Gout

New Drug Class
Gout therapeutics: new drugs for an old disease

Christopher M Burns, Robert L Wortmann
The approval of febuxostat, a non-purine-analogue inhibitor of xanthine oxidase, by the European Medicines Agency and
the US Food and Drug Administration heralds a new era in the treatment of gout. The use of modied uricases to rapidly
reduce serum urate concentrations in patients with otherwise untreatable gout is progressing. Additionally, advances in
our understanding of the transport of uric acid in the renal proximal tubule and the inammatory response to
monosodium urate crystals are translating into potential new treatments. In this Review, we focus on the clinical trials of
febuxostat. We also review results from studies of pegloticase, a pegylated uricase in development, and we summarise
data for several other pipeline drugs for gout, such as the selective uricosuric drug RDEA594 and various interleukin-1
inhibitors. Finally, we issue a word of caution about the proper use of the new drugs and the already available drugs for
gout. At a time of important advances, we need to recommit ourselves to a rational approach to the treatment of gout.
Introduction
50 years after McCarty and Hollander rediscovered
monosodium urate crystals in gouty joints,1 up to 5 million
people in the European Union and a similar number in
the USA have gout. This disease is the most common form
of inammatory arthritis in men older than 40 years, and
aects 12% of adults in developed countries,25 although
the best way to estimate the incidence and prevalence of
gout is debated.6 The last drug approved by the US Food
and Drug Administration for the treatment of gout was
allopurinol, in 1965. With approval of febuxostat by the
European Medicines Agency in 2008 and by the US Food
and Drug Administration in 2009, and with the appearance
of several novel drugs in the therapeutic pipeline, a new
era in gout treatment is beginning.
In this Review, we discuss febuxostat and several other
drugs still in development that target various steps in the
pathogenesis of gout (gure 1). New urate-lowering drugs
use two traditional strategies: inhibition of xanthine
oxidase to reduce production of uric acid and promotion
of uricosuria to increase its renal excretion. A new
approach uses pegloticase, a polymer-coupled form of
uricase, to rapidly reduce serum urate concentrations.
We focus on the approved drug febuxostat and on
pipeline drugs such as pegloticase, RDEA594, and various
interleukin-1 inhibitors in the treatment of gout (table 1).
For an update on clinical features of gout, please see the
Seminar in The Lancet.7
Approved drug: febuxostat

Febuxostat, 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4methyl-thiazole-5-carboxylic acid (gure 2), is a potent
oral inhibitor of xanthine oxidase, and lowers serum
urate concentration in a predictable way in man.810
Unlike allopurinol and its active metabolite oxypurinol,
febuxostat is not a purine analogue and inhibits only
xanthine oxidase, not other enzymes in the purine and
pyrimidine metabolic pathways.10 With 85% absorption
1 h after oral administration, and a half-life of 418 h,
once-daily dosing is eective.912 Metabolism occurs
mainly in the liver via glucuronide formation and
oxidation, with about 50% of the drug excreted in stool
and 50% appearing in urine, either unchanged or as
www.thelancet.com Vol 377 January 8, 2011
metabolic products.9 Febuxostat dose adjustments

are not needed in patients with mild to moderate
renal failure.13
Lancet 2011; 377: 16577

Published Online
August 17, 2010
DOI:10.1016/S01406736(10)60665-4
See Editorial page 97
Dartmouth Medical School,
Lebanon, NH, USA
(C M Burns MD,
Prof R L Wortmann MD)
Correspondence to:
Dr Christopher M Burns,
Dartmouth Medical School, 1
Medical Center Drive, Lebanon,
NH03756, USA
[email protected]
Randomised controlled trials

Febuxostat has been studied in one phase 2 and three
phase 3 randomised controlled trials.1417 Table 2 summarises
these phase 3 trials. In FACT, 762 patients with serum
urate concentrations of 476 mol/L or higher were
randomly assigned to receive febuxostat 80 mg or 120 mg
daily, or allopurinol 300 mg daily, for 52 weeks.15 Febuxostat
was better at achieving the primary endpoint of a serum
urate concentration lower than 357 mol/L at each of the
last three monthly measurements. In APEX, 1072 gout
patients were given febuxostat 80 mg, 120 mg, or 240 mg
daily; allopurinol 300 mg or 100 mg daily according to renal
function; or placebo for 26 weeks.16 All doses of febuxostat
were better than allopurinol and placebo, including in the
subset of patients with renal insuciency (serum
creatinine concentration of 132176 mol/L). In
CONFIRMS, 2269 patients were randomly assigned to
Search strategy and selection criteria
We searched the PubMed (Medline), EmBase, and Cochrane
library databases for articles published in English since 1990
with the search terms gout, and hyperuricemia. We also
searched for gout or hyperuricemia combined with
treatment. We searched the reference lists of publications
identied through the initial search for further citations.
Additionally, we searched the American College of
Rheumatology (ACR) and the European League Against
Rheumatism (EULAR) websites to access abstracts presented
at recent meetings so as to identify the latest information
available, with the understanding that these reports have not
all undergone peer review. Finally, we searched the websites
of the US Food and Drug Administration and European
Medicines Agency for more detailed information about the
application processes for the relevant drugs. We generally
focused on studies published in the past 5 years, but also
included often cited, older publications. Finally, select review
articles and book chapters are also cited for more thorough
coverage of topics beyond the scope of this New Drug review.
165
New Drug Class
Inhibitory eect
Stimulatory eect
Purine nucleotide
metabolism
Xanthine
Xanthine oxidase inhibitors:

allopurinol, oxypurinol,
febuxostat
Uric acid
Allantoin
Uricases:
rasburicase,
pegloticase
Uricosurics:
probenecid,
benzbromarone,
RDEA594
Renal
excretion
Gastrointestinal tract
excretion
Circulating
in excess
Urate
deposition
Uricosuria
Inammation inhibitors:
Non-steroidal anti-inammatory drugs,
colchicine, steroids, interleukin-1 inhibitors
Tophi
Inammasome activation
with acute gout attack
Figure 1: Targets for intervention in the treatment and prophylaxis of gout
Description
Dosing
Status
Non-purine xanthine
oxidase inhibitor
Oral, once daily
FDA, EMA approved for gout
Pegloticase
Pegylated recombinant
porcine-like uricase
Intravenously, every
2 or 4 weeks
Phase 3 for gout completed;

resubmission to FDA in early 2010
RDEA594
Selective URAT1 inhibitor,

uricosuric
Oral, once daily
Phase 2b underway
Anakinra
Recombinant, nonglycosylated form of

human IL-1R
Subcutaneously, daily
for 3 days for acute
gout
FDA approved for rheumatoid

arthritis, not gout
Rilonacept
Soluble receptorfragment-crystallisable
fusion protein; inhibits
interleukins 1 and 1
Subcutaneously, every
week for acute gout or
prophylaxis for
urate-lowering
FDA approved for

cryopyrin-associated periodic
syndromes, not gout; phase 2
Approved drug
Febuxostat
Pipeline drugs
IL-1 Inhibitors
Canakinumab
One subcutaneous
Fully human antiinterleukin-1 monoclonal dose for acute gout
antibody
FDA approved for cryopyrinassociated periodic syndromes,

not gout; phase 2
EMA=European Medicines Agency. FDA=US Food and Drug Administration.
Table 1: Description of new drugs for the treatment of gout
febuxostat 40 mg or 80 mg daily; or allopurinol 300 mg

daily, or 200 mg daily in patients with creatinine clearance
of 3059 mL/min.17 Febuxostat 80 mg was better than
40 mg and than allopurinol in achieving a concentration of
serum urate lower than 357 mol/L at nal visit, including
in patients with renal insuciency. Febuxostat 40 mg daily
was better than allopurinol 200 mg daily only in patients
with renal insuciency. The only signicant reduction in
tophi was recorded in patients given febuxostat 120 mg
daily compared with placebo in APEX.
In FACT, the febuxostat groups had more gout ares
than the allopurinol group in the rst 8 weeks during
166
which patients received prophylaxis (naproxen or

colchicine). Thereafter, ares decreased and did not dier
signicantly. Similar results were reported in APEX. In
CONFIRMS, prophylaxis continued for the entire
26-week study. Flares were reduced in general, but were
still more frequent with febuxostat than with allopurinol.
Other than ares, frequencies of serious and treatmentrelated adverse events were similar among groups, with
signicant dierences only noted in febuxostat 120 mg
daily versus placebo in APEX. The most frequent adverse
events related to treatment were liver function test
abnormalities, diarrhoea, headache, dizziness, and
musculoskeletal symptoms. Discontinuation rates were
highest in the febuxostat groups in all three trials. Nine
deaths occurred during the trials, none deemed related
to treatment.
In APEX, cardiovascular events, dened as chest pain,
coronary artery disease, myocardial infarction, and atrial
brillation, occurred more frequently in the febuxostat
80 mg and 120 mg groups than in the other groups (ve
in each of febuxostat groups versus one in each of the
other three groups, including febuxostat 240 mg).
Although these dierences were not signicant, the US
Food and Drug Administration required CONFIRMS to
be completed before approval. In CONFIRMS, all
cardiovascular adverse events were studied by a masked
cardiovascular safety committee using the Anti-Platelet
Trialists Collaboration (APTC) endpoints.18 One death
occurred in each of the febuxostat groups (40 mg and
80 mg), and three deaths occurred in the allopurinol
groups. Three cardiovascular events dened by APTC
occurred in patients given febuxostat 80 mg and three in
the allopurinol groups. There were no statistically
signicant dierences among groups. Findings were
similar for the 26 non-APTC cardiovascular events.17
Open label extension trials

In FOCUS, an open label extension trial of a 28-day
phase 2 randomised controlled trial, consenting patients
completing the randomised trial were given febuxostat
80 mg daily, which could subsequently be adjusted to
40 mg or 120 mg daily.19 Patients with mild renal
insuciency were included. Patients with appropriate
control of serum urate were maintained in study. At
5 years, 93% (54/58) of completing patients had
concentrations of serum urate lower than 357 mol/L.
Half of the enrolled patients discontinued prematurely,
38 in the rst year, but only 13 of them discontinued
because of an adverse event. No deaths were reported.
Gout ares were essentially eliminated and tophus
resolution occurred in 69% of 26 aected patients.
In EXCEL, an open label extension of two phase 3
randomised controlled trials, 1086 patients were
assigned to febuxostat 80 mg or 120 mg daily, or
allopurinol 300 mg daily.20 The goal was to maintain
patients at serum urate concentrations lower than
357 mol/L for up to 3 years. Adjustments were allowed
New Drug Class
during the rst 6 months to achieve serum urate

concentrations lower than 357 mol/L. At the rst
month, 80% of patients given febuxostat, but only 46%
of those given allopurinol, achieved target concentrations
of serum urate. Failures were reassigned from
allopurinol to febuxostat 80 mg daily, and from
febuxostat 80 mg to 120 mg daily. More than 80% of
patients maintained serum urate concentrations lower
than 357 mol/L thereafter, with disappearance of gout
ares. Tophi resolved in 46% of patients on febuxostat
80 mg, 36% of patients on febuxostat 120 mg, and 29%
of patients on allopurinol. Adverse events did not dier
among groups. Importantly, allopurinol dosing was
xed, inherently favouring the febuxostat groups, for
which dose adjustments were allowed.
Recommendations
The US Food and Drug Administration approved
febuxostat for gout at 40 mg and 80 mg daily in February,
2009. The European Medicines Agency approved
febuxostat at 80 mg and 120 mg daily in May, 2008, before
the CONFIRMS results.17 Cardiovascular events in FACT
and APEX were numerically higher with febuxostat than
with other treatments. In the open label extension
studies, cardiovascular events were more common in
febuxostat groups (27%) than in allopurinol groups
(112%), but when total drug exposures were taken into
account, the incidence was the same.21 Risk factors for
APTC events were a history of atherosclerotic disease or
myocardial infarction, baseline congestive heart failure,
and age older than 60 years at baseline (p=0001 for all
four factors). No association was noted for hypertension,
stroke, diabetes, or hyperlipidaemia. In Europe, the
European Medicines Agency concluded that treatment
with febuxostat of patients with ischaemic heart disease
or congestive heart failure was not recommended. The
US Food and Drug Administration accepted the results
of CONFIRMS as mitigating cardiovascular risk, but
only approved dosing of 40 mg and 80 mg daily. Takeda
has committed to a post-marketing study, designed along
with the US Food and Drug Administration.
In the USA, the recommended starting dose of
febuxostat is 40 mg daily. No dose adjustment is needed
in patients with creatinine clearance higher than
30 mL/min. Although small numbers suggest that the
use of febuxostat in patients with severe renal
insuciency is safe, no strong evidence exists to
recommend it.13 Febuxostat is safe in patients with mild
to moderate hepatic impairment, but cannot be assumed
to be risk-free in those with severe liver disease.22 Liver
function should be monitored since abnormalities are
common. A possible signal for thyroid abnormalities
induced by febuxostat has been recorded21 although the
mechanism is not obvious. In Europe, an increased
thyroid-stimulating hormone concentration is regarded
as a potential adverse event, whereas in the USA, it is
mentioned only as a possible laboratory abnormality.
Just as with allopurinol, febuxostat should not be used

with drugs metabolised by xanthine oxidase such as
theophylline, 6-mercaptopurine, and azathioprine. Toxic
concentrations with potentially fatal results such as bone
marrow failure are possible. In healthy people, no
signicant interactions with colchicine, naproxen,
indomethacin, hydrochlorothiazide, warfarin, or desipramine have been identied.2327
Concentrations of serum urate should be measured
24 weeks after starting febuxostat treatment. If values of
serum urate are 357 mol/L or higher, the dose should
be increased. The principle of dosing to target should be
followed whatever the urate-lowering drug used, with the
exception of pegloticase. The more rapid and substantial
the fall in serum urate concentration is, the greater is the
likelihood of gout ares. In patients treated with
febuxostat, ares happen earlier during treatment, but
also stop occurring sooner than with allopurinol. This
phenomenon re-emphasises the importance of
prophylaxis and education of patients. Prophylaxis should
be continued for at least 6 months irrespective of the
urate-lowering agent.
Appropriate candidates for febuxostat

Febuxostat and allopurinol have similar safety proles,
although no cases of hypersensitivity syndrome have
been reported with febuxostat. Patients with
Xanthine
Febuxostat
O
O
H
H
O
N
N
H
Allopurinol
O
N
N
O
N
H
Oxypurinol
O
H
N
N
O
N
H
Figure 2: Chemical structures of xanthine, allopurinol and its metabolite

oxypurinol, and febuxostat
167
New Drug Class
FACT (n=762), 52 weeks15
APEX (n=1072), 28 weeks16
CONFIRMS (n=2269), 26 weeks17
Treatment (n)
Febuxostat 80 mg (256)
Allopurinol 300 mg (253)
Allopurinol 100300 mg (268)
Placebo (134)
Allopurinol 200/300 mg (755)
300 mg (611); 200 mg (145 with creatinine clearance
of 3059 mL/min)
Primary Endpoint
Serum urate <357 mol/L last three monthly visits
Serum urate <357 mol/L last three monthly visits
Serum urate <357 mol/L at last visit
Primary endpoint
achieved
Febuxostat 80 mg: 53% (p<0001 vs allopurinol)

Febuxostat 120 mg: 62% (p<0001 vs allopurinol)
Allopurinol 300 mg: 21%
Febuxostat 80 mg: 48% (p<0001 vs allopurinol, placebo)

Allopurinol 100/300 mg: 22% (p<0001 vs placebo)
Placebo: 0%
Febuxostat 40 mg: 45%

Febuxostat 80 mg: 67% (p<0001 vs febuxostat
40 mg, allopurinol)
Allopurinol 200/300 mg: 42%
Primary endpoint
achieved in renal
insuciency
NA
Subset: creatinine clearance >15, 20 (n=40)

Febuxostat 80 mg: 4/9=44% (p<005 vs allopurinol)
Allopurinol 100 mg: 0/10=0%
Placebo: 0/5=0%
Subset: creatinine clearance 3089 ml/min (n=1483)

Febuxostat 40 mg: 50% (p=0021 vs allopurinol)
Febuxostat 80 mg: 72% (p<0001 vs febuxostat
40 mg, allopurinol)
First 8 weeks
Febuxostat 80 mg: 22%,

Febuxostat 120 mg: 36% (p<0001 vs others)
Allopurinol: 300 mg: 21%

Febuxostat 120 mg: 36% (p005 vs febuxostat 80 mg,
allopurinol, placebo)
Placebo: 20%
Weeks 952

Allopurinol 300 mg: 64%
Entire study
No signicant dierences among groups

Febuxostat 40 & 80 mg signicantly more than
allopurinol, but p value not reported
Secondary endpoint: All groups with decrease in median size and

tophi reduction
number, but no signicant dierences
No signicant dierences, apart from mean % decrease in

number of tophi in febuxostat 120 mg vs placebo (p005)
NA
Discontinued
treatment (%)

Allopurinol: 26%

allopurinol)
Allopurinol 21%
Placebo 25%
Febuxostat 40 mg: 17% (p=0.021 vs allopurinol)

Febuxostat 80 mg: 21% (p<0.001 vs febuxostat
40 mg, allopurinol)
Deaths (n)
Febuxostat 80 mg: 2; febuxostat 120 mg: 2;

allopurinol: 0
None
Febuxostat 40 mg: 1; febuxostat 80 mg: 1;

allopurinol: 3
Adverse events or
serious adverse
events, other than
gout ares
Liver function test abnormalities, diarrhoea,

headaches, and musculoskeletal symptoms most
common in all groups with no signicant
dierences
Febuxostat 80 mg and 120 mg more cardiovascular events

(5 in each, vs 1 in each of other 3 groups), but no signicant
dierences.
Diarrhoea and dizziness more common in febuxostat
240 mg vs other groups except placebo
No signicant dierences
APTC Events: febuxostat 40 mg: 0; febuxostat 80 mg:
3 (1 non-fatal MI, 2 non-fatal strokes); allopurinol:
3 (2 deaths, 1 non-fatal MI); no signicant dierences
Secondary endpoint:
gout ares (%)
APTC= Anti-Platelet Trialists Collaboration. MI=myocardial infarction. NA=not applicable/not done.
Table 2: Summary of three phase 3 randomised controlled trials of febuxostat
hypersensitivity reactions to allopurinol who were given

febuxostat were able to tolerate the new drug.28
Allopurinol doses used in these trials were xed and
too low; this fact cannot be emphasised enough. One
could reasonably argue that if allopurinol doses were
titrated to serum urate concentrations, the febuxostat
advantage might vanish, although the side-eect prole
of allopurinol might also change. Accordingly,
febuxostat should be considered mainly for patients
168
intolerant to allopurinol, for those whose gout is not

controlled with other urate-lowering treatments, and
for those with renal insuciency (but whose creatinine
clearance is higher than 30 mL/min). Febuxostat should
be tried before an attempt at allopurinol desensitisation,
a cumbersome and often unsuccessful strategy for
overcoming milder allopurinol reactions. Finally,
febuxostat should be used before uricosuric drugs in
patients with nephrolithiasis.
New Drug Class
Pipeline drug: pegloticase, the mammalian

uricasereversing evolution?
Uricase was lost to man and some non-human primates
via a missense mutation in the gene encoding the
enzyme.29 In other species, uricase converts urate to
allantoin, which is ve to ten times more water-soluble
and more readily eliminated than urate. Non-recombinant
uricase from Aspergillus avus was developed and used
for human tumour lysis syndrome in the late 1960s.30,31
This syndrome occurs after chemotherapy of rapidly
proliferating neoplasms, with profound hyperuricaemia
and possible renal failure.32 The non-recombinant
enzyme was eective but its production was dicult, the
half-life was short, and severe allergic reactions were
common (5%).31
Recombinant enzyme produced by genetically
modied Saccharomyces cerevisiae expressing uricase
cloned from A avus was developed in the 1990s.33 In
2002, rasburicase, a recombinant A avus uricase, was
approved by the US Food and Drug Administration for
acute tumour lysis syndrome in children with cancer.34
This agent dramatically lowers serum urate
concentrations, but enthusiasm for its use in gout was
dampened by persistent immunogenicity and short
half-life (less than 24 h).3538 In a promising study,
patients with gout that could not be treated with
allopurinol were given rasburicase; ve patients
received six monthly infusions and ve patients received
ve daily infusions of 02 mg/kg rasburicase intravenously, both after pretreatment with 60 mg of
methylprednisolone intravenously.37 Patients given the
monthly infusions had signicantly lower serum urate
concentrations after 6 months, and two of ve had
reduction in size of tophi. Patients given daily infusions
did not maintain lower serum urate concentrations and
had no change in tophi size. Unfortunately, eight of ten
patients had at least one adverse event, including two
who had hypersensitivity reactions, and eight of ten had
gout attacks despite prophylaxis. No long-term followup was reported. Non-oncological use of rasburicase is
not common.
Strategies devised to overcome these problems were
the use of mammalian uricase and the pegylation of the
uricase by covalent attachment to poly(ethylene glycol).39
Pegloticase (gure 3), a pegylated mammalian (porcinelike) recombinant uricase, has been studied in gout.39
Phase 1 studies established that intravenous administration of pegloticase was better than subcutaneous
administration.40,41 With intravenous administration of
05 mg to 12 mg, the plasma uricase activity increases
linearly with doses up to 8 mg, referring specically to
the mass of the uricase protein within the molecule. This
activitys half-life is 64138 days. With intravenous
doses equal or higher than 4 mg, the concentration of
serum urate falls dramatically in 2472 h, from a mean of
660 mol/L (SD 36) to 59 mol/L (SD 30), staying low for
21 days after infusion.40
Clinical trials
Pegloticase clinical trials are summarised in table 3. A
phase 2 open label trial randomly assigned 41 patients
whose treatment for gout had failed to 1214 weeks of
intravenous pegloticase at 412 mg every 2 or 4 weeks.42
The mean concentration of plasma urate fell to less than
357 mol/L within 6 h for all doses. The primary endpoint
of plasma urate concentrations lower than 357 mol/L
for 80% of the study duration was achieved in 5088% of
patients. The optimum dose was 8 mg given every
2 weeks. Several patients had striking reductions in tophi
after just 12 weeks.43 Most patients had gout ares (88%).
Development of antibodies to pegloticase in 31 of
41 patients led to a reduced drug half-life. Because of
reactions, infusion concentration and rate were decreased
later in the study. Infusion reaction prophylaxis was
allowed only in patients with previous reactions.
Phase 3 data from replicate 6-month randomised
controlled trials (212 patients total) were presented at the
American College of Rheumatology annual meeting in
2008 (ACR 2008) and at the European League Against
Rheumatism annual meeting in 2009 (EULAR 2009).4446
Patients were randomly assigned to either pegloticase
8 mg intravenously every 2 weeks or 4 weeks or placebo.44
The primary endpoint was plasma urate concentration
lower than 357 mol/L for 80% of the time in months 3
and 6. Colchicine or non-steroidal anti-inammatory
drugs were used for gout prophylaxis. Infusion reaction
prophylaxis consisted of oral fexofenadine and
paracetamol, and hydrocortisone 200 mg intravenously
before infusion. Pegloticase was signicantly more
eective than placebo.44 Secondary endpoints of tophus
reduction, quality of life, and disability measures favoured
pegloticase over placebo in some, but not all,
comparisons.45,46 Complete tophus response, dened as
resolution of one or more tophi without increase in size
in other tophi or development of new ones, was better
than placebo only in the group of 8 mg every 2 weeks,
probably because of measurement technique. It seemed
clear that, when tolerated, pegloticase was ecacious at
reducing tophi.45
Gout ares, infusion reactions, and serious adverse
events were signicantly more frequent in patients given
pegloticase (table 3) than in other patients. The most
common reason for withdrawal was infusion reaction.
Important relations were noted between immunogenicity,
infusion reactions, and ecacy.47 High-titre antibodies to
pegloticase (higher than 1:7290) were associated with
loss of response and infusion reactions. Antibodies to
poly(ethylene glycol) were even more predictive. All
patients with detectable antibodies to poly(ethylene
glycol) also had antibodies to pegloticase, but not vice
versa, probably indicating dierent sensitivities for each
ELISA. Importantly, 96% of patients with antibodies to
poly(ethylene glycol) from the groups assigned every-2week or every-4-week pegloticase were non-responders,
and 50% and 76%, respectively, had infusion reactions.
169
New Drug Class
Figure 3: Molecular models of uricase tetramer (AC) and of pegloticase containing 36 strands of 10-kDa poly(ethylene glycol) (PEG) per uricase tetramer (D)
(A) Cartoon model, (B) space-lling model showing tunnel, and (C) space-lling model rotated around the vertical axis so that the tunnel is not visible, of uricase
tetramer with subunits in dierent colours, based on crystal structure of A avus uricase tetramer. (D) Space-lling model of uricase tetramer, in the same orientation
as in (B), with nine strands of 10 kDa poly(ethylene glycol) attached to each uricase subunit. The scale of (D) is about half that of (AC). Reprinted from reference 39
with permission of authors and publisher (Elsevier).
These antibodies did not neutralise uricase activity in

vitro. Low-titre antibodies to pegloticase were not
predictive. At ACR 2009, further analysis showed that
development of antipegloticase antibodies was associated
with a loss of response in patients, with their plasma
urate concentrations rising above 357 mol/L.48
Furthermore, 71% of infusion reactions occurred after
this loss of response. In the group assigned pegloticase
every 2 weeks, cessation of treatment when concentrations
of plasma urate were higher than 357 mol/L would
have avoided 91% of infusion reactions. This nding
suggests that careful monitoring of concentrations of
serum urate could allow clinicians to avoid most
infusion reactions.
All patients in the pegloticase randomised trials had
some cardiovascular risk factor.44 The cardiovascular
170
adjudication committee of Savient Pharmaceuticals, Inc

identied ten of 169 patients (6%) with major
cardiovascular events in the pegloticase groups and none
of 43 patients in the placebo group. Results from the US
Food and Drug Administrations independent analysis
of these data showed eight events in the pegloticase
groups (5%) and one in the placebo groups (2%).49 The
agency noted that all events occurred in patients with
pre-existing risk factors and concluded that the number
of events was too small to lend support to a denite
cardiovascular signal.49
157 of 212 patients completed the randomised trials;
151 of them enrolled in an open label extension study.
6-month data were presented at ACR 2009.50 82 patients
received 8 mg of pegloticase every 2 weeks and 67 every 4
weeks. Two patients were merely observed. Gout attacks
New Drug Class
Phase 2 (n=41), 1214 weeks42
Phase 3 GOUT1/GOUT2 (n=212 total), 6 months each4447,50
Treatment (n)
4 mg every 2 weeks (7)


Placebo (43)
Withdrawals
15, all for adverse events, 12 for infusion day events
8 mg every 2 weeks: 26 (31%), due to adverse events 18 (21%)

8 mg every 4 weeks: 25 (30%), due to adverse events 18 (21%)
Placebo: 4 (9%), due to adverse events 1 (2%)
Primary endpoint:
(Percentage of
patients with plasma
urate 357 mol/L
80% of study)
Intention-to-treat:
4 mg every 2 weeks: 4/7 (57%)
12 mg every 4 weeks: 8/13 (62%)
(no signicant dierences among groups)
GOUT1 & GOUT2 (n=212):

8 mg every 2 weeks: 36/85 (42%) (p<0001 vs placebo)
8 mg every 4 weeks: 29/84 (35%) (p<0001 vs placebo)
Placebo: 0% 0/43 (0%)
Resolution of
1 tophus
NA
Anecdotal reports of remarkable improvement over
12 weeks43
8 mg every 2 weeks: 21/52 (p=0002 vs placebo)

8 mg every 4 weeks: 11/52
Placebo: 2/29
Gout ares
4 mg every 2 weeks: 86%

Months 13:
8 mg every 2 weeks: 64/85 (77%) (p=0016)
8 mg every 4 weeks: 68/84 (81%) (p=0002)
Placebo: 23/43 (54%)
(p values vs placebo)
Months 46:
8 mg every 2 weeks: 28/69 (41%) (p=0007)
8 mg every 4 weeks: 39/69 (57%)
Placebo: 29/43 (67%)
(p value vs placebo)
Adverse events
166 adverse events, excluding gout ares

93% of patients had an adverse event
40% related to pegloticase treatment
93% mild or moderate severity
Most common: nephrolithiasis 15%, arthralgia 12%, and
infusion day events 127%
Including infusion reactions and gout ares

8 mg every 2 weeks: 80 (94%), led to discontinuation in 16 (19%)
Placebo: 41 (95%), led to discontinuation in 1 (2%)
Nausea, headache, and nasopharyngitis most common after infusion
reaction and gout ares
Infusion day events
18/41 patients (44%)

9/18 withdrawn without rechallenge
3/9 rechallenged withdrew because of another infusion day
event
Commonest infusion day events: muscle spasm, dyspnoea,
hypersensitivity
Infusion reactions
8 mg every 2 weeks: 26%, 4 severe (5%), led to discontinuation in
9 (11%)
8 mg every 4 weeks: 40%, 8 severe (10%), led to discontinuation in
11 (13%)
Placebo: 5%, none severe (0%), led to discontinuation in none
Serious adverse
events
13 in 9 patients, 22% of patients

5 deemed pegloticase-related: anaemia, hypersensitivity,
infected tophus, gout ares (2 patients)
2 serious adverse events led to discontinuation:
hypersensitivity, infected tophus

Placebo: 5 (12%), led to discontinuation in none
Most common: infusion day events, musculoskeletal including gout
ares, and infection
Deaths
No deaths
8 mg every 2 weeks: 2 (2%); 8 mg every 4 weeks: 1 (1%); placebo: 0 (0%)
Antibody analysis
To pegloticase:
4 mg intravenously every 2 weeks: 86%
(Led to shortened half-life, higher plasma urate levels in
some patients, but no signicant dierences)
If high titre (>1:7290) antipegloticase:

1/68 (1%) responders
51/85 (60%) non-responders (p<0001)
13/25 (52%) every 2 weeks group had infusion reactions
18/27 (67%) every 4 weeks had infusion reactions
If any antibody to poly(ethylene glycol):
27/28 (96%) every 2 weeks non-responders
24/25 (96%) every 4 weeks non-responders
NA=not applicable/not done.
Table 3: Summary of phase 2 and phase 3 clinical trials of pegloticase
continued to decline in patients given pegloticase. Of

48 patients with serum urate concentrations
consistently lower than 357 mol/L on pegloticase in the
randomised trials, 43 maintained that response in the
extension. An additional 20 patients, beyond 32 patients
in the randomised trials, had complete resolution of at
least one tophus. Infusion reactions were common and
sometimes serious, frequently leading to discontinuation,

especially in patients who had received placebo in the
randomised trials (9% in placebo to every 2-week
pegloticase open label conversion and 19% in placebo to
every 4-week pegloticase open label conversion). Three
patients died during the open label extension, all deemed
unrelated to treatment.49,50
171
New Drug Class
Basolateral membrane
to circulation
Probenecid
Benzbromarone
RDEA-594
Tubule cell
Uric acid
Uric acid
OAT1
OAT3
URAT1
Organic anions
Monocarboxylates
Na+
Probenecid
Benzbromarone
SLC5A8
SLC5A12
Monocarboxylates
Uric acid
Glucose
Fructose
SLC2A9v1
(GLUT9)
SLC2A9v2
(GLUT9N)
SLC13A3
OAT4
Uric acid
Glucose
Fructose
Dicarboxylates
Uric acid
Na+
Dicarboxylates
Apical membrane
tubule lumen
Figure 4: Present understanding of uric acid reabsorption and eects of uricosuric drugs in the proximal
renal tubule
Filtered uric acid is exchanged for monocarboxylates through URAT1 and dicarboxylates through OAT4 on the
apical side of the tubule cell. SLC2A9v2 (GLUT9N) also transports uric acid into the cell, then SLC2A9v1 (GLUT9)
transports it out of the cell through the basolateral membrane and back into the circulation, along with glucose
and fructose. OAT1 and OAT3 are involved in the movement of uric acid through the basolateral membrane,
although details are unclear. RDEA594 seems to be distinct from traditional uricosuric drugs in that it inhibits only
URAT1 and not the basolateral transporters. The sodium-dependent monocarboxylate transporters SLC5A8 and
SLC5A12 and dicarboxlyate transporter SLC13A3 are also shown. Transporters involved in uric acid secretion into
the tubule are not shown. See text for references. Modied from reference 60 with permission of authors and
publisher ( Oxford University Press).
Licensing status and recommendations

A US Food and Drug Administration arthritis advisory
committee voted pegloticase to be safe and eective on
June 16, 2009. However, the agencys complete response
letter, dated July 31, 2009, denied approval and cited
production concerns due to changes in the
manufacturing process after completion of the
randomised trials. The agency also wanted more
communication with prescribing doctors about safety
and monitoring. In September, Savient announced that
a return to the original manufacturing was in process,
and that the US Food and Drug Administration would
not ask for further trials before resubmission in early
2010 for US approval.
If approved, pegloticase will have a much more
restricted target population than febuxostat does.
Careful selection will be crucial. Terkeltaub38 has
proposed guidelines for use of uricase in gout. Uricases
are appropriate for patients with tophaceous gout with
a large excess of total body urate and persisting gout
attacks, or with damaging arthropathy, who are
intolerant to conventional treatments or for whom they
were unsuccessful. Presumably, many such patients
will respond to febuxostat, but others wont. The notion
of debulking the urate load is a good way to
172
conceptualise the pegloticase strategy, and emphasises

it as adjunctive and best followed by another uratelowering treatment. Indeed, pegloticase can reduce
tophi dramatically and more quickly than
conventional treatment.43,46,50
Can patients continue pegloticase indenitely if no
alternative exists? Great strides have been made in
reduction of immunogenicity, but the issue remains,
and continuous use of pegloticase might be restricted
by antibody development. At least 25% of patients
develop antibodies, with subsequent infusion reactions,
restricted ecacy, or drug withdrawal. The estimated
frequency of anaphylaxis was 51% (14 of 273 patients),
73% in 2-week regimen and 39% in 4-week regimen.49
Gout ares were very frequent and sometimes severe.
Infusion reactions and ares occurred despite
concomitant corticosteroids with infusions, which
might further restrict use in patients with
contraindications to corticosteroids such as diabetes or
glaucoma. Pegloticase should not be given to patients
with glucose-6-phosphate-dehydrogenase deciency
since it can induce haemolysis. Yet the absence of other
options for these dicult-to-manage patients warrants
some degree of acceptance of a less than optimum
performance with novel interventions. The open label
extension data are encouraging.50 Identication of rising
concentrations of serum urate as a sign of antibody
development and impending infusion reaction should
allow for safer administration.48
Pipeline drug:
RDEA594a more selective uricosuric?
In man, most ltered urate is reabsorbed, followed by its
secretion and post-secretory reabsorption in the renal
proximal tubule, with about 10% excretion in urine.51
Most patients with gout have inecient renal excretion
of uric acid as the mechanism of hyperuricaemia.51,52
Understanding of these processes has advanced greatly.
Urateanion exchanger transporter 1 (URAT1) has been
identied as a primary transporter of uric acid from the
tubule lumen into epithelial cells of the proximal tubule
in exchange for monocarboxylates (gure 4).53,54 Organic
anion transporter 4 seems to have a similar role in
exchanging uric acid for dicarboxylates.55 Glucose
transporter 9 (GLUT9, SLC2A9), an electrogenic hexose
transporter, and its splicing variants mediate reabsorption
of uric acid, along with glucose and fructose, at the apical
membrane, through the basolateral membrane, and into
the circulation.5659 Probenecid, sulnpyrazone, and
benzbromarone are traditional uricosuric drugs used in
gout. These drugs are now known to inhibit uric acid
reabsorption by URAT1 and GLUT9.58,60
Pharmocokinetics and pharmacodynamics

Serendipitously, during clinical trials in patients with
HIV infection, the non-nucleoside reverse transcription
inhibitor RDEA806 (Ardea Biosciences, San Diego, CA,
New Drug Class
USA) was noted to have substantial uricosuric eects

traced to its active metabolite RDEA594, which inhibits
URAT1.61,62 Subsequently, RDEA594 itself was given to
healthy individuals.63 Ascending single doses (38 patients,
28 given drug) of 5 mg to 600 mg, and then ascending
daily doses (64 patients, 48 given drug) of 100 mg to
400 mg for 10 days were given to male volunteers, aged
1845 years. Mean maximum plasma concentration
occurred about 1 h after oral dosing. About 2050% of
RDEA594 was excreted unchanged in the urine within
24 h. Individuals given 100 mg and 200 mg daily doses
had 15% and 30% reductions in serum urate
concentrations, respectively, correlating with increased
uricosuria. Adverse events were mild to moderate, most
often diarrhoea, with no withdrawals or deaths.
Investigators concluded that an immediate-release dose
at breakfast would be used in gout trials.
In vitro, RDEA594 at clinically relevant doses did not
inhibit OAT1 or OAT3, whereas probenecid did.64 In vivo,
administration of parental RDEA806 and RDEA594 to
24 individuals did not alter plasma concentrations or
urinary excretion of tenofovir and emtricitabine, reverse
transcription inhibitors dependent on OAT1 and OAT3
for clearance. Thus, RDEA594 might have more
specicity for URAT1 than available uricosurics, and less
potential for drug interactions. No concerning interactions
exist in terms of pharmacokinetics and urinary excretion
between RDEA594 and allopurinol or oxypurinol in
Cynomolgus monkeys, or between RDEA594 and
febuxostat in Sprague-Dawley rats.65 These data suggest
that co-administration of a xanthine oxidase inhibitor
and RDEA594 could safely accelerate urate reduction in
gout patients.
Clinical trials and recommendations

A phase 2a open study of RDEA594 randomly assigned
21 male patients with gout who had concentrations of
serum urate equal or higher than 476 mol/L and
creatinine clearance equal or higher than 50 mL/min to
be given RDEA594 200 mg daily for 1 week, followed by
400 mg daily for 1 week; allopurinol 300 mg daily for
2 weeks; or placebo.66 Colchicine prophylaxis was used.
With such small numbers, the randomisation yielded
signicant baseline dierences among groups.
Nevertheless, at 2 weeks, six of 11 (55%) patients given
RDEA594 had achieved a serum urate concentration
lower than 357 mol/L versus ve of ve (100%) patients
given allopurinol, and none of patients given placebo.
The lowest serum urate concentration was 462%
(SEM 24) lower than baseline with RDEA, 487 % (57)
lower than baseline with allopurinol, and 24% (24)
lower with placebo. No statistical comparisons were
possible. RDEA594 enhanced urinary uric acid excretion
only to values recorded in healthy people. Adverse
eects were mild, apart from acute coronary syndrome
in one patient given allopurinol. A phase 2b study of
RDEA594 is underway.
Urate crystals
Cell surface recognition by toll-like receptors 2 and 4,

FC receptors, integrins
Crystal uptake
NALP3 inammasome recognition
Caspase cleavage and activation
Prointerleukin 1
Interleukin 1
Monocyte or
macrophage
Interleukin 1
Acute gout
Figure 5. Central role of the innate immune system and the NALP3
inammasome in acute gout
Monosodium urate crystals are recognised on the surface of monocytes by
innate immune system receptors such as toll-like receptors 2 and 4, fragmentcrystallisable receptors and integrins. The crystals are taken up by the cell and
recognised by the NALP3 (cryopyrin) inammasome. Activation of caspase
follows, with cleavage of the precursor prointerleukin 1 to active interleukin 1.
The proinammatory cytokine interleukin 1 is then secreted from the cell,
along with interleukin 18 and tumour necrosis factor . This signal is amplied
through the recruitment of other cells and the acute gout attack ensues. 6569
FC=fragment crystallisable.
The development of RDEA594 is at too early a stage for

recommendations. However, in addition to RDEA594s
selectivity, investigators point to the safety of its
concomitant use with other urate-lowering treatments.
Combination therapy can more eectively lower
concentrations of serum urate and reduce tophi, and is
worth further investigation.67,68 More selective uricosuric
drugs could improve that treatment. The tradeo is a
likelihood of earlier, more frequent, and more severe
gout ares. Aggressive prophylaxis would be essential.
Finally, patients with nephrolithiasis generally should
not be given uricosurics, including RDEA594.
Pipeline drug: interleukin-1 inhibitors

rounding up the number 1 suspect?
In animals, the NALP3 inammasome and interleukin
1 are crucial players in the gout inammatory pathway.
After cell surface recognition by the innate immune
system, including toll-like receptors 2 and 4,69 the
monosodium urate crystals are phagocytised by
monocytes or macrophages (gure 5). Resultant poorly
characterised intracellular changes lead to NALP3
assembly, caspase-1 activation, cleavage of prointerleukin 1, and secretion of active interleukin 1, a
major driver of gout inammation.70 Indeed, we have
known for more than 20 years that murine macrophages
produce interleukin 1 in response to monosodium urate
crystals.71 This eect is blocked in vitro by colchicine.70
Downstream, interleukin 1 activates other macrophages
173
New Drug Class
Urate crystal
recognition
Inammasome activation phase

Proinammatory mediators:
interleukin 1, interleukin 6, interleukin 18,
tumour necrosis factor , interleukin 10
Amplication phase
Intercritical gout
Quiescent phase
The cycle
of gout
Tissue damage mediators:

matrix metalloproteinases,
arginase, prostaglandins,
toll-like receptor signalling
Resolution phase
Anti-inammatory mediators:
CD68, PPAR-, TGF-,
-prostaglandin D synthase
Figure 6: Elucidation of the molecular details behind the characterisation of the

acute attack of gout, from twinge, to full-blown are, to subsequent resolution
On the basis of more than 20 years of research, along with new studies using the
murine air pouch model of gout, three distinct phases are likely at play. These
phases are an early proinammatory cytokine-driven phase after activation of
the inammasome, an amplication phase marked by tissue damage, and a late
resolution phase, in which anti-inammatory mediators predominate. 6569
Immune recognition of crystals is also dependent on proteins coating the
crystals such as immunoglobulin and apolipoprotein E which are
pro-inammatory and anti-inammatory, respectively. Specic mediators in
each phase have been or potentially could be exploited therapeutically.
through the myeloid dierentiation primary response

gene 88 (MyD88)-dependent interleukin-1 receptor to
produce tumour necrosis factor , interleukin 6, and
neutrophil chemotactants.69,70,72 On the basis of murine
air pouch model studies, three distinct phases might be
at play in acute gout: an early pro-inammatory cytokinedriven phase, an amplication phase marked by tissue
damage, and a late resolution phase in which antiinammatory mediators predominate (gure 6).73
Clinical trials and recommendations

Acute gout treatment traditionally consists of nonsteroidal
anti-inammatory
drugs,
colchicine,
corticotropin, or systemic or intra-articular corticosteroids.
Identication of interleukin 1 as crucial in animal
models prompted a pilot study in man with anakinra, an
interleukin-1 receptor antagonist approved for treatment
of rheumatoid arthritis.74 After demonstration that
anakinra was eective in a murine model, ten patients
with acute gout for whom standard treatment had failed
were given 100 mg of anakinra daily subcutaneously for
3 days. Complete resolution of arthritis was recorded in
nine of ten patients at day 3.
Rilonacept is a soluble interleukin-1 receptor fused to
the fragment-crystallisable (Fc) portion of human
immunoglobulin that inhibits interleukin 1 and
interleukin 1. It was approved by the US Food and Drug
Administration in 2008 for use in children with the
autoinammatory
cryopyrin-associated
periodic
174
syndromes in which interleukin 1 has a pathogenetic

role. In an acute gout trial, ten patients with one or more
inamed joints for 4 weeks or longer were given
rilonacept 320 mg subcutaneously, followed by 160 mg
subcutaneously per week for 5 subsequent weeks, in a
14-week, multicentre, non-randomised cross-over study.75
One patient withdrew because of an injection site
reaction, which is the most common adverse event. No
serious adverse events were reported. Three patients
developed non-neutralising antibodies to rilonacept
without consequence. Although there was no signicant
eect on the number of aected joints, patients selfreported median pain scores on a visual analogue scale
decreased from 50 to 28 after 2 weeks of rilonacept
treatment (p<0049), with sustained improvement at
8 weeks (13; p<0.049). C-reactive protein concentration
fell signicantly. At last treatment, 60% of patients
reported more than 50% improvement in pain
(p=000015) and 50% of patients had more than 75%
improvement (p001).
In a phase 2 double-blind randomised trial, 83 patients
with concentrations of serum urate equal or higher than
446 mol/L, with two or more gout attacks per year, and
starting allopurinol treatment, were randomly assigned
to are prophylaxis with either rilonacept 160 mg subcutaneously per week or placebo.76 Patients with acute
attacks were given non-steroidal anti-inammatory drugs
or prednisone. During the 16-week trial, 39 gout ares
occurred in 42 patients given placebo versus nine in
41 patients given rilonacept (p=00036). Of patients on
placebo, 48% had gout ares, and of those, 26% had more
than one are (p=00209). 22% of patients on rilonacept
had ares and none of them had more than one are
(p=00005). Other adverse events were similar and not
serious; infection was the most common of these events
(26% in placebo and 15% in rilonacept).
Canakinumab is a fully human monoclonal antiinterleukin 1 antibody with a 28-day half-life that
received approval from US Food and Drug Administration
in 2009 for cryopyrin-associated periodic syndromes. In
an 8-week, multicentre, masked, double-dummy study,
147 patients with acute gout, refractory or with
contraindications to non-steroidal anti-inammatory
drugs and colchicine, received one subcutaneous dose of
canakinumab (10 mg, 25 mg, 50 mg, 90 mg, or 150 mg).
57 patients with similar background received one
intramuscular injection of 40 mg triamcinolone acetonide
(half-life of 14 days).77 Canakinumab 150 mg was better
than triamcinolone acetonide at reducing pain (p<005),
and did so more rapidly (p=00006). Recurrent ares
occurred in 37% of patients given canakinumab 150 mg
versus 454% of patients given triamcinolone acetonide
during the 8-week follow up (p=0006). Single cases of
appendicitis and carotid artery stenosis in canakinumab
groups and cerebrovascular disorder in the triamcinolone
acetonide group were deemed unrelated to treatment. No
withdrawals due to adverse events occurred. One could
New Drug Class
argue that this comparison was unfair because these

drugs have very dierent half-lives, and corticosteroids
can produce rebound ares, but eective one visit-one
treatment is an advantage, and canakinumab outperformed triamcinolone acetonide in general.
Interleukin-1 inhibition is a promising treatment for
patients with gout who cannot tolerate traditional
agents, including corticosteroids. Larger clinical trials
are underway with rilonacept and canakinumab, both
for acute gout and for prophylaxis. Interleukin-1
inhibitor studies without eective treatment in the
comparator groups should be interpreted cautiously.
Furthermore, after the febuxostat and pegloticase trials,
we believe that true placebo groups in are prophylaxis
trials are now probably unacceptable, apart from
patients who are unable to take available prophylactic
drugs. Finally, these biological agents are very expensive,
but their short-term use in specic clinical situations
might be humane and also ultimately cost eective.70,78,79
Final observations
Time will tell how febuxostat or the pipeline drugs t
into gout treatment algorithms. At the risk of sounding
critical, we remind readers that confusion about how to
use long-available drugs is a persisting issue with our
management of gout. Addition of new drugs alone will
not correct these pre-existing misconceptions. The
diagnosis should be substantiated by identication of
intra-articular monosodium urate crystals, guidelines
about the start of urate-lowering treatment should be
followed, prophylaxis against ares early in such
treatment should be given, low enough concentrations
of serum urate should be targeted, and long-term
adherence by patients should be sought.8090 Most
patients with gout are handled by primary care providers
and
fewer
than
3%
by
rheumatologists.80
Rheumatologists seem to be somewhat, but not
impressively, better at achieving target concentrations
of serum urate than primary care physicians (mean
serum urate concentrations 353 versus 413 mol/L,
respectively, p=00004).81
A major concern is the continued use of allopurinol at
300 mg daily, or less in renal insuciency, since these
doses are clearly inadequate in most patients.1517, 19,20,9193
Clinicians often use suboptimum doses of allopurinol in
patients with renal insuciency for fear of precipitating
worsening renal failure or the sometimes fatal
allopurinol hypersensitivity syndrome.94 Nevertheless,
the approach should be to start low and go slow, with
careful monitoring while titrating upward to achieve
target serum urate values.95 Evidence that treatment of
hyperuricaemia in these patients might improve renal
function is encouraging.96,97 Higher doses of allopurinol
in patients with gout and renal insuciency are not
associated with increased risk of hypersensitivity, but are
associated with better achievement of target serum urate
values (86%).98,99 Undertreatment for fear of side-eects
does disservice to patients since they are on a dose of

medicine that will not achieve the therapeutic goal,
which is to stop attacks and resolve tophi, but merely
slow the rate of progression.
These same principles should apply to dosing of
febuxostat, or other urate-lowering treatments, apart
from drugs like pegloticase, for which the reason for
failure is generally the development of antibodies against
the drugs, not inadequate dosing. The excitement
generated by the appearance of new therapies oers an
ideal opportunity to re-educate our patients and ourselves
about gout so as to improve outcome in this highly
treatable disease.8890
Contributors
Both authors were involved in the conception, literature review, writing,
editing, gure creation, and reference selection for this Review.
Conicts of interest
CMB declares he has no conicts of interest. RLW is a paid consultant
for TAP/Takeda and Savient Pharmaceuticals, Inc.
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New Drug Class

Gout therapeutics: new drugs for an old disease

Approved drug: febuxostat

metabolic products.9 Febuxostat dose adjustments

Lancet 2011; 377: 16577

Randomised controlled trials

New Drug Class

Xanthine oxidase inhibitors:

Figure 1: Targets for intervention in the treatment and prophylaxis of gout

Oral, once daily

FDA, EMA approved for gout

Phase 3 for gout completed;

Selective URAT1 inhibitor,

Oral, once daily

Recombinant, nonglycosylated form of

FDA approved for rheumatoid

FDA approved for

FDA approved for cryopyrinassociated periodic syndromes,

EMA=European Medicines Agency. FDA=US Food and Drug Administration.

Table 1: Description of new drugs for the treatment of gout

febuxostat 40 mg or 80 mg daily; or allopurinol 300 mg

which patients received prophylaxis (naproxen or

Open label extension trials

New Drug Class

during the rst 6 months to achieve serum urate

Just as with allopurinol, febuxostat should not be used

Appropriate candidates for febuxostat

Figure 2: Chemical structures of xanthine, allopurinol and its metabolite

New Drug Class

FACT (n=762), 52 weeks15

APEX (n=1072), 28 weeks16

CONFIRMS (n=2269), 26 weeks17

Serum urate <357 mol/L last three monthly visits

Serum urate <357 mol/L last three monthly visits

Serum urate <357 mol/L at last visit

Febuxostat 80 mg: 53% (p<0001 vs allopurinol)

Febuxostat 80 mg: 48% (p<0001 vs allopurinol, placebo)

Febuxostat 40 mg: 45%

Subset: creatinine clearance >15, 20 (n=40)

Subset: creatinine clearance 3089 ml/min (n=1483)

Febuxostat 80 mg: 22%,

Febuxostat 80 mg: 28%

Febuxostat 80 mg: 64%,

No signicant dierences among groups

Febuxostat 40 mg: 31%

Secondary endpoint: All groups with decrease in median size and

No signicant dierences, apart from mean % decrease in

Febuxostat 80 mg: 34% (p=004 vs allopurinol)

Febuxostat 80 mg: 35% (p005 vs febuxostat 120 mg,

Febuxostat 40 mg: 17% (p=0.021 vs allopurinol)

Febuxostat 80 mg: 2; febuxostat 120 mg: 2;

Febuxostat 40 mg: 1; febuxostat 80 mg: 1;

Liver function test abnormalities, diarrhoea,

Febuxostat 80 mg and 120 mg more cardiovascular events

APTC= Anti-Platelet Trialists Collaboration. MI=myocardial infarction. NA=not applicable/not done.

Table 2: Summary of three phase 3 randomised controlled trials of febuxostat

hypersensitivity reactions to allopurinol who were given

intolerant to allopurinol, for those whose gout is not

New Drug Class

Pipeline drug: pegloticase, the mammalian