Transcript Febuxostat: the evidence for its use in the treatment of

Febuxostat: the evidence for its use
in the treatment of
hyperuricemia and gout
Angelo L Gaffo
Kenneth 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, placebocontrolled, 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 2380y/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
254
Febuxostat 80 mg/d
254
Febuxostat 120 mg/d
254
Allopurinol 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
1072 patients
Febuxostat
80 mg/d
Febuxostat
120 mg/d
Febuxostat
240 mg/d
Allopurinol
300 mg/d or
100 mg/d
Placebo
• 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
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
294
Febuxostat
80 mg/d
294
Febuxostat
120 mg/d
147
Allopurinol
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/dL
45%
SUA <6mg/dL
67%
SUA <6mg/dL
42%
Summary of evidence