# Presentation: 690751

## Oxypurinol for GoutArthritis Drugs Advisory CommitteeJune 2, 2004

- Cardiome Pharma Corp
- Vancouver, BC
- Canada

## Introduction

- Alan Moore, PhDExecutive VP, 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

- 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

- 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

- “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.”

**Notes:**
Confirm precise wording

## 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

- Ralph Snyderman, MD
- Duke University
- 	Gout: A Serious Progressive Disease
- Garth Dickinson, MD
- University of Ottawa
- Oxypurinol Efficacy and Safety

## 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

- Ralph Snyderman, MDDuke University

## 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

- First: Asymptomatic hyperuricemia
- Second: Acute recurrent gout
- Third: Intercritical gout
- Fourth: Chronic gout

## Gout and Lifestyle

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

## Debilitating Gout

## Urate Nephropathy

**Notes:**
Fig. 1. Gouty tophi in joint and kidney. Chalky white urate deposits are visible in the articular cartilage (right). The corresponding kidney (left) shows yellowish areas in the pyramids (arrow) representing fibrosis and urate deposits.

## 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

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

## 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

**7,000-14,000**

**Allopurinol Desensitization Failures **
**Unmet Medical Need**
**10,000-20,000**

**Estimated Allopurinol-Intolerant Patients**
**(2-4%)**
**20,000-40,000**

**Gout Patients Prescribed Allopurinol**
**1,000,000**

**Gout Patients in the United States**
**2,500,000**

## 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

- Garth Dickinson, MDUniversity of Ottawa

## Clinical Studies

## 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

**Notes:**
Confirm precise wording

## OXPL 21314-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
 |  |

## 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

## 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

## Change 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
 |  |

## 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

- 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

- 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 Adverse Events 

## 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%)

## CUP 3362-01 Safety Profile

|  | Number of Events |  |  |
| --- | --- | --- | --- |
| Category | Overall
(N = 533) | Unrelated toOxypurinol  | 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 > 1500

## Hepatic Adverse Events

|  | OXPL 213 (A4)
N=79 | CUP 3362-01
N=533 |
| --- | --- | --- |
| LFT allopurinol | 6 | 20 |
| LFT oxypurinol | 2 | 6 |

## 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 |

## 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

- Robert Makuch, PhDYale University

## 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.”

**Notes:**
Confirm precise wording

## 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.

**Notes:**
Confirm precise wording

## OXPL 213 Trial

**ITT (efficacy)**
**N=77**

**Enrolled and 1 dose**
**N=79**

**Completed 14 weeks**
**N=54**

**Discontinued Early**
**N=23**

## 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

- 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

## 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 |  |
|  |  |  |  |

## Patient Profiles of SUA(mg/dL) vs Time(weeks)

- 6 week

- 9 week

- 12 week

- 14 week

- 13 week

## 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

- 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

- Leonard Calabrese, DOCleveland Clinic

## Options for Allopurinol-Intolerant Patients

- Options for Allopurinol-Intolerant Patients

**Desensitize or **
**Rechallenge**

**Oxypurinol**

**Success**

**Fail**

**Symptomatic and Supportive Care**

**Fail**

**Success**

**Allopurinol-Intolerance with Therapeutic Need**

## 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

- Obtain well-controlled clinical outcome data
- Phase IV Program (underway)
- Limit access to appropriate patients
- Subpart H Risk Management Program

## 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 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

- 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

- 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

**Notes:**
Third bullet 

## Cardiome Pharma Corp.
Vancouver, BC 
Canada

- Vancouver, BC
- Canada

- Oxypurinol forArthritis Drugs Advisory CommitteeJune 2, 2004

## 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