ULORIC (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.

Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells.

Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats.

13.2 Animal Toxicology and/or Pharmacology

A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma exposure at 80 mg per day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg (approximately 35 times the human plasma exposure at 80 mg per day).

14 CLINICAL STUDIES

A serum uric acid level of less than 6 mg per dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout.

14.1 Management of Hyperuricemia in Gout

The efficacy of ULORIC was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level ≥ 8 mg per dL.

Study 1 randomized patients to: ULORIC 40 mg daily, ULORIC 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr ) ≥ 60 mL per min or 200 mg daily for patients with estimated Clcr ≥ 30 mL per min and ≤ 59 mL per min). The duration of Study 1 was 6 months.

Study 2 randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine ≤ 1.5 mg per dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg per dL and ≤ 2 mg per dL). The duration of Study 2 was 6 months.

Study 3, a 1-year study, randomized patients to: ULORIC 80 mg daily, ULORIC 120 mg daily, or allopurinol 300 mg daily. Subjects who completed Study 2 and Study 3 were eligible to enroll in a phase 3 long-term extension study in which subjects received treatment with ULORIC for over three years.

In all three studies, subjects received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1 the duration of prophylaxis was 6 months; in Study 2 and Study 3 the duration of prophylaxis was 8 weeks.

The efficacy of ULORIC was also evaluated in a 4 week dose ranging study which randomized patients to: placebo, ULORIC 40 mg daily, ULORIC 80 mg daily, or ULORIC 120 mg daily. Subjects who completed this study were eligible to enroll in a long-term extension study in which subjects received treatment with ULORIC for up to five years.

Patients in these studies were representative of the patient population for which ULORIC use is intended. Table 2 summarizes the demographics and baseline characteristics for the subjects enrolled in the studies.

Table 2: Patient Demographics and Baseline Characteristics in Study 1, Study 2 and Study 3
Male 95%
Race: Caucasian 80%
African American 10%
Ethnicity: Hispanic or Latino 7%
Alcohol User 67%
Mild to Moderate Renal Insufficiency[percent with estimated Clcr less than 90 mL per min] 59%
History of Hypertension 49%
History of Hyperlipidemia 38%
BMI ≥ 30 kg per m2 63%
Mean BMI 33 kg per m2
Baseline sUA ≥ 10 mg per dL 36%
Mean baseline sUA 9.7 mg per dL
Experienced a gout flare in previous year 85%

Serum Uric Acid Level less than 6 mg per dL at Final Visit: ULORIC 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg per dL at the final visit. ULORIC 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than 6 mg per dL at the final visit (Table 3).

Table 3: Proportion of Patients with Serum Uric Acid Levels Less Than 6 mg per dL at Final Visit
Difference in Proportion(95% CI)
Study * ULORIC40 mg daily ULORIC80 mg daily allopurinol Placebo ULORIC 40 mgvsallopurinol ULORIC 80 mgvsallopurinol
*
Randomization was balanced between treatment groups, except in Study 2 in which twice as many patients were randomized to each of the active treatment groups compared to placebo.
Study 1(6 months)(N=2268) 45% 67% 42% 3%(-2%, 8%) 25%(20%, 30%)
Study 2(6 months)(N=643) 72% 39% 1% 33%(26%, 42%)
Study 3(12 months)(N=491) 74% 36% 38%(30%, 46%)

In 76% of ULORIC 80 mg patients, reduction in serum uric acid levels to less than 6 mg per dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at 6 mg per dL or below throughout treatment in 83% of these patients.

In all treatment groups, fewer subjects with higher baseline serum urate levels (≥ 10 mg per dL) and/or tophi achieved the goal of lowering serum uric acid to less than 6 mg per dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg per dL with ULORIC 80 mg than with ULORIC 40 mg or allopurinol.

Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL per minute). The results in this sub-group of patients are shown in Table 4.

Table 4: Proportion of Patients with Serum Uric Acid Levels Less Than 6 mg per dL in Patients with Mild or Moderate Renal Impairment at Final Visit
Difference in Proportion (95% CI)
ULORIC40 mg daily(N=479) ULORIC80 mg daily(N=503) allopurinol *300 mg daily(N=501) ULORIC 40 mg vs allopurinol ULORIC 80 mg vs allopurinol
*
Allopurinol patients (n=145) with estimated Clcr ≥ 30 mL per min and Clcr ≤ 59 mL per min were dosed at 200 mg daily.
50% 72% 42% 7%(1%, 14%) 29%(23%, 35%)

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