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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 - PowerPoint PPT Presentation
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Oxypurinol for GoutArthritis Drugs Advisory Committee
June 2, 2004
Oxypurinol for GoutArthritis Drugs Advisory Committee
June 2, 2004Cardiome Pharma Corp
Vancouver, BC
Canada
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IntroductionIntroduction
Alan Moore, PhDExecutive VP, Cardiome Pharma Corp.
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Cardiome Pharma Corp.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
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Oxypurinol Regulatory HistoryOxypurinol Regulatory History
1966 – Burroughs Wellcome filed IND for compassionate use
1996 – ILEX acquired IND 1998 – Orphan Drug designation1999 – OXPL 213 pivotal trial initiated 2002 – Cardiome acquired IND2003 – Cardiome filed NDA
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Benefits of Subpart H Approval vs. Compassionate Use
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
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Proposed IndicationProposed 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.”
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Oxypurinol for Allopurinol-Intolerant Gout Patients:
Oxypurinol for Allopurinol-Intolerant Gout Patients:
Addresses an important unmet medical need
Demonstrates clinical efficacyWell tolerated in majority of allopurinol-
intolerant patientsAdditional safety and efficacy issues
addressed by: Subpart H Risk Management Program Phase IV study (underway)
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Speakers and TopicsSpeakers and Topics
Ralph Snyderman, MD Duke University
Gout: A Serious Progressive Disease
Garth Dickinson, MD University of Ottawa
Oxypurinol Efficacy and Safety
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Speakers and TopicsSpeakers and Topics
Robert Makuch, PhD Yale UniversityOXPL 213 Analysis
Leonard Calabrese, DO Cleveland Clinic
Clinical Experience and Post-approval Issues
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Gout: A Serious Progressive Disease
Gout: A Serious Progressive Disease
Ralph Snyderman, MDDuke University
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Gout:Serious, Progressive, Debilitating
Gout:Serious, Progressive, Debilitating
Gout is a serious metabolic diseaseGout is chronic, progressive and
debilitating Gout is the most common cause of
inflammatory arthritis in men over 40Many patients with gout have renal
insufficiency
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Stages of GoutStages of Gout
First: Asymptomatic hyperuricemiaSecond: Acute recurrent goutThird: Intercritical goutFourth: Chronic gout
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Gout and LifestyleGout and Lifestyle
More than a sore toe from excess rich food and drink
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Debilitating GoutDebilitating Gout
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Urate NephropathyUrate Nephropathy
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PathogenesisPathogenesis
At pH 7.4 and 37º C, uric acid precipitates as monosodium urate crystals at a serum uric acid (SUA)
> 7.0 mg/dL.
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Management of GoutManagement of Gout
Acute Gouty Arthritis Colchicine NSAIDS Corticosteroids
Chronic Gout Uricosuric agents Xanthine Oxidase Inhibitors
• allopurinol; oxypurinol
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Therapeutic GoalsTherapeutic Goals
Reduce:SUA and prevent continued deposition of
monosodium urate crystals
Frequency of acute gout attacksTophi Urate nephropathiesRenal colic
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Estimated Number of Patients who Tolerate Oxypurinol
7,000-14,000
Estimated Number of Patients who Tolerate Oxypurinol
7,000-14,000
Allopurinol Desensitization Failures Unmet Medical Need
10,000-20,000
Allopurinol Desensitization Failures Unmet Medical Need
10,000-20,000
Estimated Allopurinol-Intolerant Patients(2-4%)
20,000-40,000
Estimated Allopurinol-Intolerant Patients(2-4%)
20,000-40,000
The Unmet Medical NeedThe Unmet Medical Need
Gout Patients Prescribed Allopurinol1,000,000
Gout Patients Prescribed Allopurinol1,000,000
Gout Patients in the United States2,500,000
Gout Patients in the United States2,500,000
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Other Orphan DiseasesOther 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
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Oxypurinol Efficacy and Safety
Oxypurinol Efficacy and Safety
Garth Dickinson, MDUniversity of Ottawa
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Clinical StudiesClinical Studies
Study ID Total # of patients
Pivotal Phase II OXPL 213 79
Pivotal Phase II Extension OXPL 213-A4 48
Compassionate Use CUP 3362-01 533
Pharmacokinetics I AAI-US-175 48
Phase IV OXPL 401 240
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OXPL 213 TrialOXPL 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
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OXPL 21314-Week Reduction in Serum Uric Acid
OXPL 21314-Week Reduction in Serum Uric Acid
Baseline
Value(N=77)
ITT Reduction
(N=77)
Completer Reduction
(N=54)
Mean SUA
(mg/dL) 10.11 1.90 2.32
95% CI 1.61, 2.18 2.07, 2.57
p<0.0001
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OXPL 213Clinically Relevant SUA Reduction
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
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CUP 3362-01 Overview(Compassionate Use Program)CUP 3362-01 Overview(Compassionate Use Program)
533 patients since 196638% 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
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Change in Serum Uric Acid: Baseline to Year 1Change in Serum Uric Acid: Baseline to Year 1
OXPL 213-A4(N=14)
CUP 3362-01 (N=190)
Mean Reduction(mg/dL) 2.85 2.87
95% CI 2.34, 3.36 2.45, 3.15
p<0.0001
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Gout Flares on OxypurinolGout 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.
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Efficacy ConclusionsEfficacy 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
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SafetySafety
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
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OXPL 213 Adverse Events OXPL 213 Adverse Events
Category Number of Patients
N=79 Number of
Events Oxypurinol-Related
Events
Any Adverse Event 57 129 30
Any Serious AE 10 13 0
Death 1 1 0
Any Life -Threatening AE 5 5 0
Any Severe Intensity AE 7 7 3
AE leading to discontinuation 22 22 21
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OXPL 213 Discontinuations Due to Adverse Events Related to Oxypurinol
OXPL 213 Discontinuations Due to Adverse Events Related to Oxypurinol
Type of Reaction to Allopurinol
Type of Reaction to Oxypurinol
Distribution
Dermatologic Dermatologic 16
Dermatologic/Malaise Dermatologic 1
Dermatologic/Renal Dermatologic 1
Dermatologic Thrombocytopenia 1
Elevated LFTs Elevated LFTs 1
Malaise/Elevated LFTs/Renal GI (Nausea) 1
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OXPL 213 Discontinuations Due to Adverse Events Related to Oxypurinol
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%)
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CUP 3362-01 Safety ProfileCUP 3362-01 Safety Profile
Number of Events
CategoryOverall
(N = 533)Unrelated toOxypurinol
Related toOxypurinol
Any Serious Adverse Event (SAE) 99 99 0
Any Adverse Event (AE) 221 101 120
Any Adverse Event Graded Life-Threatening
74 74 0
Any Adverse Event Graded Severe 28 18 10
Total patient years of dosing > 1500
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Hepatic Adverse EventsHepatic Adverse Events
OXPL 213 (A4)
N=79
CUP 3362-01
N=533
LFT allopurinol 6 20
LFT oxypurinol 2 6
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Hepatic Toxicity in OXPL 213/OXPL 213-A4
Hepatic Toxicity in OXPL 213/OXPL 213-A4
Allopurinol Intolerance
Trial OutcomeRelationship to
Oxypurinol
Elevated LFTs Elevated LFTs probable
rash Protocol Violation unrelated
Elevated LFTs Completer probable
rash Completer unrelated
rash Completer unrelated
rash Completer unrelated
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Safety Conclusions for OxypurinolSafety 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
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OXPL 213 AnalysisOXPL 213 Analysis
Robert Makuch, PhDYale University
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OXPL 213 TrialPrimary Efficacy Objective
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.”
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OXPL 213 TrialPrimary Efficacy Endpoint
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.
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N=2No post-baseline
SUA. Discontinued for reasons unrelated
to study drug (per protocol for ITT
efficacy population)
N=2No post-baseline
SUA. Discontinued for reasons unrelated
to study drug (per protocol for ITT
efficacy population)
OXPL 213 TrialOXPL 213 Trial
ITT (efficacy)N=77
ITT (efficacy)N=77
Enrolled and 1 doseN=79
Enrolled and 1 doseN=79
Completed 14 weeksN=54
Completed 14 weeksN=54
Discontinued EarlyN=23
Discontinued EarlyN=23
No Post Baseline SUAN=8
No Post Baseline SUAN=8
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Statistical IssuesStatistical 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
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Analyses of OXPL 213Analyses 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
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Change from Average Baseline to Last Value
Change from Average Baseline to Last Value
ITT
Baseline
(N=77)
Post-baseline
(N=77)
Reduction
(N=77)
Mean 10.11 8.16 1.95
95% CI 1.61, 2.18
p< 0.0001
All Patients with a Post-baseline SUA
Baseline
(N=69)
Post-baseline
(N=69)
Reduction
(N=69)
Mean 10.08 7.96 2.12
95% CI 1.84, 2.39
p< 0.0001
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Patient Profiles of SUA(mg/dL) vs Time(weeks)Patient Profiles of SUA(mg/dL) vs Time(weeks)
6 week 9 week 12 week 14 week13 week
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Regression AnalysisRegression 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
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ConclusionsConclusions
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
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Clinical Experience and Post-approval Issues
Clinical Experience and Post-approval Issues
Leonard Calabrese, DOCleveland Clinic
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Options for Allopurinol-Intolerant Patients
Options for Allopurinol-Intolerant Patients
Desensitize or Rechallenge
Desensitize or Rechallenge
OxypurinolOxypurinol
SuccessSuccess
FailFail
Symptomatic and Supportive CareSymptomatic and Supportive Care
FailFail
SuccessSuccess
Allopurinol-Intolerance with Therapeutic NeedAllopurinol-Intolerance with Therapeutic Need
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Personal Clinical Experience with Oxypurinol
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
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Addressing Outstanding IssuesAddressing Outstanding Issues
Obtain well-controlled clinical outcome data Phase IV Program (underway)
Limit access to appropriate patients Subpart H Risk Management Program
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Phase IV Protocol 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
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Subpart H Risk Management ProgramSubpart 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
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Benefit - Risk ConsiderationsBenefit - 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
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ConclusionConclusion
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
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Cardiome Pharma Corp.
Vancouver, BC
Canada
Oxypurinol forArthritis Drugs Advisory Committee
June 2, 2004
Oxypurinol forArthritis Drugs Advisory Committee
June 2, 2004
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Commitment of Cardiome to Oxypurinol
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