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Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients

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

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

  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. 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/oxypurinolcomparison

  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

  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. Allopurinol DesensitizationA&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. OxypurinolCompassionate 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. 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. OXPL-213Study 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. 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. 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. 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. 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. OXPL-213 Baseline characteristics • History of prior allopurinol intolerance • Skin (63) • Hepatic (7) • Renal (4) • Malaise (6) • Hepatic, renal, malaise (1) • Fever (1)

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

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

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

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

  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