Oxypurinol for Gout Arthritis Drugs Advisory Committee June 2, 2004

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Oxypurinol for GoutArthritis Drugs Advisory
CommitteeJune 2, 2004

• Cardiome Pharma Corp
• Vancouver, BC
• Canada

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Introduction

• Alan Moore, PhDExecutive VP, Cardiome Pharma
  Corp.

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Cardiome Pharma Corp.

• RD company based in Vancouver, British Columbia,
  Canada
• Focus on cardiovascular drug development
• Frequent interactions with both FDAs
  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

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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 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

• Addresses an important unmet medical need
• Demonstrates clinical efficacy
• Well tolerated in majority of allopurinol-intolera
  nt patients
• Additional safety and efficacy issues addressed
  by
• Subpart H Risk Management Program
• Phase IV study (underway)

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Speakers 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 Topics

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

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Gout A Serious Progressive Disease

• Ralph Snyderman, MDDuke University

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GoutSerious, 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

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Stages of Gout

• First Asymptomatic hyperuricemia
• Second Acute recurrent gout
• Third Intercritical gout
• Fourth Chronic gout

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Gout and Lifestyle

• More than a sore toe from excess rich food and
  drink

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Debilitating Gout
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Urate Nephropathy
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Pathogenesis

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

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Management of Gout

• Acute Gouty Arthritis
• Colchicine
• NSAIDS
• Corticosteroids
• Chronic Gout
• Uricosuric agents
• Xanthine Oxidase Inhibitors
• allopurinol oxypurinol

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Therapeutic Goals

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

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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
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Other Orphan Diseases

• Disease Incidence in US
• Cystic Fibrosis 30,000
• Hemophilia 20,000
• Allo-Intolerant Gout 7,000-14,000
• Addisons Disease 9,000
• Gauchers Disease 2,500

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Oxypurinol Efficacy and Safety

• Garth Dickinson, MDUniversity of Ottawa

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Clinical Studies
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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

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OXPL 21314-Week Reduction in Serum Uric Acid
Baseline Value(N77) ITT Reduction (N77) Completer Reduction (N54)
Mean SUA (mg/dL) 10.11 1.90 2.32
95 CI 1.61, 2.18 2.07, 2.57
plt0.0001
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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)

• 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

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Change in Serum Uric Acid Baseline to Year 1
OXPL 213-A4(N14) CUP 3362-01 (N190)
Mean Reduction(mg/dL) 2.85 2.87
95 CI 2.34, 3.36 2.45, 3.15
plt0.0001 plt0.0001
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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.

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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

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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

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OXPL 213 Adverse Events
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OXPL 213 Discontinuations Due to Adverse Events
Related to Oxypurinol
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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 Profile
Number of Events Number of Events Number of Events
Category Overall (N 533) Unrelated toOxypurinol Related to Oxypurinol
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 gt 1500
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Hepatic Adverse Events
OXPL 213 (A4) N79 CUP 3362-01 N533
LFT allopurinol 6 20
LFT oxypurinol 2 6
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Hepatic Toxicity in OXPL 213/OXPL 213-A4
Allopurinol Intolerance Trial Outcome Relationship 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 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 Analysis

• Robert Makuch, PhDYale University

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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

• 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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OXPL 213 Trial
Enrolled and 1 dose N79
N2No post-baseline SUA. Discontinued for
reasons unrelated to study drug (per protocol for
ITT efficacy population)
ITT (efficacy) N77
Completed 14 weeks N54
Discontinued Early N23
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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

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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 (N77)
• No data imputation

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Change from Average Baseline to Last Value
ITT ITT ITT
Baseline (N77) Post-baseline (N77) Reduction (N77)
Mean 10.11 8.16 1.95
95 CI 1.61, 2.18
plt 0.0001

All Patients with a Post-baseline SUA All Patients with a Post-baseline SUA All Patients with a Post-baseline SUA
Baseline (N69) Post-baseline (N69) Reduction (N69)
Mean 10.08 7.96 2.12
95 CI 1.84, 2.39
plt 0.0001

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

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Conclusions

• Alternate endpoint analyses
• N77 mean drop 1.95 mg/dL (plt0.0001)
• N69 mean drop 2.17 mg/dL (plt0.0001)
• Regression analysis
• N77 mean drop 2.37 mg/dL (plt0.0001)
• All analyses show a highly statistically
  significant reduction in SUA

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Clinical Experience and Post-approval Issues

• Leonard Calabrese, DOCleveland Clinic

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Options for Allopurinol-Intolerant Patients
Allopurinol-Intolerance with Therapeutic Need
Desensitize or Rechallenge
Success
Fail
Oxypurinol
Success
Fail
Symptomatic and Supportive Care
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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 gt10
  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 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

• 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 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 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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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

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Oxypurinol forArthritis Drugs Advisory
CommitteeJune 2, 2004

• Cardiome Pharma Corp.
• Vancouver, BC
• Canada

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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