1. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20041 Arthritis Drugs Advisory Committee TAP Pharmaceutical Products Inc. June 2, 2004

2. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20042 Hyperuricemia and Chronic Gout Nancy Joseph-Ridge, MD Therapeutic Area Head, Rheumatology/Internal Medicine

3. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20043 Management of Hyperuricemia Treatment of hyperuricemia is indicated for –Gout –Tophaceous gout –Renal calculi due to uric acid Goal - reduce and maintain serum urate < 6.0 mg/dl NEJM 334(7): 445-451, 1996;. Ruddy: Kelley’s Textbook of Rheumatology 6 th ed. Chapter 89: 1339-1348. 2001 Harrison’s Principles of Internal Medicine 14 th ed. Part Thirteen, Chapter 344: 2158-2165, 1998. Goldman:Cecil Textbook of Medicine 21 st ed. Chapter 299, 1542-1548, 2000. Rheumatic Disease Clinics of NA. 26(3): 1-11, 2000

4. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20044 Management of Hyperuricemia Treatment of hyperuricemia with allopurinol (2-10 years) –57 subjects studied prospectively for 10 years –Serum UA < 6.0 mg/dl was associated with Reduction in tophus size Fewer crystals in joint fluid aspirates Fewer gout attacks over 2 years JRheum 28(3):577-580,2001

5. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20045 Recent Publication on Urate Lowering Agents and Reduction of Tophi 63 patients treated with allopurinol, benzbromarone, or both Tophi measured using calipers Mean duration until tophi resolution 20.8±10.2 months Resolution rates and serum urate levels: –Allopurinol: 0.57 ± 0.18*mm/month, 5.37 ± 0.79 mg/dL –Benzbromarone: 1.21 ± 0.67 mm/month; 4.22 ± 1.01 mg/dL –Combined: 1.53 ± 0.45 mm/month; 3.97 ± 0.76 mg/dL * P<0.01; Arth and Rheum (Arth Care & Res), 47(4):356-360, 2002

6. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20046 Clinical Trial Design Primary Endpoint – maintenance of reduction in serum urate < 6.0 mg/dL Secondary Endpoints – clinical –Tophi reduction –Reduction in Gout Flares Inclusion of comparator –e.g., allopurinol and/or placebo Minimally demonstrate equivalence to comparator Consider safety dose –e.g., 2 x maximum clinical dose

7. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20047 Clinical Trial Design – Cont’d Long Term Controlled Clinical Studies –One study at least 1 year duration Study Population –Inclusion of subjects with renal impairment and other co-morbidities –A proportion of subjects with high baseline serum urate

8. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20048 Proposed Patient Reported Outcomes for Chronic Gout Treatment Jane T. Osterhaus, PhD

9. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 20049 Humanistic Burden of gout deserves better understanding Renewed interest in gout treatments Prevalence of gout expected to increase –Aging population –Obesity –Type 2 diabetes mellitus Patient Reported Outcomes (PROs) are an important source of information (HRQOL, functional status, work productivity)

10. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 200410 No existing guidance on PROs for gout clinical trials Gout is a chronic disease with bothersome symptoms (pain, swelling, tophi) Reasonable to consider measuring: –Functioning –Well-being –Symptom relief –Satisfaction with treatment

11. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 200411 General Health Status Measures to include in chronic gout clinical trials SF-36 –8 general domains –Reliable & valid –Used in randomized controlled trials in various therapeutic areas –Allow comparisons across conditions

12. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 200412 Disease-Specific Arthritis Measure Health Assessment Questionnaire - disability index (HAQ-DI) 8 domains (dressing & grooming, arising, eating, walking, hygiene, reach, grip, activities) 20 items

13. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 200413 Disease-Specific Aspects of Gout No gout-specific PRO in the literature Focuses on specific aspects of condition not captured in general assessments, but still important to patients TAP has developed Gout Assessment Questionnaire (GAQ) –21 items –7 domains Gout Concern Well-Being Productivity Gout Pain and Severity Treatment Satisfaction Treatment Convenience Treatment Bother

14. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 200414 Current Status of GAQ Good internal consistency Adequate reliability (for initial use) Ongoing: –Confirm scales –More experience in different gout populations –Understand relationship with clinical measures –Understand change over time

15. TAP PHARMACEUTICAL PRODUCTS INC. June 2, 200415 Timing of measures Initiation of therapy may result in more acute gout flares May take up to 1 year for total body urate load to decrease to normal Evaluate longer term data when considering impact of gout treatment from patients perspective