CENTER FOR DRUG EVALUATION AND
RESEARCH

APPLICATION NUMBER:

2079880rig1s000

SUMMARY REVIEW

 

SUMMARY REVIEW OF REGULATORY ACTION
Date:

November 23, 2015

From:

Badrul A. Chowdhury, MD, PhD
Director, Division of Pulmonary, Allergy, and Rheumatology
Products, CDER, FDA

Subject:
NDA Number:
Applicant Name:
Date of Submission:
PDUFA Goal Date:
Proprietary Name:
Established Name:
Dosage form:
Strength:
Proposed Indications:

Division Director Summary Review
207988
Ardea Biosciences
December 29, 2014
December 29, 2015
Zurampic
Lesinurad
Tablet
200 mg
Treatment of hyperuricemia associated with gout in combination
with xanthine oxidase inhibitor
Approval, pending finalized labeling, and outcome of CDER
regulatory briefing scheduled for December 11, 2015

Action:

1. Introduction
Ardea Biosciences submitted this 505(b)(1) NDA to support approval of the use of
lesinurad tablet at a dose of 200 mg once daily in combination with a xanthine oxidase
inhibitor for the treatment of hyperuricemia associated with gout. This summary review
provides an overview of the application with emphasis on the clinical section.

2. Background
Gout is an inflammatory arthritis associated with hyperuricemia and caused by the
deposition of monosodium urate crystals in and around the tissues of joints and soft
tissues, urate nephropathy, and nephrolithiasis. Symptomatic crystal deposition includes
attacks of acute inflammatory arthritis, a chronic destructive arthropathy, and soft tissue
accumulation of monosodium urate crystals (tophi). The prevalence of gout has been
increasing over the past few decades, and has been recently estimated to affect
approximately 3.9% of adults in the United States (8.3 million) 1. The condition affects
primarily middle-aged and older men and post-menopausal women. Obesity,
hyperlipidemia, diabetes, hypertension, chronic renal insufficiency, metabolic syndrome,
and cardiovascular disease are frequent comorbidities in patients with gout.
The course of gout is characterized by acute attacks of gouty arthritis alternating with
attack-free periods of intercritical gout. A typical gouty arthritis attack (or gout flare) is
1

Zhu Y, Pandya BJ, Choi HK, “Prevalence of gout and hyperuricemia in the US general population: the
National Health and Nutrition Examination Survey 2007-2008.” Arthritis Rheum 2011; 63:3136-3141.

Reference ID: 3850773

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characterized by acute inflammation of the affected joint and surrounding tissues
associated with often excruciating pain, tenderness, erythema, and swelling. If left
untreated, the acute inflammatory episode is self-limited, typically peaking within 24-48
hours and eventually subsiding within 7-10 days.
Treatment of acute attacks utilizes anti-inflammatory treatment of various mechanisms,
such as colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids.
During initiation of uric acid lowering therapy for long-term management of gout (see
paragraph below), patients are at increased risk of acute gouty attacks. It is common
practice to use an agent to help reduce the frequency and severity of acute gout attacks
during initiation of uric-acid lowering therapies. To this end, maintenance doses of either
colchicine or an NSAID are continued; typically until the serum uric acid level has been
maintained within the target range and there have been no acute attacks for 3 to 6 months.
Chronic management of gout is founded upon control of hyperuricemia, as this approach
targets the underlying pathology of the disease. The approaches to lower serum uric acid
include the following:
(1) Lowering uric acid production, which is currently the most common approach of
chronic management of gout. Drugs in this class include xanthine oxidase inhibitors,
such as allopurinol, and febuxostat.
(2) Increasing urinary uric acid excretion (uricosurics) by inhibiting active renal
reabsorption of uric acid through urate transporters in the proximal renal tubule epithelial
cells (predominantly URAT1), resulting in increasing uric acid excretion. Drugs in this
class include probenecid.
(3) Direct enzyme breakdown of uric acid by uricase into more soluble allantoin, which
can be excreted in the urine. Human do not have endogenous uricase, therefore, animal
derived proteins have been developed for human use. Drugs in this class include
pegloticase and rasburicase.
Copyright Material Withheld

Figure 1. Schematic of lesinurad in current treatment options of gout (Source, Applicant submission)

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Lesinurad, the subject of this NDA, is proposed to act by increasing uric acid excretion
by inhibiting active renal reabsorption of uric acid primarily by inhibition of URAT1.
The basic mechanism of lesinurad is similar to probenecid.
The current options for gout treatment are shown in Table 1. The approved doses of
these agents, particularly allopurinol, and the major efficacy and safety considered of
these products are relevant to place the lesinurad efficacy and safety data (discussed in
section 7 and section 8 below) in context.
Table 1. Current treatment options for gout
Products
Approved Dosing
Efficacy and Safety
First Line Treatment: Xanthine Oxidase Inhibitors (XOI)
Allopurinol
100-800 mg per day
Efficacy: ~ 2- 3.5 mg/dL mean ↓sUA at 300 mg dose
BID dosing for >300 mg/day Safety: hypersensitivity reactions, cutaneous
reactions, GI intolerance
Febuxostat
40-80 mg QD
Efficacy: ~ 4.5 mg/dL mean ↓sUA at 80 mg dose
Safety: ↑LFT, skin rash, possible CV risk
Second Line Treatment: Uricosuric Agents
Probenecid
500-1000 mg BID
Efficacy: ~ 2.9 mg/dL mean ↓sUA at 1.3 g/day dose
Safety: nephrolithiasis
Third Line Treatment: Uricase
Pegloticase
8 mg IV every 2 weeks
Efficacy: ~ 6.8 mg/dL mean ↓sUA
Safety: anaphylaxis, infusion reaction, exacerbation
of CHF
Source: Febuxostat NDA at Drugs@FDA (for allopurinol and febuxostat), Pegloticase NDA at Drugs@fda
(for Pegloticase); Pui et al, J Rheum 2013 (for probenecid)

Regulatory interaction between the Agency and Ardea Biosciences:
The Division and Ardea Biosciences had typical milestone meetings on lesinurad that
included an End-of-Phase 2 meeting in July 2011, a general advice meeting (written
feedback) in February 2014, and Pre-NDA meeting in September 2014. At the End-ofPhase 2 meeting and subsequent general advice meeting, there was an agreement on the
primary endpoint of proportion of patients achieving a serum uric acid reduction to less
than 6 mg/dL. The Agency raised concerns with renal adverse events and MACE related
adverse events, particularly with lesinurad monotherapy and at high doses of lesinurad.
The Agency raised questions about the justification of once-daily dosing regimen and
whether a twice-daily dosing regimen would allow for a lower nominal dose. The
Agency also expressed concern with using suboptimal dose of allopurinol in the studies.
At the Pre-NDA meeting, the content and format of the NDA was discussed, and
concerns raised about safety and dosing that were raised at earlier meetings were
reiterated. The Agency noted that it was unclear whether Risk Evaluation and Mitigation
Strategies (REMS) would be sufficient to address the identified safety concerns with high
doses of lesinurad.

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3. Chemistry, Manufacturing, and Controls
The proposed commercial drug product, Zurampic tablets, contains 200 mg of lesinurad
and standard compendial excipients. The drug product will be packaged as bottles of 5,
30, or 90 tablets. The manufacturing processes for the drug substance and drug product
are traditional and standard with no unique features. All manufacturing and testing
facilities associated with this application have acceptable inspection status. The various
DMFs associated with the manufacture of the product are adequate or do not require
review due to adequate information in the NDA. An expiry of 36 months is proposed and
supported by submitted data.

4. Nonclinical Pharmacology and Toxicology
The non-clinical development program for lesinurad consisted of toxicology studies in
rats and monkeys, standard genotoxicity assays, carcinogenicity studies, and reproductive
toxicology studies. The target organs of toxicity in rats and monkeys included the kidney
and the GI tract. In rats, the dose of 600 mg/kg/day (119 x clinical exposure) was lethal
due to kidney toxicity (tubular degeneration and single cell necrosis) and gastrointestinal
toxicity (erosion, hemorrhage, congestion, single necrosis). At the dose of 300
mg/kg/day (36 x clinical exposure), kidney findings were limited to tubular dilatation and
changes of clinical chemistry parameters. Low incidences of GI tract erosion were also
observed. In monkeys, the dose of 600 mg/kg/day (11 x clinical exposure) was lethal due
to GI tract toxicity (erosions and hemorrhage in colon and rectum and severe diarrhea and
emesis). There was no GI tract toxicity at lower doses; however, bile duct hyperplasia
was observed at 200 mg/kg/day. NOAELs of 100 mg/kg/day in both rats and monkeys
provide exposure margins of 15- and 3-fold relative to the clinical exposure.
Lesinurad was negative in standard genotoxicity assays. There was no evidence of
tumorigenic potential in a 2-year carcinogenicity study in rats and in a 26-weeek
carcinogenicity study in transgenic mice. In reproductive toxicology studies, fertility and
reproductive performance were unaffected in rats, and there was no evidence of
teratogenicity or other embryo-fetal developmental toxicity in rats or rabbits. There were
decreases in pup viability and body weight as well as developmental delays in the pre-and
post-natal development study in rats that may have been influenced by maternal toxicity.
Human subjects were found to form a didhydrodiol metabolite, termed M4, at 20.7% of
total systemic drug exposure. The M4 metabolite was formed in humans by an epoxide
intermediate termed M3c. Epoxide functional groups are known structural alerts for
mutagenicity. Monkeys had evidence of forming the M3c metabolite; the epoxide
metabolite was qualified for safety in the 12-month toxicology study in monkeys.
Although the metabolite was not qualified for safety with respect to carcinogenicity, no
additional nonclinical studies were required. Some concern with regard to the potential
carcinogenic effects of M3c may be mitigated by its transient nature and the fact that, in
humans, this molecule is detoxified to a didhydrodiol (M4).

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The nonclinical team is the lead discipline in the determination of the Established
Pharmacologic Class (EPC) of a product. Lesinurad decreases the reabsorption of uric
acid from the renal proximal tubule by inhibiting the function of the transporters
URAT1 and OAT4, located on the apical surface of renal tubular epithelial cells. Like
probenecid, lesinurad also inhibits the in vitro function of OAT1 and OAT3 (transporters
responsible for uric acid secretion). The nonclinical team agrees with the Sponsor’s
proposal to use URAT1 inhibitor as the EPC given that URAT1 is the principal
transporter responsible for uric acid reabsorption in humans.

5. Clinical Pharmacology and Biopharmaceutics
Ardea Biosciences submitted results from a comprehensive clinical pharmacology
program that included studies to assess the pharmacokinetics and metabolism of the drug
product.
The absolute bioavailability of lesinurad is approximately 100% after oral dosing with no
significant food effect with Cmax occurring within 1 to 4 hours. Lesinurad is extensively
bound to plasma proteins (greater than 98%), mainly to albumin. Lesinurad undergoes
oxidative metabolism mainly via CYP2C9. Elimination of lesinurad is through urine
(over 60%) and feces (approximately 30%). Patients with renal impairment have
increased lesinurad exposure, approximately 31%, 50-73%, and 113%, with mild,
moderate, and severe renal impairment, respectively. Hepatic impairment has about 7%
and 33% increased exposure with mild and moderate impairment, respectively. In
various drug interaction studies, the findings of note were increased lesinurad exposure
with inhibitors of CYP2C9, and reduced plasma concentration of CYP3A4 substrates
with lesinurad.
Dose dependent decrease in serum uric acid was seen with lesinurad doses studied that
ranged from 100 mg to 600 mg once daily. Ardea Biosciences proposed 200 mg once
daily as the proposed dose primarily because of renal adverse effects with 400 mg once
daily dose. Although pharmacokinetic data is suggestive of more frequent dosing, such
as twice daily, Ardea Biosciences proposed once daily dosing primarily to avoid uric acid
urolithiasis that may be associated with evening dosing. Exposure data with 200 mg and
400 mg once daily dosing from phase 3 studies showed that mean exposure was higher
with higher lesinurad dose, but there was substantial overlap of exposure between the two
dose groups. This raises the question of whether a lower nominal dose given twice daily
may have provided similar efficacy with a better safety profile.

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Cavg by Dose Cavg by Dose
400 rig

Figure 2. Exposure to lesinurad in phase 3 studies shown as box and whisker plots. Left panel shows
exposure data from all patients for all studies (studies 301, 302, 303, and 304). Right panel shows
exposure data from patients with normal renal function in studies on background xanthine oxidase
inhibitors (studies 301, 302, and 304).

6. Clinical Microbiology
Not applicable.

7. Clinical and Statistical Efficacy
a. Overview of the clinical program
Some characteristics of the relevant clinical studies that form the basis of the review and
regulatory decision for this application are shown in Table 2. The design and conduct of
these studies are brie?y described below, followed by ef?cacy ?ndings and conclusions.
Safety ?ndings are discussed in the following section.

Table 2. Relevant clinical studies

 

 

 

 

 

 

 

 

 

 

 

ID Study Characteristics Treatment groups 3: Primary ef?cacy Countries
Year - Patient age, mean (range) variables
- Patient characteristics
Studv duration
Pivotal Ef?cacy and Safety Studies lesimuad \xith backgromid allopurinol 300 mg QD or lower
301 - 52 (22-81) yr Les 200 mg QD+Allo 201 Proportion of US (100%)
[02/12 - 26.5 mg/dL despite being Les 400 mg QD+Allo 201 patients achieving
- on at least 300 mg QD Placebo A110 201 serum mic acid <6.0
07a"l4] allopurinol for 28 weeks. and mg/dL at month 6
2 gout ?ares in prior year
- 12 month
302 - 51 (21-82) yr Les 200 mg QD+Allo 204 Proportion of US 
[12/11 - 26.5 mg/dL despite being Les 400 mg QD+Allo 200 patients achieving Canada. Europe.
- on at least 300 mg QD Placebo A110 206 serum m?ic acid <6.0 Australia. New
allopurinol for 28 weeks. and 2 mgde at month 6 Zealand. South
2 gout ?ares in prior year A?ica
- 12 month
Pivotal E?icacy and Safety Studies lesinurad monotherapy

 

 

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7

N
Study Characteristics †
Treatment groups ‡
Primary efficacy
Countries
- Patient age, mean (range)
variables
- Patient characteristics
- Study duration
- 54 (25-82) yr
Les 400 mg QD
107 Proportion of
US (73%),
303
[02/12 - sUA ≥6.5 mg/dL, intolerance
Placebo
107 patients achieving
Canada, Europe,
or contraindication to treatment
serum uric acid <6.0 Australia, New
10/13] with XOI
mg/dL at month 6
Zealand, South
- 12 month
Africa
Pivotal Efficacy and Safety Studies – lesinurad with background febuxostat 80 mg QD
- 54 (22-82) yr
Les 200 mg QD+Fbx
106 Proportion of
US (75%),
304
[02/12 - sUA ≥8 mg/dL for those on no
Les 400 mg QD+Fbx
109 patients achieving
Canada, Europe,
ULT or ≥6 mg/dL for those on
Placebo + Fbx
109 serum uric acid <5.0 Australia, New
04/14] ULT, and ≥1 tophus
mg/dL at month 6
Zealand
- 12 month
Safety Studies
- Open OLE of study 303;
Les 400 mg QD
143 Safety (Les
305
terminated based on renal safety
monotherapy)
- Ongoing OLE up to 30 month
Les 200 mg QD+Allo 361 Safety (Les with
306
of study 301 and study 302
Les 400 mg QD+Allo 353 allopurinol)
- Ongoing OLE up to 30 month
Les 200 mg QD+Fbx
97
Safety (Les with
307
of study 304
Les 400 mg QD+Fbx
99
febuxostat)
* [Month/year study started-completed]
† sUA = Serum uric acid, XOI = xanthine oxidase inhibitor, ULT = urate lowering therapy, OLE = open label
extension
Les = Lesinurad; Allo = Allopurinol. Fbx: febuxostat
§ Number randomized

ID
Year *

b. Design and conduct of the studies
The pivotal Studies 301, 302, 303, and 304 assessed efficacy and safety of lesinurad in
patients with differing disease characteristics and differing background treatments as
shown in Tables 2 and 3. Patients in Studies 301 and 302 were on background
allopurinol at least 300 mg/day (200 mg/day in patients with estimated renal clearance of
less than 60 ml/min), and patients in Study 304 were on background febuxostat 80
mg/day. Patients in Study 303 had intolerance or contraindication to treatment with a
xanthine oxidase inhibitor, and lesinurad was used as monotherapy (the lesinurad
monotherapy treatment option was later dropped by Ardea Biosciences because of renal
safety concerns). The study design and conduct are shown in Table 2 and Figure 3. In all
studies patients received gout flare prophylaxis with colchicine or NSAIDs. Patients
were instructed to take lesinurad at the same time as the morning dose of xanthine
oxidase inhibitor (Studies 301, 302, and 304) with at least 8 oz or 240 mL of water. In a
later protocol amendment patients were instructed to stay well hydrated (68 oz or 2 L of
liquid per day) as a precautionary measure for renal safety. The primary efficacy variable
in all studies were the proportion of patients with sUA (serum uric acid) <6 mg/dL
(Studies 301, 302, and 303) or <5 mg/dL (Study 304) by month 6. Secondary efficacy
variables protected for multiplicity were gout flares requiring treatment from end of
month 6 to end of month 12 (Studies 301 and 302), complete resolution of ≥1 target
tophus by month 12 (Studies 301, 302, and 304), complete or partial (≥50%) resolution of
≥1 target tophus by month 12 (Study 304), and improvemnt from baseline in HAQ-DI of
least 0.25 at month 12 (Study 304).

Reference ID: 3850773

 8

Figure 3. Study design for Studies 301 and 302 (add-on to allopurinol) in left panel, and for Study
304 (combination with febuxostat) in right panel [Source: Ardea Biosciences Advisory Committee
briefing document]

c. Efficacy findings and conclusions
The submitted data from the clinical program support efficacy of lesinurad at a dose of
200 mg once daily dosed in the morning in combination with a xanthine oxidase inhibitor
for the treatment of hyperuricemia associated with gout.
Dose and dosing schedule:
In the early development program, a range of doses was explored. Doses of 25 mg or
less had essentially no sUA lowering effect, and the efficacy of the100 mg dose was not
sustained over 24 hours. Doses of 200, 400, and 600 mg resulted in sustained sUA
reduction over 24 hours. In lesinurad monotherapy studies, 400 and 600 mg seemed to
be effective, but the 200 mg dose had minimum effect. In the lesinurad combination
studies with xanthine oxidase inhibitors, all three doses were effective, but there was no
incremental benefit with the 600 mg dose over the 400 mg dose. Based on these findings,
Ardea Biosciences carried forward the 200 mg and 400 mg doses into the pivotal studies
(Table 2), which is reasonable. In the phase 3 studies (described below), lesinurad 400
mg monotherapy was associated with higher rates of renal adverse events, which is the
reason Ardea Biosciences is not pursuing the 400 mg dose or monotherapy with lesinurad
any further.
The once daily dosing frequency is based on the observation from earlier studies that
lesinurad increased maximum urinary uric acid excretion within 6 hours following
dosing. The once daily morning dosing was the only dose studied in the pivotal studies
with the justification to avoid high urinary acid concentration during nighttime when
urine pH and urine volume is low, thereby reducing the risk of urinary uric acid
precipitation and risk of stone formulation. This justification seems reasonable.
Efficacy findings:
Patients enrolled in the studies were typical of gout program with longstanding
symptomatic gout with elevated sUA levels (Table 3).
In patients with gout receiving background allopurinol (Studies 301 and 302), a
significantly higher proportion of patients in both lesinurad treatment groups achieved the
primary target sUA by month 6 compared to placebo (Table 4). For the proposed dose of

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 9

200 mg, approximately 30% more patients reached the target sUA in both studies. In
patients with gout receiving background febuxostat (Study 304), although a higher
proportion of patients in both lesinurad treatment groups achieved the primary target sUA
by month 6 compared to placebo, the difference for the proposed dose of 200 mg was
10% and not statistically significant. However, in this study, approximately 50% of
patients had already reached the target sUA with a three week run-in period of febuxostat
before adding lesinurad, and thus had less room for further benefit. Secondary efficacy
variables were generally not supportive of a beneficial response of lesinurad and some of
the responses seemed to benefit placebo over lesinurad (Table 4). The secondary efficacy
measures, some of which, particularly gout flares, are direct measures of clinical benefit,
were not considered pivotal for demonstration of efficacy partly because studies lasting
up to 12 months are not considered to be sufficient in duration to assess such benefits.
Data estimating the magnitude of long-term benefit in these direct measures that should
be expected based on specific changes in serum uric acid are not available. A target
serum uric acid level of 6 mg/dL or lower is the recommended goal of urate lowering
therapy in widely accepted gout treatment guidelines issued by the professional societies
such as the American College of Rheumatology (ACR), 2 and the European League
Against Rheumatism (EULAR). 3
Although both the 200 mg and 400 mg doses of lesinurad achieved the primary target
level of sUA more frequently than placebo and the 400 mg dose was numerically superior
to the 200 mg dose, Ardea Biosciences is proposing the 200 mg dose in combination with
xanthine oxidase inhibitor because of renal safety concerns with the 400 mg dose
(discussed further in section 8). For the same renal safety concerns, monotherapy with
lesinurad is also not proposed. The dose of allopurinol used in these studies was 300 mg
per day, which is less than the labeled highest dose of allopurinol. Ardea Bioscience’s
reasoning for using this lower dose of allopurinol was that because of safety concerns
allopurinol is generally not used in clinical practice at doses higher than 300 mg per day.
Table 3. Summary of key baseline characteristics for the pivotal studies
Study 301
Study 302
Add-on allopurinol
Add-on allopurinol
Les
Les
Pbo
Les
Les
Pbo
200
400
200
400
Duration since gout diagnosis (years)
13
11
12
12
11
11
Number of gout flares in past 12 months (mean)
4.8
4.9
4.8
6.7
6.1
5.8
Tophi at baseline (mean number of target tophi)
1.8
2.1
1.8
2.0
2.5
2.2
Renal function (% of patients)
Cr Cl <90
58
62
61
61
57
65
Cr Cl <60
22
20
20
14
15
19
2

Study 303
Monotherapy
Les
Pbo
400

Study 304
Add on febuxostat
Les
Les
Pbo
200
400

11

11

16

13

15

6.2

6.2

6.9

7.0

6.1

1.8

1.8

1.9

65
26

62
20

72
23

59
16

59
20

Khanna D et al., “2012 American College of Rheumatology Guidelines for Management of Gout. Part 1:
Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia.” Arthritis
Care & Research, October 2012; 64(10):1431-1446.
3
Zhang W et al., “EULAR evidence-based recommendations for gout. Part II: Management. Report of a
task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics
(ESCISIT).” Ann Rheum Dis. 2006; 65:1312-1324.

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 10

Study 301
Add-on allopurinol
Cr Cl <45
6
8
10
sUA level mean (mg/dL) at baseline
7.0
6.8
7.0

Study 302
Add-on allopurinol
3
3
5
6.8

6.9

7.0

Study 303
Monotherapy
7
12
9.5

9.2

Study 304
Add on febuxostat
8
7
4
5.4

5.2

5.2

Table 4. Summary efficacy results for the pivotal studies
Study 301
Study 302
Study 303
Study 304
Add-on allopurinol
Add-on allopurinol
Monotherapy
Add on febuxostat
Les
Les
Pbo
Les
Les
Pbo
Les
Pbo
Les
Les
Pbo
200
400
200
400
400
200
400
Primary efficacy variable
Proportion of patients with sUA <6 mg/dL (Studies 301, 302, 303) and <5 mg/dL (Study 304) at month 6
% patients
54
59
28
55
67
23
30
2
57
76
47
Δ vs pbo
0.26
0.31
0.32
0.43
0.28
0.10
0.29
95% CI
0.17,
0.22,
0.23,
0.34,
0.19,
-0.03,
0.17,
0.36
0.41
0.41
0.52
0.37
0.23
0.42
P vs pbo
<0.001 <0.001
<0.001 <0.001
<0.001
0.13
<0.001
Serum uric acid reduction from baseline to month 6, Adjusted differences
Mean
-1.00
-1.23
-1.08
-1.36
-1.58
-0.79
-1.88
95% CI
-1.35,
-1.58,
-1.41,
-1.69,
-2.03,
-1.28,
-2.36,
-0.66
-0.89
-0.75
-1.03
-1.13
-0.30
-1.40
P vs pbo
<0.001 <0.001
<0.001 <0.001
<0.001
0.002 <0.001
Secondary efficacy variables
Gout flares requiring treatment during months 6, Adjusted rate (Studies 301, 302, and 304) or proportions (Study 303)
Rate or Prop.
0.57
0.51
0.58
0.73
0.77
0.83
12%
15%
1.5
0.7
1.3
Rate ratio
0.99
0.88
0.88
0.93
3%
1.2
0.5
P vs pbo
0.98
0.61
0.57
0.75
0.68
0.55
0.04
Complete resolution of ≥1 target tophus by month 12, Difference in proportions
Proportion
00
21%
29%
31%
28%
33%
NA
NA
26%
30%
21%
Δ vs pbo
-29%
-8%
-2%
-6%
NA
NA
4%
9%
P vs pbo
0.02
0.60
0.85
0.63
NA
NA
0.45
0.12
HAQ-DI improvement of ≥0.25, month 12 (Studies 301, 302, and 304), month 6 (Study 303), Difference in proportions
Proportion
30%
29%
35%
30%
38%
39%
33%
32%
44%
33%
53%
Δ vs pbo
-5%
-6%
-10%
-1%
1%
-8%
-19%
P vs pbo
0.41
0.27
0.10
0.82
0.92
0.30
0.02
-

A caveat in the efficacy finding is that lesinurad may be less effective with increasing
degree of renal impairment. FDA review of Studies 301 and 302 appears to show that
despite higher exposure in patients with greatest renal impairment, the reduction in sUA
compared to placebo appears to be smaller in this group. The number of patients with
moderate or severe renal impairment in these studies was small, therefore, limiting the
strength of this conclusion and the numerical trends varied with dose. Nevertheless, it
would be reasonable to limit the use of lesinurad to patients with normal or near normal
renal function. The Agency and Ardea Biosciences are conducing further analysis of the
data to determine the renal function cut off that would be used in the labeling. This
analysis has not been completed at the time this review was finalized.

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8.

Safety
a. Safety database
The safety assessment of lesinurad was primarily based on the studies shown in Table 1.
The safety database was large and adequate.
b. Safety findings and conclusion
The submitted data support the safety of lesinurad at a dose of 200 mg once daily dosed
in the morning in combination with a xanthine oxidase inhibitor (allopurinol or
febuxostat) for the treatment of hyperuricemia associated with gout.
Ardea Biosciences conducted a comprehensive safety analysis of the available data.
Safety assessment in the clinical studies included evaluation of deaths, serious adverse
events (SAEs 4), common adverse events (AEs), vital signs, physical examination, clinical
laboratory and hematology measures, and ECGs. Given the mechanism of action of
lesinurad and the target patient population, safety events of interest were renal, and
cardiovascular safety and major cardiovascular events (MACE).
Deaths, SAEs, dropouts and discontinuations:
Death was an infrequently reported event in the lesinurad clinical development program.
Deaths occurring after active treatment included 6 during pivotal placebo-controlled
studies, and 9 during open label extension studies. None of the deaths were considered
by the investigator or Ardea Biosciences to be related to treatment with lesinurad.
Serious adverse events (SAEs) occurred with 8.6%, 4.7%, and 5.6% frequency for the
lesinurad 400 mg, lesinurad 200 mg, and placebo group, respectively. Events most
frequently reported as SAE were related to renal and urinary disorders, cardiac disorders,
and infections.
Adverse events leading to discontinuations occurred with 9.4%, 6.3%, and 5.4%
frequency for the lesinurad 400 mg, lesinurad 200 mg, and placebo group, respectively.
Increased blood creatinine was the most common adverse event leading to
discontinuation with 1.8%, 0.8%, and 0.8% frequency for the lesinurad 400 mg, lesinurad
200 mg, and placebo group, respectively.
Common adverse events:
Common adverse events that were seen with at least 2% or higher frequency, and with
1% or higher frequency in the lesinurad treatment groups compared to placebo included
4

Serious Adverse Drug Experience is defined in 21 CFR 312.32 as any adverse drug experience occurring
at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience
(defined in the same regulation as any adverse drug experience that places the patient or subject, in the
view of the investigator, at immediate risk of death from the reaction as it occurred), inpatient
hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity,
or a congenital anomaly/birth defect.

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hypertension, headache, influenza, increased blood creatinine, and gastroesophageal
reflex disease.
Laboratory findings and ECGs:
No clinically meaningful effects on hematologic or chemistry or ECG parameters were
noted in the clinical program except for renal function tests, which are described below.
Renal safety:
Adverse events related to kidneys occurred in a dose-depended fashion with lesinurad
(Table 5). Frequencies of these adverse events were higher for the 400 mg dose
compared to placebo, and were more comparable for the 200 mg dose and placebo. Dose
related renal adverse events are not surprising given the increased uric acid excretion
with lesinurad and the underlying risk of patients with gout for renal injury.
During the controlled studies, one patient developed a SAE of acute renal failure. This
patient was on lesinurad 400 mg monotherapy (Study 303). He was 25 years old and had
normal renal function at baseline. On Day 5 of treatment the patient was hospitalized
with abdominal pain and renal function abnormality (serum creatinine of 8.86 mg/dL and
BUN 46 mg/dL). The patient was on concomitant naproxen and omeprazole. Renal
biopsy showed acute tubular necrosis and minimal tubulointerstitial fibrosis. The
patient’s acute renal failure resolved by Day 26 without hemodialysis. However, two
other patients in an open label long-term extension study on lesinurad 200 mg developed
acute-on-chronic renal failure requiring dialysis (at day 381 and day 567). An additional
patient with normal renal function at baseline in an open label long-term extension study
on lesinurad 400 mg developed acute renal failure at Day 413 and underwent renal biopsy
that showed acute tubular cell injury. His acute renal failure resolved on Day 448
without hemodialysis. All these patients had comorbidities or concomitant medications
that could increase risk for renal complications, however, it is likely that lesinurad was an
additional risk factor that contributed to these renal adverse events.
Based on this finding, along with the MACE findings (described below), Ardea
Biosciences is no longer pursuing the 400 mg dose.
Table 5. Incidence of renal-related adverse events in pivotal studies 301, 302, and 304

Blood creatinine increased
Blood urea increased
Renal failure
Renal failure, acute
Nephrolithiasis

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Lesinurad 400 mg
+ XOA
(n = 510)
11.8 %
7.8 %
1.2 %
0.8 %
2.2 %

Lesinurad 200 mg
+ XOI
(n= 511)
5.7 %
4.3 %
0.8 %
0.0 %
0.6 %

Placebo
+ XOI
( n= 516)
4.5 %
2.3 %
1.2 %
0.4 %
1.7 %

 13

Cardiovascular adverse events, and MACE events:
Adverse events related to cardiovascular safety occurred in a dose dependent fashion with
lesinurad. This is a finding of concern because of underlying cardiovascular comorbidity with gout. Blood pressure, blood lipid levels, and ECGs findings were not
effected by lesinurad. There was a numerical trend in blood pressure increase, with
6.9%, 6.1%, and 4.8% frequency for the lesinurad 400 mg, lesinurad 200 mg, and
placebo group, respectively. The number of MACE events was generally low in the
clinical program, but there was a numerical imbalance, particularly with the 400 mg dose.
Ardea Biosciences is no longer pursuing the 400 mg dose because of these findings and
the renal safety findings described above.
Table 6. Incidence of adjudicated MACE events (Studies 301, 302, and 304)

Number of patients with
adjudicated CV events
MACE
CV death
Nonfatal MI
Nonfatal stroke

Lesinurad 400 mg
+ XOA
(n = 510)
15

Lesinurad 200 mg
+ XOI
(n= 511)
18

Placebo
+ XOI
( n= 516)
17

8
2
7
0

4
2
2
0

3
0
1
3

c. REMS/RiskMAP
Ardea Biosciences submitted a risk management plan that included a medication guide
and communication plan, in addition to routine surveillance. No REMS will be required
for this product. Although there are safety issues with lesinurad as noted in Section 8
above, it was thought a REMS or RiskMAP would not be useful to mitigate these.

9. Advisory Committee Meeting
A meeting of the Arthritis Advisory Committee (AAC) was held on October 23, 2015, to
discuss this application. Issues for discussion were the proposed dose of lesinurad 200
mg and the proposed dosing frequency of once daily, the clinical meaningfulness of the
magnitude of the sUA reduction observed, the safety of the proposed dose with specific
focus on renal and cardiovascular safety, and the dose dependency of safety findings with
lesinurad in light of the unacceptable safety profile of the lesinurad 400 mg once daily
dose. Voting questions were on efficacy, safety and approvability. The committee was
of the opinion that the submitted studies demonstrated that lesinurad at the proposed dose
of 200 mg once daily decreased sUA of a magnitude that was clinically meaningful. The
committee expressed concerns about the safety of lesinurad in patients with moderate to
severe renal insufficiency; however, the Committee found it difficult to draw a specific
conclusion because of seemingly conflicting conclusions presented by Ardea Biosciences
and the FDA. The Committee noted the narrow therapeutic index of the drug for renal

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adverse reactions. The committee was not overly concerned about the cardiovascular
safety given the small number of events. The Committee generally noted that the product
could be safely used with appropriate labeling to communicate the safety findings and
having some renal function monitoring in place. The voting, as shown in Table 7,
reflects the discussion that occurred at the meeting.
Table 7. AC voting on efficacy, safety, and approvability
Efficacy
Safety
Approval

Yes
14
7
10

No
0
6
4

Abstain
0
1
0

10. Pediatric
Ardea Biosciences submitted a request for waiver of pediatric studies because gout is an
adult disease and rarely occurs in children; therefore, specific pediatric studies are not
feasible. In children, gout occurs almost exclusively in the setting of hypoxanthineguanine phosphoribosyltransferase (HGPRT) deficiency (also known as Lesch-Nyhan
syndrome and Kelley-Seegmiller syndrome), which are rare diseases. This application
was discussed at the Center’s Pediatric Review Committee (PeRC) meeting on July 8,
2015, and PeRC agreed with the requested waiver.

11. Other Relevant Regulatory Issues
a. DSI Audits
DSI audited two clinic representative sites from the pivotal studies. The clinical and
statistical review teams recommended the sites because these sites enrolled larger number
of patients compared to other sites. No irregularities were identified that would impact
data integrity. During review of the submission, no irregularities were found that would
raise concerns regarding data integrity. No ethical issues were present. All studies were
performed in accordance with the acceptable ethical standards.
b. Financial Disclosure
The applicant submitted acceptable financial disclosure statements. No potentially
conflicting financial interests were identified.
c. Others
There are no outstanding issues with consults received so far from other groups in CDER.
Some of the consults are pending, particularly because the labeling review is ongoing and
not finalized at the time of finalizing this review.

12. Labeling
a. Proprietary Name
The proprietary name Zurampic was reviewed by DMEPA and found to be acceptable.

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b. Physician Labeling
The labeling review is still ongoing at the time of finalizing this review. The major
issues for labeling, which need to be finalized with Ardea Biosciences, are appropriate
communication of the safety findings in the label, specifically renal safety findings, the
apparent lesser efficacy seen in patients with renal insufficiency, and the target gout
patients for lesinurad. The target patients will likely be limited to exclude patients with
renal insufficiency, the exact magnitude of which has not yet been finalized.
c. Carton and Immediate Container Labels
There are no outstanding issues noted so far from other groups in CDER. Final review
decision on these are still pending.
d. Patient Labeling and Medication Guide
Lesinurad will have a Medication Guide.
13. Action and Risk Benefit Assessment
a. Regulatory Action
Ardea Biosciences has submitted adequate data to support approval of the use of
lesinurad tablet at a dose of 200 mg once daily in combination with a xanthine oxidase
inhibitor for the treatment of hyperuricemia associated with gout. The proposed
regulatory action is approval, pending finalized labeling, and outcome of CDER
regulatory briefing scheduled for December 11, 2015.
b. Risk Benefit Assessment
The overall risk benefit assessment supports approval of the use of lesinurad tablet at a
dose of 200 mg once daily in combination with a xanthine oxidase inhibitor for the
treatment of hyperuricemia associated with gout. The major risk identified is the adverse
events related to kidneys occurred in a dose-depended fashion with lesinurad, which was
not acceptable for the 400 mg dose, but seemed to occur at a lower frequency with the
proposed dose of 200 mg dose that was more comparable to the placebo group than the
400 mg group. Appropriate labeling to restrict use of lesinurad based on renal function
and periodic monitoring of renal function would be adequate to assure safe use of the
product. The submitted efficacy data showed that in patients with gout receiving
background allopurinol, a significantly higher proportion of patients achieved the primary
target by month 6 compared to placebo with the proposed dose of 200 mg once daily. A
target serum uric acid level 6 mg/dL or lower is the recommended goal of urate lowering
therapy in widely accepted gout treatment guidelines issued by the professional societies
such as the American College of Rheumatology (ACR), and the European League
Against Rheumatism (EULAR), which was achieved by lesinurad at the proposed dose of
200 mg once daily added to xanthine oxidase inhibitor allopurinol.
c. Post-marketing Risk Management Activities
No other post-marketing risk management activities are required.

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 None.

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d. Post?marketing Study Commitments

16

--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------BADRUL A CHOWDHURY
11/23/2015

Reference ID: 3850773