1

Oxypurinol for GoutArthritis Drugs Advisory Committee

June 2, 2004

Oxypurinol for GoutArthritis Drugs Advisory Committee

June 2, 2004Cardiome Pharma Corp

Vancouver, BC

Canada

2

IntroductionIntroduction

Alan Moore, PhDExecutive VP, Cardiome Pharma Corp.

3

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

4

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

5

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

6

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.”

7

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)

8

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

9

Speakers and TopicsSpeakers and Topics

Robert Makuch, PhD Yale UniversityOXPL 213 Analysis

Leonard Calabrese, DO Cleveland Clinic

Clinical Experience and Post-approval Issues

10

Gout: A Serious Progressive Disease

Gout: A Serious Progressive Disease

Ralph Snyderman, MDDuke University

11

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

12

Stages of GoutStages of Gout

First: Asymptomatic hyperuricemiaSecond: Acute recurrent goutThird: Intercritical goutFourth: Chronic gout

13

Gout and LifestyleGout and Lifestyle

More than a sore toe from excess rich food and drink

14

Debilitating GoutDebilitating Gout

15

Urate NephropathyUrate Nephropathy

16

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.

17

Management of GoutManagement of Gout

Acute Gouty Arthritis Colchicine NSAIDS Corticosteroids

Chronic Gout Uricosuric agents Xanthine Oxidase Inhibitors

• allopurinol; oxypurinol

18

Therapeutic GoalsTherapeutic Goals

Reduce:SUA and prevent continued deposition of

monosodium urate crystals

Frequency of acute gout attacksTophi Urate nephropathiesRenal colic

19

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

20

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

21

Oxypurinol Efficacy and Safety

Oxypurinol Efficacy and Safety

Garth Dickinson, MDUniversity of Ottawa

22

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

23

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

24

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

25

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

26

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

27

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

28

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.

29

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

30

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

31

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

32

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

33

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%)

34

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

35

Hepatic Adverse EventsHepatic Adverse Events

OXPL 213 (A4)

N=79

CUP 3362-01

N=533

LFT allopurinol 6 20

LFT oxypurinol 2 6

36

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

37

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

38

OXPL 213 AnalysisOXPL 213 Analysis

Robert Makuch, PhDYale University

39

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.”

40

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.

41

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

42

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

43

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

44

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

45

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

46

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

47

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

48

Clinical Experience and Post-approval Issues

Clinical Experience and Post-approval Issues

Leonard Calabrese, DOCleveland Clinic

49

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

50

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

51

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

52

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

53

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

54

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

55

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

56

Cardiome Pharma Corp.

Vancouver, BC

Canada

Oxypurinol forArthritis Drugs Advisory Committee

June 2, 2004

Oxypurinol forArthritis Drugs Advisory Committee

June 2, 2004

57

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