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Embargoed For Release at 5:30 pm PT, Sunday Nov. 13, 2005

Arthritis News

New Treatment Shows Promise for Gout

SAN DIEGO, CALIFORNIA – A new treatment called febuxostat, the first new gout treatment in 40 years, may be superior at lowering levels of serum uric acid in patients with gout compared to allopurinol and placebo, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in San Diego.

Gout is a chronic, potentially disabling form of arthritis that includes symptoms such as intense attacks of painful swelling in single joints, often in the feet and most commonly in the big toe. The underlying cause of gout is hyperuricemia , or levels of uric acid in the blood greater than 6.8 mg/dL. Gout affects more than five million Americans. It is the most common form of arthritis in men over the age of 40, and though women are less commonly affected, the prevalence of gout may be rising among postmenopausal women with other conditions like high blood pressure.

The study compared the impact of multiple dosage levels of febuxostat to allopurinol, a current standard gout treatment, and to placebo. Researchers examined uric acid levels in blood samples among patients receiving daily doses of 80, 120 or a safety dose of 240 mg of febuxostat over 28 weeks. These results were compared to results for patients receiving 100 or 300 mg of allopurinol (the dose amount depended upon kidney function) and for patients receiving placebo.

The primary endpoint of the study was the number of patients whose uric acid blood levels were less than 6 mg/dL at the last three monthly visits. The target reduction was achieved by 48 percent of patients taking febuxostat 80 mg/day, 65 percent of patients taking 120 mg/day, and 69 percent of patients taking 240 mg/day. Only 22 percent of patients taking allopurinol and zero percent of patients taking daily placebo achieved the same target.

When a single visit at week 28 was evaluated, those patients whose uric acid level was reduced to <6 mg/dL was 76 percent taking febuxostat 80 mg/day, 87 percent taking 120 mg/day, and 94 percent taking 240 mg/day, compared to 41 percent taking allopurinol and one percent of patients taking placebo. Results showed that when compared to allopurinol, febuxostat is at least twice as effective in reducing serum uric acid levels.

The trial was meant to determine the effectiveness and safety of febuxostat. Patients in the study included those with risk factors such as hypertension, elevated cholesterol, cardiovascular disease, obesity and alcohol use. Most were men with a mean age of 52. Adverse events, which included digestive disturbances, headache and liver abnormalities, were similar across all treatment groups, and of the 34 serious adverse events across all treatment groups, most were cardiac disorders in patients with pre-existing cardiovascular disease.

“This study is very encouraging because it shows that febuxostat was superior at lowering serum uric acid levels compared to allopurinol, the current standard of treatment,” said Robert Wortmann, MD, lead researcher for the study and professor of medicine at the University of Oklahoma.

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see www.rheumatology.org/annual.

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Editor's Notes: This research will be presented in a scientific session at the ACR Annual Scientific Meeting from 2:30-4:00 pm PT on Wednesday, November 16, in Room 28 of the San DiegoConvention Center. Dr. Wortmann will be available for media questions during a briefing at 8:30am Monday, November 14 in Room 23 A of the Convention Center.

Presentation Number: 1837

Febuxostat vs Allopurinol and Placebo in Subjects with Hyperuricemia and Gout: The 28-Week APEX Study

H. R. Schumacher 1, M. A. Becker 2, R. L. Wortmann 3, P. A. MacDonald 4, B. Hunt 4, J. Streit 4, C. Lademacher 4, N. Joseph-Ridge 4. 1 University of Pennsylvania/VAMC., Phildaelphia, PA; 2 University of Chicago, Chicago, IL; 3 University of Oklahoma, Tulsa, OK; 4 TAP Pharmaceutical Products Inc., Lake Forest, IL

Purpose: Comparison of febuxostat, a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO), versus allopurinol and placebo in a 28-week study in subjects with hyperuricemia and gout. This study also uniquely included 40 subjects with moderately impaired renal function (SCr 1.6-=2.0 mg/dL ) and a high dose of febuxostat for safety evaluation.

Subjects and Methods : 1067 subjects with gout and serum urate levels (sUA) =8.0 mg/dL were randomized to once daily (fixed dose): placebo, febuxostat 80 mg, 120 mg or 240 mg (safety dose) or allopurinol in a 1:2:2:1:2 ratio. No dose adjustments were made in the placebo or febuxostat treatment groups based on renal function. The dose subjects randomized to allopurinol received depended on baseline serum creatinine: 300 mg/day if SCr was = 1.5 mg/dL and 100 mg/day for SCr 1.6-=2.0 mg/dL. The primary endpoint was the proportion of subjects with sUA <6.0 mg/dL at each of the last 3 visits.

Results: Most subjects were male (94%) and Caucasian (78%). Mean age was 52 years and mean duration of disease was 11 years. Baseline sUA exceeded 10 mg/dL in 39% of subjects (mean 9.85 mg/dL) and 20% had tophi. Comorbid conditions included: hypertension (47%), hyperlipidemia (33%), cardiovascular (CV) disease (13%), obesity (62%) and alcohol use (66%).

Subjects with moderate renal impairment achieved sUA < 6 mg/dL in each of the last 3 visits in febuxostat 80 mg (44%; 4/9); 120 mg (45%; 5/11), and 240 mg (60%; 3/5) compared with allopurinol (0%; 1/10) and placebo (0%; 0/5) groups. Treatment-related AEs, including liver function abnormalities, headache, nausea and vomiting, abdominal pain, and dizziness, were similar in incidences across treatment groups. Diarrhea incidence was (4%, 3%, 2%, 7%, 1%, respectively), in the placebo, febuxostat 80 mg, 120 mg, 240 mg and allopurinol groups. There were no increases in AEs in subjects with moderate renal insufficiency including those receiving febuxostat 240 mg daily. There were no deaths. 34 subjects reported serious adverse events (SAE), with no difference across treatment groups. Most SAEs were cardiac disorders in those with underlying CV disease and/or risk factors.

Conclusion: Febuxostat (80 mg, 120 mg, or 240 mg) demonstrated superior efficacy vs placebo and allouprinol (300 or 100 mg) in reducing and maintaining sUA <6.0 mg/dL. Febuxostat was generally safe and well tolerated at all doses.

Disclosure: H.R. Schumacher, TAP Pharmaceutical Products Inc. 5; M.A. Becker, TAP Pharmaceutical Products Inc. 5; R.L. Wortmann, TAP Pharmaceutical Products Inc. 5; P.A. MacDonald, TAP Pharmaceutical Products Inc 3; B. Hunt, TAP Pharmaceutical Products Inc. 3; J. Streit, TAP Pharmaceutical Products Inc. 3; C. Lademacher, TAP Pharmaceutical Products Inc. 3; N. Joseph-Ridge, TAP Pharmaceutical Products Inc. 3.