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Oxypurinol for Gout Arthritis Drugs Advisory Committee June 2, 2004. Cardiome Pharma Corp Vancouver, BC Canada. Introduction. Alan Moore, PhD Executive VP, Cardiome Pharma Corp. Cardiome Pharma Corp. R&D company based in Vancouver, British Columbia, Canada

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Oxypurinol for Gout Arthritis Drugs Advisory Committee June 2, 2004


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    1. Oxypurinol for GoutArthritis Drugs Advisory CommitteeJune 2, 2004 Cardiome Pharma Corp Vancouver, BC Canada

    2. Introduction Alan Moore, PhDExecutive VP, Cardiome Pharma Corp.

    3. Cardiome Pharma Corp. • R&D company based in Vancouver, British Columbia, Canada • Focus on cardiovascular drug development • Frequent interactions with both FDA’s Cardio-Renal and Anti-Inflammatory drug divisions

    4. Oxypurinol Regulatory History • 1966 – Burroughs Wellcome filed IND for compassionate use • 1996 – ILEX acquired IND • 1998 – Orphan Drug designation • 1999 – OXPL 213 pivotal trial initiated • 2002 – Cardiome acquired IND • 2003 – Cardiome filed NDA

    5. Benefits of Subpart H Approval vs. Compassionate Use • Subpart H approval provides • Patient education • Restrictive patient enrollment criteria • Patient registry • Physician education & training • Collection of safety data • Fewer patients lost to follow up

    6. Proposed Indication “Oxypurinol is indicated to treat hyperuricemia in patients with symptomatic gout who are intolerant to allopurinol and have failed either rechallenge or desensitization with allopurinol.”

    7. Oxypurinol for Allopurinol-Intolerant Gout Patients: • Addresses an important unmet medical need • Demonstrates clinical efficacy • Well tolerated in majority of allopurinol-intolerant patients • Additional safety and efficacy issues addressed by: • Subpart H Risk Management Program • Phase IV study (underway)

    8. Speakers and Topics • Ralph Snyderman, MD • Duke University Gout: A Serious Progressive Disease • Garth Dickinson, MD • University of Ottawa Oxypurinol Efficacy and Safety

    9. Speakers and Topics • Robert Makuch, PhD • Yale University OXPL 213 Analysis • Leonard Calabrese, DO • Cleveland Clinic Clinical Experience and Post-approval Issues

    10. Gout: A Serious Progressive Disease Ralph Snyderman, MDDuke University

    11. Gout:Serious, Progressive, Debilitating • Gout is a serious metabolic disease • Gout is chronic, progressive and debilitating • Gout is the most common cause of inflammatory arthritis in men over 40 • Many patients with gout have renal insufficiency

    12. Stages of Gout • First: Asymptomatic hyperuricemia • Second: Acute recurrent gout • Third: Intercritical gout • Fourth: Chronic gout

    13. Gout and Lifestyle More than a sore toe from excess rich food and drink

    14. Debilitating Gout

    15. Urate Nephropathy

    16. Pathogenesis At pH 7.4 and 37º C, uric acid precipitates as monosodium urate crystals at a serum uric acid (SUA) > 7.0 mg/dL.

    17. Management of Gout • Acute Gouty Arthritis • Colchicine • NSAIDS • Corticosteroids • Chronic Gout • Uricosuric agents • Xanthine Oxidase Inhibitors • allopurinol; oxypurinol

    18. Therapeutic Goals Reduce: SUA and prevent continued deposition of monosodium urate crystals • Frequency of acute gout attacks • Tophi • Urate nephropathies • Renal colic

    19. The Unmet Medical Need Gout Patients in the United States 2,500,000 Gout Patients Prescribed Allopurinol 1,000,000 Estimated Allopurinol-Intolerant Patients (2-4%) 20,000-40,000 Allopurinol Desensitization Failures Unmet Medical Need 10,000-20,000 Estimated Number of Patients who Tolerate Oxypurinol 7,000-14,000

    20. Other Orphan Diseases Disease Incidence in US Cystic Fibrosis 30,000 Hemophilia 20,000 Allo-Intolerant Gout 7,000-14,000 Addison’s Disease 9,000 Gaucher’s Disease 2,500

    21. Oxypurinol Efficacy and Safety Garth Dickinson, MDUniversity of Ottawa

    22. Clinical Studies

    23. OXPL 213 Trial • Open-label, single arm, multicenter trial • Enrolled 79 allopurinol-intolerant patients – 14 week trial • Mild to moderate allopurinol intolerance • Primary efficacy endpoint - SUA reduction of 2 mg/dL

    24. OXPL 21314-Week Reduction in Serum Uric Acid

    25. OXPL 213Clinically Relevant SUA Reduction • 29 of 77 (38%) of the ITT population had SUA reduction to normal range • 27 of 54 (50%) of completers had SUA reduction to normal range at 14 weeks • 20 of 54 (37%) had SUA ≤ 7 mg/dL • 9 of 54 (17%) had SUA ≤ 6 mg/dL

    26. CUP 3362-01 Overview(Compassionate Use Program) • 533 patients since 1966 • 38% renal failure (creatinine ≥ 2 mg/dL) • Average dose 372 mg at 1 year • dose range 100 to 1800 mg/day • Average duration of treatment 3.2 years • 22 years maximum treatment duration • 162 patients currently on oxypurinol

    27. Change in Serum Uric Acid: Baseline to Year 1

    28. Gout Flares on Oxypurinol • 24 gout flares were experienced by 12 patients during OXPL 213 and OXPL 213-A4 • Rate of gout flares with oxypurinol • 12 of 77 (16%), none discontinued • Rate of gout flares with allopurinol • 10% to 24% (Fam 1995) • Conclusion: Initiation of treatment with oxypurinol precipitates gout flares at a similar frequency as with the initiation of treatment with allopurinol.

    29. Efficacy Conclusions • Oxypurinol is effective in reducing SUA in allopurinol-intolerant patients • SUA reductions in allopurinol-intolerant patients treated with oxypurinol are similar in magnitude to SUA reductions achieved with allopurinol

    30. Safety • Our safety case is built on data from • OXPL 213 • CUP 3362-01 • Safety issues primarily relate to the 30% of allopurinol-intolerant patients who are also intolerant of oxypurinol

    31. OXPL 213 Adverse Events

    32. OXPL 213 Discontinuations Due to Adverse Events Related to Oxypurinol

    33. OXPL 213 Discontinuations Due to Adverse Events Related to Oxypurinol Early: 15 of 21 (71%) within 1 week 21 of 21 (100%) within 9 weeks Predictable: 19 of 21 (90%) same as with allopurinol Severity: 19 of 21 (90%) mild or moderate 2 of 21 (10%) severe Reversible: 21 of 21 (100%)

    34. CUP 3362-01 Safety Profile Total patient years of dosing > 1500

    35. Hepatic Adverse Events

    36. Hepatic Toxicity in OXPL 213/OXPL 213-A4

    37. Safety Conclusions for Oxypurinol • 70% can tolerate oxypurinol • AEs occur early (71% in first week) • AEs are predictable (90% same as allopurinol) • AEs are reversible • Risk of hepatic toxicity • Similar to allopurinol • Must be closely monitored • No drug-related SAEs reported In the intended population oxypurinol is much safer than allopurinol

    38. OXPL 213 Analysis Robert Makuch, PhDYale University

    39. OXPL 213 TrialPrimary Efficacy Objective “2.1 Primary Objectives (1) To demonstrate the efficacy of oxypurinol in lowering serum uric acid by at least 2 mg/dL after 14 weeks of its administration to symptomatic, hyperuricemic patients who have developed an intolerance to allopurinol.”

    40. OXPL 213 TrialPrimary Efficacy Endpoint • The mean of the three baseline assessments, minus • The mean of the assessments made at weeks 12, 13, and 14 • For patients who discontinued prior to week 14, the last available assessment was used in the analysis.

    41. No Post Baseline SUA N=8 OXPL 213 Trial Enrolled and 1 dose N=79 N=2No post-baseline SUA. Discontinued for reasons unrelated to study drug (per protocol for ITT efficacy population) ITT (efficacy) N=77 Discontinued Early N=23 Completed 14 weeks N=54

    42. Statistical Issues • Eight patients without a post baseline SUA value were originally assigned a SUA change value of zero • Compromised ability to detect a SUA reduction of 2.0 • This is not optimal statistical approach

    43. Analyses of OXPL 213 • Alternative endpoints • Proportion reverting to normal SUA level • Baseline average minus last value • Regression analysis • Uses all data in ITT population (N=77) • No data imputation

    44. Change from Average Baseline to Last Value

    45. Patient Profiles of SUA(mg/dL) vs Time(weeks) 13 week 6 week 9 week 12 week 14 week

    46. Regression Analysis • Linear regression with both linear and quadratic terms • At week 14 there is a mean drop of 2.37 mg/dL in SUA • 95% confidence limit equals 2.06, 2.67

    47. Conclusions • Alternate endpoint analyses: • N=77 mean drop 1.95 mg/dL (p<0.0001) • N=69 mean drop 2.17 mg/dL (p<0.0001) • Regression analysis: • N=77 mean drop 2.37 mg/dL (p<0.0001) • All analyses show a highly statistically significant reduction in SUA

    48. Clinical Experience and Post-approval Issues Leonard Calabrese, DOCleveland Clinic

    49. Options for Allopurinol-Intolerant Patients Allopurinol-Intolerance with Therapeutic Need Desensitize or Rechallenge Success Fail Oxypurinol Success Fail Symptomatic and Supportive Care

    50. Personal Clinical Experience with Oxypurinol • 13 patients treated with oxypurinol in CUP since 1984; 3 in pivotal trial • 2 patients intolerant to oxypurinol • 11 patients on oxypurinol from 4 weeks to >10 years • currently have 3 patients • 1 chronic tophaceous gout • 1 chronic recurrent gouty attacks • 1 renal transplant with refractory tophaceous gout