Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients

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 lt 2 hr.
• Oxypurinol T ½ 13 - 29 hr.
• Limited data on allopurinol/oxypurinol comparison
  

5
PK Study AAI-US-175

• Open-label, dose linearity, fasted/fed,
  bioequivalence study (N42)
• 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 Desensitization AR 44(1) 231-238,
2001

• For moderate skin intolerance
• retrospective evaluation, N32
• 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 (N79) for 14 weeks
• Extension (A4) (N48, 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 lt2 mg/dL at wk 6, dose up to
  600 mg/d
• - If SUA change lt 2mg/dL at wk 9,
  dose up to 800 mg/d

12
OXPL-213 Endpoints

• SUA level (no central lab)
• Baseline (N3)
• Wk 6
• Wk 9 (only those with SUA drop lt 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 (N26)

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 lt 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 (N79) 10 (13) 2
  (3)
• Completers (N54) 9 (17) 2 (4)
• - No evidence of dose response

18
OXPL-213Results

• Gouty flares N12 (15)
• 5 during base study
• 4 during open extension
• 3 during both base and extension
• Tophi complications (N4)
• infection, drainage, pain
• Oxypurinol effect or spontaneous flare?

19
OXPL-213 Deaths

• Deaths (N5)
• 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

• N25
• 16 skin
• 1 liver
• 1 thrombocytopenia
• 1 pancreatic carcinoma (death)
• 1 protocol violator
• 5 miscellaneous

22
OXPL-213 Base study Discontinuations (contd)

• Miscellaneous (N5)
• 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 (n26) Discontinuations

• Hypersensitivity reactions (N10, 40)
• 7 base study (5 skin, 1 liver, 1 nausea)
• 1 after completion of base study (skin)
• 2 during extension (skin)
• Deaths (N3)
• 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