685 – 0.965) P = .016
    34. 34. Other Protocol-Specified Efficacy Analyses Study M00-211 <ul><li>Mean change in bone alkaline phosphatase </li></ul><ul><li>Mean change in PSA </li></ul><ul><li>Quality of life </li></ul>
    35. 35. Mean Change in Bone Alkaline Phosphatase Study M00-211 ITT Bone Metastases *** ** *** *** ** P < .01; *** P < .001 *** ** ** *** 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
    36. 36. Mean Change in PSA Study M00-211 ITT Bone Metastases ** ** * * ** *** * * Time from randomization (week) * P < .05; ** P < .01; *** P < .001 369 383 351 351 324 319 384 387 326 322 308 295 285 265 338 325 Number of patients Atrasentan Placebo
    37. 37. Atrasentan Has a Consistent Benefit in Quality of Life Compared to Placebo Study M00-211 Mean treatment difference in change from baseline to final assessment (standardized 95% CI) FACT-P FACT-G EORTC Global PCS Favors atrasentan -5 -3 -1 0 1 ITT Favors atrasentan -5 -3 -1 0 1 Bone Metastases
    38. 38. Mean Change in Prostate Cancer Subscore Study M00-211 ITT Bone Metastases * Time from randomization (week) * P < .05; ** P < .01 345 360 305 302 365 369 304 301 267 250 322 308 * ** Number of patients Atrasentan Placebo *
    39. 39. Time to 50% Worsening in PCS Pain Score Study M00-211 – Patients With Bone Metastases HR = 0.644 (95% CI = 0.478 – 0.868) P = .003
    40. 40. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases 0.4 0.6 0.8 1.0 0.2 Favors atrasentan Hazard ratio (95% CI) M00-211 Time to disease progression
    41. 41. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases Across Multiple Measures and Studies 0.4 0.6 0.8 1.0 0.2 Favors atrasentan Hazard ratio (95% CI) M00-211 Time to disease progression Radiographic Clinical
    42. 42. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases Across Multiple Measures and Studies 0.4 0.6 0.8 1.0 0.2 Favors atrasentan Hazard ratio (95% CI) M00-211 Time to disease progression BAP progression PSA progression Radiographic Clinical
    43. 43. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases Across Multiple Measures and Studies 0.4 0.6 0.8 1.0 0.2 Favors atrasentan Hazard ratio (95% CI) M00-211 Time to disease progression BAP progression PSA progression 50% decline in FACT-P pain score (>56 days) Opioid initiation (85 days) Adverse event of bone pain (40 days) Radiographic Clinical
    44. 44. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases Across Multiple Measures and Studies 0.4 0.6 0.8 1.0 0.2 Favors atrasentan Hazard ratio (95% CI) M00-211 M96-594 Time to disease progression BAP progression PSA progression 50% decline in FACT-P pain score (>56 days) Opioid initiation (85 days) Adverse event of bone pain (40 days) Radiographic Clinical 1.4 1.6 1.2
    45. 45. Xinlay™ (atrasentan) Safety Gary Gordon, MD Oncology Vice President Abbott Laboratories C
    46. 46. Atrasentan Safety Experience <ul><li>35 Abbott-sponsored studies </li></ul><ul><ul><li>1696 individuals received atrasentan (0.2 – 139.5 mg) </li></ul></ul><ul><ul><li>Healthy volunteers </li></ul></ul><ul><ul><li>Special populations </li></ul></ul><ul><ul><li>Prostate cancer patients </li></ul></ul><ul><li>1159 prostate cancer patients received atrasentan </li></ul><ul><ul><li>676 in phase 2/3 placebo-controlled studies </li></ul></ul><ul><ul><li>Mean long-term exposure greater than 270 days </li></ul></ul><ul><ul><li>584 treated for longer than 6 months </li></ul></ul><ul><ul><li>294 treated for longer than 1 year </li></ul></ul>
    47. 47. Atrasentan Is a Vasoactive Compound <ul><li>Atrasentan is a targeted and potent ET A antagonist </li></ul><ul><ul><li>Vasodilation </li></ul></ul><ul><ul><li>Fluid retention </li></ul></ul><ul><li>Most adverse events were </li></ul><ul><ul><li>Mild </li></ul></ul><ul><ul><li>Resolved </li></ul></ul>
    48. 48. Overview of Adverse Events Phase 2/3 Placebo-Controlled Studies (Studies M96-500, M96-594, M00-211) 93 (17) 13 (10) 76 (14) Discontinuation due to adverse events 173 (32) 48 (35) 152 (28) Serious adverse events 31 (6) 9 (7) 28 (5) Death due to adverse events 221 (41) 528 (98) Atrasentan 10 mg n = 541 55 (40) 130 (96) Atrasentan 2.5 mg n = 136 Patients n (%) 218 (40) Grade 3/4 (severe) adverse events 523 (96) Total adverse events Placebo n = 544
    49. 49. Statistically Significant Adverse Events ≥ 10% Phase 2/3 Placebo-Controlled Studies * P < .05 3 (0.6) 0 61 (11)* 39 (7) Infection 7 (1) 3 (0.6) 56 (10)* 21 (4) Dyspnea 77 (14)* 117 (22)* 185 (34)* 208 (38)* 239 (44) Atrasentan 10 mg n = 541 Any Grade 3/4 19 (3) 2 (0.4) 0 8 (1) 75 (14)* Placebo n = 544 7 (1) 76 (14) Peripheral edema 0 73 (13) Rhinitis Patients, n (%) 22 (4) 51 (9) Anemia 4 (0.7) 74 (14) Headache 49 (9) 277 (51)* Bone pain Atrasentan 10 mg n = 541 Placebo n = 544 Adverse Event
    50. 50. Cardiovascular Events <ul><li>Arrhythmia </li></ul><ul><li>Heart failure </li></ul><ul><ul><li>Adjudicator </li></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul><ul><li>Myocardial infarction </li></ul><ul><ul><li>Adjudicators </li></ul></ul><ul><ul><ul><li>John Teerlink, MD </li></ul></ul></ul><ul><ul><ul><li>Michael Parmacek, MD; Chief, Division of Cardiovascular Medicine, Herbert C. Rorer Professor of Medical Sciences; University of Pennsylvania Medical Center </li></ul></ul></ul>
    51. 51. Arrhythmias <ul><li>No arrhythmia seen in pre-clinical models </li></ul><ul><li>Few grade 3/4 events </li></ul><ul><li>No deaths resulting from arrhythmia </li></ul>
    52. 52. Arrhythmias Phase 2/3 Placebo-Controlled Studies * P < .05 1 (0.2) 0 1 (0.2) 0 Bradycardia 4 (0.7) 3 (0.6) 29 (5.4)* 11 (2.0) Total Unique Patients 4 (0.7) 2 (0.4) 9 (1.7) 3 (0.6) Atrial fibrillation 0 0 3 (0.6) 0 Atrial flutter 1 (0.2) 0 1 (0.2) 0 Supraventricular tachycardia 0 0 1 (0.2) 0 Supraventricular extrasystoles 0 0 1 (0.2) 3 (0.6) Ventricular extrasystoles 0 0 0 0 Ventricular tachycardia 0 0 0 0 Ventricular fibrillation 0 0 6 (1.1) 2 (0.4) Palpitation 0 0 9 (1.7)* 1 (0.2) Tachycardia 0 0 1 (0.2) 0 Extrasystoles 3 (0.6) Atrasentan 10 mg n=541 Any Grade 3/4 (Severe) 1 (0.2) Placebo n=544 Patients, n (%) 0 2 (0.4) Arrhythmia Atrasentan 10 mg n=541 Placebo n=544 Adverse event
    53. 53. Heart Failure a Phase 2/3 Placebo-Controlled Studies a Includes heart failure, left heart failure, congestive heart failure, lung edema, and cardiogenic shock. * P < .05; statistical significance tested between placebo and 10 mg atrasentan. <ul><li>Review of serious fluid-related events did not identify additional cases </li></ul>Patients, n (%) 23 (4)* 5 (4) 5 (1) All events 7 (1)* 0 1 (0.2) Resulted in death 10 (2)* 3 (2) 2 (0.4) Discontinuations 16 (3)* 2 (1) 3 (1) Grade 3/4 events Atrasentan 2.5 mg n = 136 Atrasentan 10 mg n = 541 Placebo n = 544
    54. 54. Outcome of Heart Failure Phase 2/3 Placebo-Controlled Studies <ul><li>18 resolved </li></ul><ul><ul><li>10 continued or interrupted atrasentan therapy </li></ul></ul><ul><ul><li>8 discontinued atrasentan therapy </li></ul></ul><ul><li>3 not resolved as of last follow-up </li></ul><ul><li>7 deaths attributed to heart failure by investigator </li></ul><ul><ul><li>4 adjudicated as cardiovascular events </li></ul></ul><ul><ul><ul><li>2 had antecedent myocardial infarction </li></ul></ul></ul><ul><ul><ul><ul><li>Abruptly discontinued  -blockers </li></ul></ul></ul></ul><ul><ul><li>3 adjudicated as prostate cancer </li></ul></ul><ul><ul><ul><li>Minimal evidence of heart failure at death </li></ul></ul></ul>
    55. 55. Myocardial Infarction Phase 2/3 Placebo-Controlled Studies Patients, n (%) 9 (1.7) 0 2 (0.4) All events 2 (0.4) - 1 (0.2) Resulted in death 4 (0.7) - 2 (0.4) Discontinuations 7 (1.3) - 2 (0.4) Grade 3/4 events Atrasentan 2.5 mg n = 136 Atrasentan 10 mg n = 541 Placebo n = 544
    56. 56. Potential Preceding Events for Adjudicated Myocardial Infarction Phase 2/3 Placebo-Controlled Studies (n = 10) <ul><li>8/10 patients had history of underlying ischemic heart disease </li></ul><ul><li>7/10 patients had one or more preceding events </li></ul><ul><ul><li>Worsening angina (n = 4) </li></ul></ul><ul><ul><li> -blocker discontinuation (n = 2) </li></ul></ul><ul><ul><li>Hemoglobin <10 g/dL (n = 4) </li></ul></ul>
    57. 57. Summary of Cardiovascular Events <ul><li>Arrhythmia </li></ul><ul><ul><li>Few grade 3/4 events </li></ul></ul><ul><ul><li>No deaths </li></ul></ul><ul><li>Heart failure/myocardial infarction </li></ul><ul><ul><li>Adjudicated </li></ul></ul><ul><ul><li>Not under-reported </li></ul></ul><ul><ul><li>Most are manageable </li></ul></ul><ul><ul><li>Identifiable risk factors </li></ul></ul>
    58. 58. Cardiovascular Safety Recommendations <ul><li>As with other vasoactive compounds in the elderly </li></ul><ul><ul><li>Consider cardiovascular risk factors prior to therapy </li></ul></ul><ul><ul><li>Physician monitoring of patients with cardiovascular risk factors and history </li></ul></ul><ul><ul><li>Treatment of volume overload and heart failure </li></ul></ul>
    59. 59. Safety Summary Atrasentan Is Generally Well-Tolerated <ul><li>Extensive safety experience </li></ul><ul><li>Overall safety profile similar to placebo for grade 3/4 events, discontinuations, and deaths </li></ul><ul><li>Serious cardiovascular events are infrequent and with monitoring can be managed </li></ul><ul><li>No drug interactions warranting dose adjustment </li></ul><ul><li>No significant hepatic, renal, or marrow toxicities </li></ul>
    60. 60. Xinlay ™ (atrasentan) Place in Therapy Michael A. Carducci, MD Co-Leader, Prostate Cancer Program Director, Translational Drug Development Kimmel Cancer Center at Johns Hopkins
    61. 61. Clinical Course of a Patient With HRPC and Bone Metastases Is Predictable <ul><li>Most succumb to disease </li></ul><ul><li>Most experience symptoms of metastases </li></ul><ul><li>For those without symptoms, delaying the development of symptoms is an important goal of treatment </li></ul><ul><li>More options and choices are needed </li></ul>Death from other causes Death from disease Bone metastases: Hormone-refractory Asymptomatic Time Bone metastases: Hormone-refractory Symptomatic
    62. 62. What Are the Options and What Can They Achieve? <ul><li>Symptoms present </li></ul><ul><ul><li>Analgesics </li></ul></ul><ul><ul><li>Radiation therapy </li></ul></ul><ul><ul><li>Bisphosphonates </li></ul></ul><ul><ul><li>Radiopharmaceuticals </li></ul></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><ul><li>Mitoxantrone and prednisone </li></ul></ul></ul><ul><ul><ul><li>Docetaxel-based chemotherapy </li></ul></ul></ul>
    63. 63. What Are the Options and What Can They Achieve? <ul><li>No symptoms </li></ul><ul><ul><li>Secondary hormones </li></ul></ul><ul><ul><ul><li>Simple </li></ul></ul></ul><ul><ul><ul><li>Non-toxic </li></ul></ul></ul><ul><ul><li>Taxotere-based chemotherapy </li></ul></ul><ul><ul><ul><li>IV </li></ul></ul></ul><ul><ul><ul><li>Survival benefit </li></ul></ul></ul><ul><ul><ul><li>Timing is controversial </li></ul></ul></ul><ul><ul><ul><li>Nearly all patients progress; median TTP 6 months </li></ul></ul></ul>Additional options are needed
    64. 64. Consider a 68-Year-Old Male With Hormone Refractory Disease, Progressive Bone Metastases, and No Symptoms 6 Months One Year 0 Months
    65. 65. His Future Illustrates the Clinical Dilemma <ul><li>Further progression of disease </li></ul><ul><li>Pain that will require opiates is inevitable </li></ul><ul><li>At risk for </li></ul><ul><ul><li>Significant morbidity from bone metastases – </li></ul></ul><ul><ul><li>pain and spinal cord compression </li></ul></ul><ul><ul><li>the medications needed to control the morbidity </li></ul></ul><ul><ul><li>Resulting in loss of mobility, fatigue, constipation, weight loss, and an overall deterioration </li></ul></ul>
    66. 66. The Clinical Dilemma <ul><li>His goal </li></ul><ul><ul><li>Maintain quality of life for as long as possible </li></ul></ul><ul><li>His question </li></ul><ul><ul><li>Are there additional options before or instead of chemotherapy? </li></ul></ul><ul><ul><li>Are there more convenient treatment options? </li></ul></ul><ul><ul><li>Are there any options that will delay progression? </li></ul></ul>
    67. 67. Atrasentan Blocks the Osteoblastic Response in Bone 4 Atrasentan Osteoblastic factors (ET-1) Bone-derived growth factors New bone Prostate cancer cells Osteoclasts Mineralized bone matrix Osteoblasts Osteolytic factors ET A
    68. 68. Clinical Benefit of Atrasentan Consistent Benefit for Patients With Bone Metastases Across Multiple Measures and Studies 0.4 0.6 0.8 1.0 0.2 Favors atrasentan Hazard ratio (95% CI) M00-211 M96-594 Time to disease progression BAP progression PSA progression 50% decline in FACT-P pain score (>56 days) Opioid initiation (85 days) Adverse event of bone pain (40 days) Radiographic Clinical 1.4 1.6 1.2
    69. 69. Xinlay™ (atrasentan) <ul><li>A novel targeted treatment for HRPC </li></ul><ul><li>Compelling scientific rationale </li></ul><ul><li>Extensively evaluated in randomized trials </li></ul><ul><li>Convenient once-daily oral therapy </li></ul><ul><li>Acceptable benefit-risk profile </li></ul>

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