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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

Oxypurinol for GoutArthritis Drugs Advisory CommitteeJune 2, 2004

Cardiome Pharma Corp

Vancouver, BC

Canada

introduction

Introduction

Alan Moore, PhDExecutive VP, Cardiome Pharma Corp.

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
oxypurinol regulatory history
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
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
proposed indication
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.”

oxypurinol for allopurinol intolerant gout patients
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)
speakers and topics
Speakers and Topics
  • Ralph Snyderman, MD
    • Duke University

Gout: A Serious Progressive Disease

  • Garth Dickinson, MD
    • University of Ottawa

Oxypurinol Efficacy and Safety

speakers and topics1
Speakers and Topics
  • Robert Makuch, PhD
    • Yale University

OXPL 213 Analysis

  • Leonard Calabrese, DO
    • Cleveland Clinic

Clinical Experience and Post-approval Issues

gout a serious progressive disease

Gout: A Serious Progressive Disease

Ralph Snyderman, MDDuke University

gout serious progressive debilitating
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
stages of gout
Stages of Gout
  • First: Asymptomatic hyperuricemia
  • Second: Acute recurrent gout
  • Third: Intercritical gout
  • Fourth: Chronic gout
gout and lifestyle
Gout and Lifestyle

More than a sore toe from excess rich food and drink

pathogenesis
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.

management of gout
Management of Gout
  • Acute Gouty Arthritis
    • Colchicine
    • NSAIDS
    • Corticosteroids
  • Chronic Gout
    • Uricosuric agents
    • Xanthine Oxidase Inhibitors
      • allopurinol; oxypurinol
therapeutic goals
Therapeutic Goals

Reduce:

SUA and prevent continued deposition of monosodium urate crystals

  • Frequency of acute gout attacks
  • Tophi
  • Urate nephropathies
  • Renal colic
the unmet medical need
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

other orphan diseases
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

oxypurinol efficacy and safety

Oxypurinol Efficacy and Safety

Garth Dickinson, MDUniversity of Ottawa

oxpl 213 trial
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
oxpl 213 clinically 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
cup 3362 01 overview compassionate use program
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
gout flares on oxypurinol
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.
efficacy conclusions
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
safety
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
oxpl 213 discontinuations due to adverse events related to oxypurinol1
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%)

cup 3362 01 safety profile
CUP 3362-01 Safety Profile

Total patient years of dosing > 1500

safety conclusions for oxypurinol
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

oxpl 213 analysis

OXPL 213 Analysis

Robert Makuch, PhDYale University

oxpl 213 trial primary 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.”

oxpl 213 trial primary 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.
oxpl 213 trial1

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

statistical issues
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
analyses of oxpl 213
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
patient profiles of sua mg dl vs time weeks
Patient Profiles of SUA(mg/dL) vs Time(weeks)

13 week

6 week

9 week

12 week

14 week

regression analysis
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
conclusions
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
clinical experience and post approval issues

Clinical Experience and Post-approval Issues

Leonard Calabrese, DOCleveland Clinic

options for allopurinol intolerant patients
Options for Allopurinol-Intolerant Patients

Allopurinol-Intolerance with Therapeutic Need

Desensitize or

Rechallenge

Success

Fail

Oxypurinol

Success

Fail

Symptomatic and Supportive Care

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
addressing outstanding issues
Addressing Outstanding Issues
  • Obtain well-controlled clinical outcome data
    • Phase IV Program (underway)
  • Limit access to appropriate patients
    • Subpart H Risk Management Program
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
subpart h risk management program
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
benefit risk considerations
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
conclusion
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
oxypurinol for arthritis drugs advisory committee june 2 2004

Oxypurinol forArthritis Drugs Advisory CommitteeJune 2, 2004

Cardiome Pharma Corp.

Vancouver, BC

Canada

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