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1 Oxypurinol for Gout Arthritis Drugs Advisory Committee June 2, 2004 Cardiome Pharma Corp Vancouver, BC Canada.

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Presentation on theme: "1 Oxypurinol for Gout Arthritis Drugs Advisory Committee June 2, 2004 Cardiome Pharma Corp Vancouver, BC Canada."— Presentation transcript:

1 1 Oxypurinol for Gout Arthritis Drugs Advisory Committee June 2, 2004 Cardiome Pharma Corp Vancouver, BC Canada

2 2 Introduction Alan Moore, PhD Executive VP, Cardiome Pharma Corp.

3 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 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 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 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 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 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 9 Speakers and Topics  Robert Makuch, PhD  Yale University OXPL 213 Analysis  Leonard Calabrese, DO  Cleveland Clinic Clinical Experience and Post-approval Issues

10 10 Gout: A Serious Progressive Disease Ralph Snyderman, MD Duke University

11 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 12 Stages of Gout  First: Asymptomatic hyperuricemia  Second: Acute recurrent gout  Third: Intercritical gout  Fourth: Chronic gout

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

14 14 Debilitating Gout

15 15 Urate Nephropathy

16 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 17 Management of Gout  Acute Gouty Arthritis  Colchicine  NSAIDS  Corticosteroids  Chronic Gout  Uricosuric agents  Xanthine Oxidase Inhibitors allopurinol; oxypurinol

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

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

20 20 Other Orphan Diseases Disease Incidence in US Cystic Fibrosis30,000 Hemophilia20,000 Allo-Intolerant Gout7,000-14,000 Addison’s Disease9,000 Gaucher’s Disease2,500

21 21 Oxypurinol Efficacy and Safety Garth Dickinson, MD University of Ottawa

22 22 Clinical Studies

23 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 24 OXPL Week Reduction in Serum Uric Acid Baseline Value (N=77) ITT Reduction (N=77) Completer Reduction (N=54) Mean SUA (mg/dL) % CI1.61, , 2.57 p<0.0001

25 25 OXPL 213 Clinically 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 26 CUP 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 27 Change in Serum Uric Acid: Baseline to Year 1 OXPL 213-A4 (N=14) CUP (N=190) Mean Reduction (mg/dL) % CI2.34, , 3.15 p<0.0001

28 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 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 30 Safety  Our safety case is built on data from  OXPL 213  CUP  Safety issues primarily relate to the 30% of allopurinol-intolerant patients who are also intolerant of oxypurinol

31 31 OXPL 213 Adverse Events

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

33 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 34 CUP Safety Profile Number of Events Category Overall (N = 533) Unrelated to Oxypurinol Related to Oxypurinol Any Serious Adverse Event (SAE)99 0 Any Adverse Event (AE) Any Adverse Event Graded Life-Threatening 74 0 Any Adverse Event Graded Severe Total patient years of dosing > 1500

35 35 Hepatic Adverse Events OXPL 213 (A4) N=79 CUP N=533 LFT allopurinol620 LFT oxypurinol26

36 36 Hepatic Toxicity in OXPL 213/OXPL 213-A4 Allopurinol Intolerance Trial Outcome Relationship to Oxypurinol Elevated LFTs probable rashProtocol Violationunrelated Elevated LFTsCompleterprobable rashCompleterunrelated rashCompleterunrelated rashCompleterunrelated

37 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 38 OXPL 213 Analysis Robert Makuch, PhD Yale University

39 39 OXPL 213 Trial Primary 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 40 OXPL 213 Trial Primary 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 41 N=2 No post-baseline SUA. Discontinued for reasons unrelated to study drug (per protocol for ITT efficacy population) OXPL 213 Trial ITT (efficacy) N=77 Enrolled and 1 dose N=79 Completed 14 weeks N=54 Discontinued Early N=23 No Post Baseline SUA N=8

42 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 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 44 Change from Average Baseline to Last Value ITT Baseline (N=77) Post-baseline (N=77) Reduction (N=77) Mean % CI1.61, 2.18 p< All Patients with a Post-baseline SUA Baseline (N=69) Post-baseline (N=69) Reduction (N=69) Mean % CI1.84, 2.39 p<

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

46 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 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 48 Clinical Experience and Post-approval Issues Leonard Calabrese, DO Cleveland Clinic

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

50 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

51 51 Addressing Outstanding Issues  Obtain well-controlled clinical outcome data  Phase IV Program (underway)  Limit access to appropriate patients  Subpart H Risk Management Program

52 52 Phase IV Protocol  A 2-year, placebo-controlled prospective randomized trial in 240 patients  Clinical endpoints  Frequency of gout attacks (primary)  Tophi reduction  Quality of life  SUA reduction  Correlate clinical outcomes to SUA  This trial is underway

53 53 Subpart H Risk Management Program  Subpart H Risk Management Program after marketing begins  Centralized drug distribution  Physician education program  Patient education program  Patient eligibility must be verified by physician and reviewed by the coordinator of the program  Patient registry to track outcomes  Ongoing analysis of AEs and patient safety

54 54 Benefit - Risk Considerations  Efficacy (i.e., SUA reduction) has been established  Safety has been acceptable and no drug related SAEs have been reported  Oxypurinol has a positive benefit-risk balance  The potential for SAEs will be managed through limited distribution

55 55 Conclusion  Allopurinol-intolerant patients have no therapeutic alternatives  Oxypurinol appears to have a positive benefit to risk balance  The Subpart H Risk Management Program is a better way to manage patients than the compassionate use program  Drug more accessible to patients  Better monitoring, control and data

56 56 Cardiome Pharma Corp. Vancouver, BC Canada Oxypurinol for Arthritis Drugs Advisory Committee June 2, 2004

57 57 Commitment of Cardiome to Oxypurinol  Committed to bringing the product to the market based on the existing database  Committed to Subpart H Risk Management Program  Committed to the Phase IV trial that will address important medical questions  The Phase IV trial has begun


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