1. Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients Lourdes Villalba, M.D. DAAODP, CDER, FDA Arthritis Advisory Committee Meeting June 2, 2004

2. 2 Goal –Clinical trial design for chronic gout –Data from a specific NDA as an example for discussion

3. 3 Oxypurinol  Proposed indication: “Treatment of hyperuricemia in patients with symptomatic gout who are intolerant to allopurinol and have failed either rechallenge or desensitization with allopurinol”

4. 4 Allopurinol  Effectively reduces serum uric acid (SUA) at doses 300 – 800 mg daily  Active metabolite is oxypurinol  Allopurinol T ½ < 2 hr.  Oxypurinol T ½ : 13 - 29 hr.  Limited data on allopurinol/oxypurinol comparison

5. 5 PK Study AAI-US-175  Open-label, dose linearity, fasted/fed, bioequivalence study (N=42)  Relative bioavailability of single dose of oxypurinol is about 30% of allopurinol  No data on multiple-dose conversion Oxy (mg)100300600800 Allo (mg)587881112

6. 6 Allopurinol Safety  Hypersensitivity reactions (2-4%) –Skin (mild to severe; fatal) –Fever, hepatitis, nephritis, hematologic –AHS (allopurinol hypersensitivity syndrome) –Mechanism: type IV ?  Non-immunologic toxicity –renal, liver –animal toxicity: renal, liver, cardiac  Unclear whether hypersensitivity related to allopurinol, oxypurinol or other metabolite

7. 7 Allopurinol Desensitization A&R 44(1): 231-238, 2001 For moderate skin intolerance –retrospective evaluation, N=32 –desensitization over one month, mean FU 32 m, mean creatinine 2.8 mg/dL –88% tolerated doses up to 50-100 mg/d –13% developed skin reactions that required discontinuation –final SUA 5.3 mg/dL (10.4 start)

8. 8 Oxypurinol Compassionate Use Program (CUP)  1966 - Open label, uncontrolled (N= 533) –data analysis plan written in 2003.  Less than optimal documentation of: –allopurinol intolerance before entry –efficacy and safety (clinical labs) –baseline and post-baseline data  SUA missing data  baseline (32%)  post-baseline (24%) –Patient disposition (28% lost to FU)

9. 9 Oxypurinol Protocol (OXPL-213) Initiation: 2000  SUA as surrogate endpoint  Primary analysis: mean change of at least 2 mg/dL  Safety If study successful: post-marketing study for evaluation of meaningful clinical endpoints

10. 10 OXPL-213 Study Design  Prospective, open-label, uncontrolled, dose-escalation –Base study (N=79) for 14 weeks  Extension (A4) (N=48, ongoing)  Entry criteria –Symptomatic hyperuricemia with documented allopurinol intolerance  Exclusion criteria: –Severe prior reaction to allopurinol –Diuretic and uricosuric agents –Creatinine ≥ 2 mg/dL, ALT ≥ 3x ULN

11. 11 OXPL-213 Oxypurinol Treatment 100 mg/d x first wk, 200 mg/d x second wk and 300 mg/d wk 3 to 6 - If SUA change <2 mg/dL at wk 6, dose up to 600 mg/d - If SUA change < 2mg/dL at wk 9, dose up to 800 mg/d

12. 12 OXPL-213 Endpoints  SUA level (no central lab) –Baseline (N=3) –Wk 6 –Wk 9 (only those with SUA drop < 2 mg/dL) –End of study (wk 12, 13 & 14)  Landmark analysis –Change from baseline in the ITT population –Decrease of at least 2 mg/dL (lower bound of 95% CI ≥ 2)

13. 13 OXPL-213 Baseline characteristics  Mean age 61 yr (27 to 83)  52% male  Mean SUA 10.1 mg/dL (7.7 – 13.7)  Mean Creatinine 1.3 mg/dL (0.8 – 2.2)  Failed prior rechallenge or desensitization (N=26)

14. 14 OXPL-213 Baseline characteristics  Concomitant medications at entry Colchicine 34 (43) Low dose ASA 5 (6) Diuretics 42 (53) NSAIDS/COX-2 39 (49) N (%)

15. 15 OXPL-213 Baseline characteristics  History of prior allopurinol intolerance  Skin (63)  Hepatic (7)  Renal (4)  Malaise (6)  Hepatic, renal, malaise (1)  Fever (1)

16. 16 OXPL-213 Results (SUA)  ITT analysis at wk 14 (N= 79) –Mean change from baseline  1.78 mg/dL (95% CI 1.47, 2.08)  p < 0.001 (rejects null hypothesis that change = zero)  Completer analysis at wk 14 (N = 54) –Mean change from baseline  2.32 mg/dL (95% CI 2.07, 2.57)

17. 17 OXPL-213 Results - Final mean SUA in ITT population: 8.0 mg/dL - Patients who achieved SUA of: ≤ 6 mg/dL ≤ 5 mg/dL ITT (N=79) 10 (13%) 2 (3%) Completers (N=54) 9 (17%) 2 (4%) - No evidence of dose response

18. 18 OXPL-213 Results  Gouty flares: N=12 (15%) –5 during base study –4 during open extension –3 during both base and extension  Tophi complications (N=4) –infection, drainage, pain  Oxypurinol effect or spontaneous flare?

19. 19 OXPL-213 Deaths Deaths (N=5) –1 during base study (pancreatic ca.) –4 during extension  1 end-stage liver disease  1 sudden death  1 GI/COPD  1 sepsis

20. 20 OXPL-213 Serious Adverse Events (AEs) Base study (14 weeks) –7 events  2 MI  1 CHF (? MI) Extension (ongoing) –15 events  1 MI  1 unstable angina

21. 21 OXPL-213 Base study Discontinuations N=25 –16 skin –1 liver –1 thrombocytopenia –1 pancreatic carcinoma (death) –1 protocol violator –5 miscellaneous

22. 22 OXPL-213 Base study Discontinuations (cont’d) –Miscellaneous (N=5)  monitor decision (fever, chills, skin sensitivity, polyarthralgias, viral syndrome)  hypersensitivity NOS  fever, chills, allergic rhinitis  nausea/vomiting  elevation of ALT and BUN /protocol violator

23. 23 OXPL-213 Base study Discontinuations Summary  70% skin intolerance  70% within first wk  Most same as prior intolerance  None of them considered serious

24. 24 OXPL-213 Base and Extension Re-challenged patients (n=26) Discontinuations Hypersensitivity reactions (N=10, 40%)  7 base study (5 skin, 1 liver, 1 nausea)  1 after completion of base study (skin)  2 during extension (skin) Deaths (N=3)  1 base study  2 during extension (1 sepsis, 1 end stage liver disease)

25. 25 OXPL-213 Summary  79 enrolled –54 completed Base study  48 entered open extension  37 available in safety population  10 and 2 patients achieved SUA ≤ 6 mg/dL and ≤ 5 mg/dL, respectively, at 14 wk  12 had gouty flares (8 in base study)

26. 26 OXPL-213 Summary Adverse events in base study –No serious hypersensitivity –Similar to prior allopurinol intolerance –70% within first week (100 mg/day) –70% skin –Others: liver, thrombocytopenia, “viral syndrome” –Population: - no prior serious intolerance - excluded moderate/severe renal insufficiency

27. 27 Oxypurinol Challenge Define a population for a favorable risk benefit: –Benefit: modest decrease in SUA –Risk: intolerance

28. 28 Discussion Points  Value of SUA as a surrogate –change vs. target SUA level?  Additional endpoints: flares?  Eligibility –baseline SUA –concomitant medications/diet –renal insufficiency  Duration  Control group  Safety assessments