# Presentation: 690750

##      Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients

- Lourdes Villalba, M.D.
- DAAODP, CDER, FDA
- Arthritis Advisory Committee Meeting
- June 2, 2004

## Goal

- Clinical trial design for chronic gout
- Data from a specific NDA as an example for discussion

## 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”

## Allopurinol  

- Effectively reduces serum uric acid (SUA) at doses 300 – 800 mg daily
- Active metabolite is oxypurinol
- Allopurinol T 1⁄2 < 2 hr.
- Oxypurinol T 1⁄2 : 13 - 29 hr.
- Limited data on allopurinol/oxypurinol** **comparison

## 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) | 100 | 300 | 600 | 800 |
| --- | --- | --- | --- | --- |
| Allo (mg) | 58 | 78 | 81 | 112 |

## 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

## 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)

## 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)

## 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

## 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

## 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

## 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)

## 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)

## 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   (%)

## OXPL-213 Baseline characteristics 

- History of prior allopurinol intolerance
- Skin (63)
- Hepatic (7)
- Renal (4)
- Malaise (6)
- Hepatic, renal, malaise (1)
- Fever (1)

## 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)

## 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

## 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?

## 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

## 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

## OXPL-213 Base study Discontinuations 

- N=25
- 16 skin
- 1 liver
- 1 thrombocytopenia
- 1 pancreatic carcinoma (death)
- 1 protocol violator
- 5 miscellaneous

## 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

## OXPL-213 Base study Discontinuations Summary

- 70% skin intolerance
- 70% within first wk
- Most same as prior intolerance
- None of them considered serious

## 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)

## 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)

## 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

## Oxypurinol Challenge

- Define a population for a favorable risk benefit:
- Benefit: modest decrease in SUA
- Risk:  intolerance

## 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