Febuxostat: the evidence for its usein the treatment of

hyperuricemia and gout

Angelo L GaffoKenneth G Saag

Core Evidence 2009:4 25–36

Objective

• Review the clinical evidence of effectiveness of febuxostat (TEI-3420, or TMX-67) on outcomes and its potential for clinical management of hyperuricemia and gout.

Methods• Phases II and III

evidence• Literature searches

– PubMed– Cochrane database– American College of

Rheumatology– European League

Against Rheumatism

• (?) Inclusion exclusion criteria not mentioned

Febuxostat

• Orally administered, nonpurine selective inhibitor of xanthine oxidase.

• Binds to a channel in the molybdenum center of the enzyme, leading to a very stable and long-lived enzyme-inhibitor interactions with both oxidized and reduced forms of the enzyme

Phase II data

• 28-day, multicenter, double-blind, placebo-controlled, dose response clinical trial

• Determine safety and efficacy of once daily febuxostat– 40, 80, 120 mg

• Inclusion: patients with American College of Rheumatology criteria-defined gout aged 23-80y/o

• Exclusion: absence of kidney dysfunction or taking drugs known to affect serum urate (aspirin or diuretics)

Phase II data

• Cases of reduction seen in as early as 7 days after start of treatment

• Dose-dependent effect• Incidence of gout flares, due to sudden removal

and mobilization of uric acid crystals from the tissues– Despite pretreatment with colchicine

• Diarrhea, abdominal pain• Abnormal liver function tests

– 40mg (14%), 80mg (8%), 120mg (8%)

Other Phase II data

• Reductions on tophi volume (by MRI)• Good tolerance in allopurinol-intolerant patient• 3 month colchicine prophylaxis in patients

starting with febuxostat• Diarrhea, GI motility disorders, headache,

abnormal liver function tests, hyperlipidemia• Japan (128 patients)

– reduced SUA regardless of underexcretors or overproducers

– Safe and well tolerated– Abnormal liver function tests and gout flares

Phase III data

• FACT

• APEX

• EXCEL

• CONFIRMS

Phase III data - FACT

• Febuxostat versus Allopurinol Controlled Trial (FACT)

• Randomized, double-blind, 52-week, multicenter– Febuxostat 80 and 120 mg/day dose– Allopurinol 300 mg/day fixed dose

• Inclusion: adult patients with American College of Rheumatology-defined gout and SUA at least 8.0 mg/dL

• Exclusion: kidney dysfunction, concomitant drugs known to affect serum urate, BMI >50, active liver disease, pregnancy, use of prednisone >10 mg/d, or alcohol abuse

Phase III data - FACT

• Primary endpoint – SUA of 6.0 mg/dL

• Clinical endpoint – reduction in tophus area, change in number of tophi, and proportion of patients requiring treatment for acute gout flares

• Prophylaxis with colchicine or naproxen during a 2-week washout period

Phase III data - FACT

762 patients

254Febuxostat 80 mg/d

254Febuxostat 120 mg/d

254Allopurinol 80 mg/d

Discontinued 88 (34%)

Discontinued 98 (39%)

Discontinued 66 (26%)

Losses to follow-up, adverse events, and gout flares

Phase III data - FACT

Primary endpoint

Febuxostat 80 mg/d Febuxostat 120 mg/d Allopurinol 300 mg/d

53% 62% 21%

Phase III data - FACT

• Rates of total advers events and serious adverse events were similar

• Liver function test abnormalitis (4-5%), diarrhea (3%), headaches (1-3%)

• 4 patients in febuxostat group died– Cardiovascular events– Considered unrelated to administration of

study medications

Phase III data - APEX• Allopurinol and Placebo-Controlled, Efficacy

Study of Febuxostat (APEX)• Additional patients with mild to moderate renal

dysfunction (creatinine 2.0 mg/dL)– Febuxostat at 80, 120, 240 mg/d– Allopurinol 300 mg/d (crea 1.5mg/dL), 100 mg/d (crea

1.5-2.0 mg/dL)• Inclusion: 18-85 y/o, American College of

Rheumatology-defined gout, SUA ≥8.0 mg/dL, creatinine up to 2.0 mg/dL

• Exclusion: intolerances to allopurinol, colchicine, naproxen, history of renal calculi, heavy alcohol intake, baseline transaminases ≥1.5 upper limit of normal

Phase III data - APEX

• More gout flares in febuxostat 120 and 240 mg/d arm in first 8 weeks

• Similar rates in 8-28 weeks• Diarrhea, liver function test abnormalities

1072 patients

Febuxostat 80 mg/d

Febuxostat 120 mg/d

Febuxostat 240 mg/d

PlaceboAllopurinol

300 mg/d or 100 mg/d

Phase III - EXCEL

• Open-label phase III extension of FACT

• Continue evaluation response to treatment

• Allopurinol compared to febuxostat failed to achieve continuous reduction of SUA 6.0 mg/dL

735 patients

294Febuxostat

80 mg/d

294Febuxostat 120 mg/d

147Allopurinol

80 mg/d

Phase III - CONFIRMS

• Randomized, controlled, multicenter, double-blind

2269 patients

Febuxostat 40 mg/d

Febuxostat 80 mg/d

Allopurinol 200 or 300 mg/d

SUA <6mg/dL45%

SUA <6mg/dL 67%

SUA <6mg/dL 42%

Summary of evidence