Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Lesinurad for the treatment of hyperuricaemia in

people with gout

Philip C Robinson & Nicola Dalbeth

To cite this article: Philip C Robinson & Nicola Dalbeth (2017): Lesinurad for the
treatment of hyperuricaemia in people with gout, Expert Opinion on Pharmacotherapy, DOI:
10.1080/14656566.2017.1401609

To link to this article: http://dx.doi.org/10.1080/14656566.2017.1401609

Accepted author version posted online: 06

Nov 2017.

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 Lesinurad for the treatment of hyperuricaemia in people with gout

Philip C Robinson1 and Nicola Dalbeth2

1. University of Queensland, Brisbane, Australia

2. University of Auckland, Bone & Joint Res Grp – Dept. Med, Fac Med & Hlth Sci, Auckland,

New Zealand

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Corresponding author:

Professor Nicola Dalbeth

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University of Auckland

None and Joint Research Group

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Department of Medicine, Faculty of Medical and Health Sciences

Auckland
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New Zealand

n.dalbeth@auckland.ac.nz
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Funding
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This paper was not funded

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Declaration of interest

P C Robinson has received research funding and speaker fees from AstraZeneca and

consulting and speaking fees from Menarini and Novartis. N Dalbeth has received consulting

fees, speaker fees or grants from Takeda, Menarini, Teijin, Pfizer, Andrea Biosciences,

AstraZeneca, Horizon and Cymabay. N Dalbeth was the principal investigator for the

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 CRYSTAL phase III study and was an investigator on CLEAR2 and LIGHT phase III trials.

The authors have no other relevant affiliations or financial involvement with any organization

or entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript

have no relevant financial or other relationships to disclose.

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Abstract

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Introduction: Gout is a common form of inflammatory arthritis caused by deposition of

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monosodium urate crystals. The central strategy for effective long-term management of gout
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is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase

inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits
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urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a

xanthine oxidase is approved for urate-lowering therapy in patients with gout.

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Areas covered: The published literature was searched using Pubmed and additional information was
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obtained from publically available regulatory documents. Pre-clinical data and clinical trials of
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lesinurad are described. Serum urate-lowering efficacy and effects on other clinical endpoints are

discussed. Adverse event data, focusing on renal safety are also presented.
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Expert opinion: Lesinurad is an effective urate-lowering drug that has a generally acceptable

safety profile when used at 200mg daily dosing in combination with a xanthine oxidase

inhibitor. The recent approval of fixed dose combination pills of lesinurad with allopurinol

is an important step in improving adherence and reducing risk of renal adverse events. It

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 remains to be seen if this therapy will provide additional benefit for gout management above

improved use of widely available generic therapies.

Keywords: lesinurad, urate, gout, kidney

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1.0 Introduction

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The central strategy for effective long-term gout management is serum urate (SU) lowering,

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which promotes dissolution of monosodium urate (MSU) crystals, and in turn, prevention of
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gout flares and regression of tophi. For most people with gout, the target SU is <0.36mmol/L

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(6mg/dL) 1, 2. For people with severe disease, particularly those with tophi, the target SU is
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<0.30mmol/L (5mg/dL).
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Urate is the final product of the purine degradation pathway, and its production is catabolised

by xanthine oxidase. The central factor contributing to hyperuricaemia in people with gout is
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renal under-excretion of uric acid 3, 4. Many transporters in the proximal renal tubule

promote either reabsorption or secretion of uric acid, including the reabsorptive uric acid-
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anion exchanger URAT1/SLC22A12 present on the apical (lumen) surface 5. Lesinurad is a

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novel urate-lowering drug (ULD) that inhibits reabsorption of uric acid through interactions

with URAT1 in the proximal renal tubule 6. This article summarises current knowledge about
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lesinurad for treatment of gout. The published literature was searched using Pubmed and

additional information was obtained from publically available regulatory documents 7, 8.

2.0 Body of review

2.1 Overview of the market

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 Gout is the most common form of inflammatory arthritis, affecting approximately 4% of the

US adult population 9. Gout occurs more frequently in men, with increasing prevalence in

older age. A number of oral ULD are approved, including the xanthine oxidase inhibitors

allopurinol and febuxostat that inhibit urate production, and the uricosuric agent probenecid.

Both allopurinol and probenecid have been available as ULDs for more than 50 years.

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Despite these widely available options, gout is poorly managed world-wide. Most studies

show low rates of ULD initiation, poor continuation rates, and very low achievement of SU

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targets 10, 11. Febuxostat is a xanthine oxidase inhibitor approved by the FDA in 2009.

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Febuxostat 80mg daily is substantially more effective at urate-lowering than fixed dose

allopurinol at 300mg daily (or 200mg daily in patients with moderate renal impairment)12.
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However, even in a clinical trial setting, almost half of participants did not achieve SU target

at the last three monthly visits with febuxostat 80mg daily (the maximum approved dose in
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the US) 12.

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Probenecid is a moderately effective ULD, but requires twice daily dosing and interacts with
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a number of medications. Probenecid is used very infrequently for gout management in

contemporary clinical practice 13.

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Pegloticase is a pegylated recombinant uricase, administered as a fortnightly intravenous

infusion and approved as a ULD for gout that is ‘refactory to conventional therapy’. In

pegloticase responders, profound reductions in SU are observed, leading to rapid regression

of MSU crystal deposition and clinical improvements 14. However, infusion reactions occur

in almost half of patients receiving this agent, usually associated with loss of urate lowering

efficacy 15. Therefore, although a number of ULD are available, a large unmet need remains.

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 Several other novel uricosuric agents are in development, including verinurad (RDEA3170)
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and arhalofenate 17. Phase III data have not been presented for these compounds.

2.2 Introduction to the compound

Lesinurad was discovered serendipitously when scientists working on compounds to treat

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human immunodeficiency virus found that the pro-drug of lesinurad (RDEA806), a non-

nucleoside reverse transcriptase inhibitor, significantly reduced SU 18. Lesinurad has no anti-

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viral activity but lowers SU by inhibiting the reabsorption of uric acid, and thus increases the

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urinary fractional excretion of uric acid. Lesinurad inhibits URAT1, as well as the organic

anion transporter (OAT) 4 in the renal proximal tubule 6. It does not affect other urate
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transporters such as GLUT9 or ABCG2.
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2.3 Chemistry

Lesinurad has a molecular weight of 404 gm/mol and a molecular formula of

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C17H14BrN3O2S. Its International Union of Pure and Applied Chemistry name is 2-[[5-bromo-
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4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetic acid. The two

dimensional structure is shown in Figure 1.

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2.4 Pharmacodynamics

In pharmacodynamics studies, doses of lesinurad over 100mg and up to 600mg showed a

dose dependent reduction in SU. 19. The maximum observed effect using 100-600mg

occurred 6 hours post dose and was in the order of -22 to -39% of baseline SU. Dosing

between 100-400mg repeatedly resulted in maximum SU reductions at 6-7 days. The steady

state effect of lesinurad on SU lowering was achieved in approximately 7 days 19. In small

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 short-term pharmacokinetic and pharmacodynamic studies repeated doses of 100-400mg had

no effect on creatinine clearance.

A dose dependent effect on urinary uric acid excretion was also seen with doses of lesinurad

ranging from 100-600mg. At 100-200mg urinary uric acid excretion normalised by 12 hours

and at 400-600mg by 30 hours 19.

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2.5 Pharmacokinetics and metabolism

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2.5.1 Pharmacokinetics

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In pharmacokinetic studies, the median time to maximum observed plasma concentration was

15-90 minutes 19. Peak plasma concentrations increased proportional to dose from 5mg to
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1200mg. The mean estimated terminal half-life observed in the studies was 2.7-12.7 hours,

approximately 5 hours overall 7, 19. Multiple dosing did not result in drug accumulation. The
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absolute bioavailability under fed conditions was complete (~100%) following oral

administration 19. The area under the curve is similar between dosing in a fasted or fed
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subject. However the maximum concentration was reduced in fasted participants as the time
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to maximum concentration was delayed by 4 hours. The area under the curve (AUC) was

significantly increased by renal impairment, with an increase of 31% in those with mild renal
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impairment (eCrCl>60 mL/min), an increase of 50-74% in those with an eCrCl of 45-<60

mL/min, and an increase of 113% in those with an eCrCl <45mL/min 20.

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2.5.2 Metabolism

Lesinurad is metabolised by the liver, renal excretion and by biliary uptake 7. The mean

amount of lesinurad in urine in studies was 63%, and almost half of this was unmetabolised,

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 with around 32% eliminated in the faeces 7. Half of the oral dose is metabolised by CYP2C9

oxidative metabolism 21.

2.5.3 Drug-drug interactions

The CYP2C9 inhibitor fluconazole increases the exposure of lesinurad (56% increase in

AUC) 7, 21. Other CYP2C9 inhibitors such as valproate, amiodarone, promethazine, isoniazid,

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probenecid, sertraline and sulphamethoxazole are likely to have the same effect. CYP2C9

inducers such as rifampicin decrease lesinurad exposure. Lesinurad is also a weak inducer of

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CYP3A4 and lesinurad reduces CYP3A4 substrates such as sildenafil and amlodipine 7, 21.

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This also means that lesinurad has the potential to impact on the efficacy of hormonal

contraception 7, 21.
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An analysis of drug-drug interactions of lesinurad with drugs used to treat gout flares showed
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that lesinurad modestly altered exposure to colchicine (≤25% decrease in AUC) and

indomethacin (35% increase in AUC) with no effect on naproxen 22. Naproxen, but not
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indomethacin, modestly decreased the Cmax of lesinurad by ∼27%.

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2.5.4 Preclinical Toxicity

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In monkeys, a dose equivalent to 11 times clinical exposure (600mg/kg/day) caused GI tract

toxicity with erosions and colonic haemorrhage, diarrhoea and vomiting that was lethal 7. In
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rats, a dose equivalent to 119 times clinical exposures caused death due to renal toxicity of

tubular degeneration and cellular necrosis, as well as gastrointestinal tract toxicity with

erosion and haemorrhage. At 36 times clinical exposure in rats (300mg/kg/day) the toxicity

caused renal tubular dilatation and changes in serum metabolites, with reduced

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 gastrointestinal toxicity at this dose 7. The assessment of comparable toxicity in rats

compared to humans is limited by the functional uricase in rats.

2.6 Clinical efficacy

2.6.1 Phase I studies

A phase Ib study combined febuxostat and lesinurad in people with gout and

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SU>0.48mmol/L 23. In one group, 12 participants took febuxostat 40mg daily for 7 days, then

added lesinurad 400mg for 7 days, with lesinurad increased to 600mg for the final 7 days.

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The second group of 9 participants took febuxostat 80mg daily for 7 days, then added

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lesinurad 400mg for 7 days, with lesinurad increased to 600mg for the final 7 days. All

participants achieved SU<0.36mmol/L after the addition of lesinurad 400mg. All participants
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in the febuxostat 80mg group also achieved SU<0.30mmol/L with lesinurad 400mg and 82%

in the febuxostat 40mg group achieved this with lesinuard 400mg. All participants in both
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groups achieved SU<0.30mmol/L after addition of lesinurad 600mg.

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2.6.2 Phase II studies

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The only published phase II lesinurad study is summarised in Table 1. This study of 227

participants with inadequate response to allopurinol compared lesinurad 200mg, 400mg,

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600mg and placebo in combination with allopurinol (200-600mg/day) 24. The primary
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endpoint was percentage reduction in SU after 4 weeks. SU reduced by 16%, 22%, 30% and

3% for 200mg lesinurad/allopurinol, 400mg lesinurad/allopurinol, 600mg

lesinurad/allopurinol, and placebo/allopurinol, respectively. The most common treatment

emergent adverse events (TEAEs) were gout flare, arthralgia, headache and nasopharyngitis.

2.6.3 Phase III studies

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 Serum urate lowering

Four phase III studies have been published; CLEAR 1, CLEAR 2, CRYSTAL, and LIGHT 25-
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. For all studies, creatinine clearance <30mL/min was an exclusion criterion. These studies

are summarised in Table 1.

CLEAR 1 and CLEAR 2 were identical randomized, double-blind, placebo-controlled trials

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combining lesinurad and allopurinol. CLEAR 1 was undertaken solely in the US 25.

Participants with normal renal function were taking 300-900mg of allopurinol, and those with

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moderate renal impairment were taking at least 200mg of allopurinol (n=603). Participants

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were randomised to receive daily 200mg lesinurad, 400mg of lesinurad or placebo in

combination with allopurinol. The primary end point was the proportion of participants with
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SU<0.36mmol/L at month 6. In CLEAR 1, 54% and 59% and 28% achieved the primary

endpoint with 200mg lesinurad/allopurinol, 400mg lesinurad/allopurinol, and

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placebo/allopurinol, respectively.
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CLEAR 2 was undertaken in the US, Europe, South Africa, Australia and New Zealand
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(n=610) 26. The primary outcome of the proportion of participants with SU<0.36mmol/L at

month 6 was achieved in 55%, 67% and 23% with 200mg lesinurad/allopurinol, 400mg
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lesinurad/allopurinol, and placebo/allopurinol, respectively.

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In CRYSTAL, participants with tophaceous gout were randomised to receive daily 200mg

lesinurad, 400mg of lesinurad or placebo in combination with 80mg febuxostat (n=324) 27. At

study entry, participants had SU≥0.48mmol/L, or ≥0.36mmol/L on ULT, and at least one

tophus. The primary endpoint was the proportion of participants with a SU<0.30mmol/L at

month 6. This endpoint was achieved at 6 months in 57%, 76%, and 47% with 200mg

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 lesinurad/80mg febuxostat, 400mg lesinurad/80mg febuxostat, and placebo/80mg febuxostat

respectively. This endpoint was achieved at 12 months in 57%, 61% and 41% respectively.

LIGHT compared 400mg lesinurad monotherapy with placebo (n = 214) 28. Participants with

intolerance or contraindication to allopurinol or febuxostat were included, and those with a

history or suspicion of kidney stones were excluded. Participants received lesinurad 400mg

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daily or placebo for 6 months, with an open-label extension phase of lesinurad 400mg daily.

The primary endpoint was a SU<0.36mmol/L at month 6. This endpoint was achieved in

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30% with 400mg lesinurad compared to 2% with placebo. SU<0.30mmol/L was achieved in

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14% with 400mg lesinurad and 0% with placebo.
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Other clinical efficacy outcomes

None of the phase III RCTs demonstrated differences in gout flare rates over the observation
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period. Extension studies have been undertaken to examine this endpoint and are not yet
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published. In the CRYSTAL study, the rates of complete resolution of at least one target

tophus did not differ between groups 27. However, after 12 months, the percent change in
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sum of the areas for all target tophi was significantly greater for the lesinurad groups

compared with placebo; -50.1% for 200mg lesinurad/80mg febuxostat, -52.9% for 400mg
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lesinurad/80mg febuxostat and -28.3% for placebo/80mg febuxostat 27.

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2.7 Safety and tolerability

In the phase III studies of combination treatment with a xanthine oxidase inhibitor, overall

rates of serious adverse events with 200mg lesinurad were similar to placebo 25-27. In both

CLEAR studies, serious adverse events were more common with 400mg lesinurad compared

to placebo 25, 26. In the LIGHT monotherapy study, serious adverse events were also more

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 common with 400mg lesinurad compared with placebo 28. There were numerically more

cardiovascular TEAEs in the CRYSTAL study with lesinurad 27, but no difference in the

other phase III studies (Table 1). Due to the mechanism of action of lesinurad, particular

areas of safety interest were serum creatinine elevations and kidney stones.

Serum creatinine elevations

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In CLEAR 1, increases in serum creatinine occurred in 3.5%, 7%, and 1% with 200mg

lesinurad/allopurinol, 400mg lesinurad/allopurinol, and placebo/allopurinol respectively 25.

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Serum creatinine elevation >2x baseline were observed in 1%, 6% and 0% participants with

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200mg lesinurad/allopurinol, 400mg lesinurad/allopurinol, and placebo/allopurinol

respectively. At the last study visit, unresolved serum creatinine elevation >2x baseline was
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observed in none of the 200mg lesinurad/allopurinol group and 2 participants in the 400mg

lesinurad/allopurinol group.
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In CLEAR 2, increases in serum creatinine occurred in 3.9%, 9.5%, and 3.4% with 200mg

lesinurad/allopurinol, 400mg lesinurad/allopurinol, and placebo/allopurinol respectively 26.

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At the last study visit, unresolved serum creatinine elevation >2x baseline was observed in

none of the 200mg lesinurad/allopurinol group and 5 participants in the 400mg

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lesinurad/allopurinol group.
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In CRYSTAL, serum creatinine elevation >2x baseline were observed in 2.8%, 5.5% and 0%

with 200mg lesinurad/80mg febuxostat, 400mg lesinurad/80mg febuxostat, and

placebo/80mg febuxostat respectively.27. At the last study visit, unresolved serum creatinine

elevation >2x baseline was observed in 1 participant receiving 200mg lesinurad/80mg

febuxostat and 1 participant receiving 400mg lesinurad/80mg febuxostat 27.

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 In the LIGHT monotherapy study, serious renal related adverse effects occurred in 5% with

400mg lesinurad and 0% placebo 28. Serum creatinine elevation >1.5x baseline were observed

in 24% with 400mg lesinurad and 0% placebo. Serum creatinine elevation >2x baseline were

observed in 8.4% with 400mg and 0% placebo. At the last study visit, unresolved serum

creatinine elevation >2x baseline was observed in 3 participants receiving 400mg lesinurad

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monotherapy.

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Kidney stones

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None of the phase III RCTs showed an increased rate of kidney stone TEAEs for lesinurad

200mg daily in combination with a xanthine oxidase inhibitor (Table 1). In the 6-month RCT
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phase of LIGHT, kidney stone TEAEs occurred in 1% with 400mg lesinurad monotherapy

and 0% placebo, with kidney stone TEAEs in 4% with 400mg lesinurad monotherapy in the
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open-label extension phase 28.

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3.0 Regulatory affairs

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The 200mg lesinurad dose in combination with a xanthine oxidase inhibitor was approved by

the FDA in 2015 and EMA in 2016. In August 2017, the FDA approved the fixed dose
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combination pills of lesinurad 200mg with allopurinol 200mg and 300mg (DUZALLO),
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based on the CLEAR studies and a pharmacokinetic study that compared the bioequivalence

of the fixed-dose combination of lesinurad and allopurinol to separate lesinurad and

allopurinol tablets 8.

4.0 Conclusion

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 The clinical evidence presented demonstrates that lesinurad is an effective urate-lowering

drug when used in combination with a xanthine oxidase inhibitor. Co-prescription with a

xanthine oxidase inhibitor is essential, and close monitoring of renal function is required in

patients receiving lesinurad.

5.0 Expert opinion

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The phase III clinical trials demonstrate that lesinurad in combination with the xanthine

oxidase inhibitors allopurinol or febuxostat leads to substantially lower SU concentrations

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and greater numbers of people with gout achieving SU targets than xanthine oxidase inhibitor

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therapy alone. The dual mechanism of action of this combination therapy, with both

inhibition of urate production and promotion of uric acid excretion, is mechanistically

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appealing.
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At present, it remains to be seen whether availability of this therapy will lead to major
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improvements in gout management. Allopurinol and febuxostat are effective urate-lowering

drugs for many people with gout, and dose escalation of allopurinol to achieve SU target is a
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safe and effective strategy 29, 30. Nevertheless, prescriptions rates of these drugs remain very

low, with a minority of people with gout receiving long-term therapy 11. The intermittent
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nature of symptoms for most people with gout provides a further barrier to adherence to

urate-lowering therapy 31. It is likely that low rates of prescription and adherence may also
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be an issue for lesinurad.

The requirement for co-administration with a xanthine oxidase inhibitor may be a further

barrier to prescription for lesinurad. The fixed dose combination pills of lesinurad 200mg

with allopurinol 200mg and 300mg (DUZALLO) represent a major advance, as a single

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 combination pill will ensure that there is co-administration of allopurinol with lesinurad

(providing greater reassurance about renal safety) and reduce the number of daily tablets,

which may also improve patient adherence.

Recent randomised controlled trial data have shown that allopurinol dose escalation can

safely lead to achievement SU targets for most people with gout 29, 30. Allopurinol is a widely

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available and inexpensive generic medication. Furthermore, probenecid, another generic

drug, is a uricosuric drug that is frequently effective in combination with allopurinol 32.

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Acute kidney renal failure is not a common side effect of probenecid, even when used as

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monotherapy 33. It is currently unclear whether addition of lesinurad to allopurinol is a safer

or more cost-effective strategy, compared with allopurinol dose escalation or addition of

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probenecid for patients who have not achieved treatment target on standard doses of

allopurinol.
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Co-prescription of lesinurad 200mg and febuxostat 80mg daily may be of particular benefit

for patients with extensive MSU crystal deposits. Pegloticase is a very effective agent for
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these patients 14, but its widespread use is limited by high cost, the need for fortnightly

intravenous infusions, and loss of response to therapy due to antidrug antibodies. Although
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combination lesinurad 200mg and febuxostat 80mg therapy does not lead to such intensive
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serum urate lowering as pegloticase, this treatment does allow many patients to achieve very

low SU concentrations with substantial reductions in tophus size over a one year period 27.

Although studies have shown lower rates of renal adverse events of lesinurad when combined

with xanthine oxidase inhibitors and at 200mg daily dosing, renal safety remains an important

consideration. The risk of acute renal failure is currently a boxed warning and careful

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 monitoring of serum creatinine is needed for all patients taking lesinurad. Patients on

lesinurad should also be advised to take the tablet in the morning with the xanthine oxidase

inhibitor and drink at least 2 litres of fluid per day. It is currently unknown whether concerns

about renal safety will influence prescriber or patient willingness to use this medication.

In summary, lesinurad is an effective urate-lowering drug that has a generally acceptable

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safety profile when used at 200mg daily dosing in combination with a xanthine oxidase

inhibitor. The availability of fixed dose combination pills of lesinurad with allopurinol is an

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important step in improving adherence and reducing the risk of renal adverse events. It

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remains to be seen if this therapy will provide additional benefit for gout therapy above

improved use of widely available generic therapies.

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Drug summary box

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Drug: Lesinurad

Current Phase: FDA approved

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Indication: Gout

Mechanism of action: Uricouretic/Uricosuric

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Route: Oral
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Chemiccal Structuree:

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Pivotal Trials: CLEAR
R 1, CLEAR
R 2, CRYST
TAL and LIIGHT
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7.0 Refferences

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J Khannaa PP, Bae S, Singh MK
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m t of gout. Paart 1: system
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macologic theerapeutic ap
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o hyperuriccemia. Arthrritis

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3. Gibson T, Highton
H J, Potter
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A. Renal im
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and gout. An
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4. Perez-Ruiz F, Calabozzo M, Erausskin GG, Ru

uibal A, Herrrero-Beitess AM. Renaal

underexxcretion of uric
u acid is present in ppatients with
h apparent high
h urinaryy uric acid output.
o

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 *5. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et al.

Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

Nature 2002 May 23;417(6887):447-52.

This paper described URAT1 as a renal urate anion exchanger regulating serum urate

levels and target for uricosuric therapy.

**6. Miner J, Tan PK, Hyndman D, Liu S, Iverson C, Nanavati P, et al. Lesinurad, a novel,

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This paper descibes the mechanism of action of lesinurad, reporting the inhibition of

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URAT1 and OAT4.

7. Department of Health and Human Services Food and Drug Administration. FDA
an
Briefing Package. NDA 207988: Lesinurad for the proposed indication of treatment of

hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor; 2015.
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8. U.S. Food and Drug Administration.

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https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo

=209203. [cited 6/9/17]; Available from:

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9. 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
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Rheum 2011 Oct;63(10):3136-41.

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10. Robinson PC, Taylor WJ, Dalbeth N. An Observational Study of Gout Prevalence and

Quality of Care in a National Australian General Practice Population. J Rheumatol 2015

Sep;42(9):1702-7.

11. Singh JA, Akhras KS, Shiozawa A. Comparative effectiveness of urate lowering with

febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort. Arthritis

Res Ther 2015 May 12;17:120.

17
 12. Becker MA, Schumacher HR, Jr., Wortmann RL, MacDonald PA, Eustace D, Palo

WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N

Engl J Med 2005 Dec 08;353(23):2450-61.

13. Krishnan E, Chen L. Trends in physician diagnosed gout and gout therapies in the US:

results from the national ambulatory health care surveys 1993 to 2009. Arthritis Res Ther

2013 Nov 06;15(6):R181.

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ip
14. Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, et

al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients

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refractory to conventional treatment: two randomized controlled trials. JAMA 2011 Aug

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17;306(7):711-20.

15. Lipsky PE, Calabrese LH, Kavanaugh A, Sundy JS, Wright D, Wolfson M, et al.
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Pegloticase immunogenicity: the relationship between efficacy and antibody development in

patients treated for refractory chronic gout. Arthritis Res Ther 2014 Mar 04;16(2):R60.
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16. Shen Z, Gillen M, Miner JN, Bucci G, Wilson DM, Hall JW. Pharmacokinetics,
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pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor,

in healthy adult male subjects. Drug design, development and therapy 2017;11:2077-86.
pt

17. Steinberg AS, Vince BD, Choi YJ, Martin RL, McWherter CA, Boudes PF. The

Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with

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Febuxostat When Treating Hyperuricemia Associated with Gout. J Rheumatol 2017

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Mar;44(3):374-79.

18. Cartwright H. AstraZeneca Looks to Replenish Late-Stage Pipeline with US$1.26 B

Ardea Biosciences Acquisition. PharmaDeals Reviews 2012;2012(4):62.

**19. Shen Z, Rowlings C, Kerr B, Hingorani V, Manhard K, Quart B, et al.

Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid

18
 reabsorption inhibitor, in healthy adult males. Drug design, development and therapy

2015;9:3423-34.

This paper described dosing studies in healthy volunteers to characterize

pharmacokinetiecs and pharmacodynamics of lesinurad.

20. Gillen M, Valdez S, Zhou D, Kerr B, Lee CA, Shen Z. Effects of renal function on

pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers. Drug design,

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ip
development and therapy 2016;10:3555-62.

21. Gillen M, Yang C, Wilson D, Valdez S, Lee C, Kerr B, et al. Evaluation of

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Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption

us
Inhibitor, and CYP Enzyme Substrates Sildenafil, Amlodipine, Tolbutamide, and

Repaglinide. Clin Pharmacol Drug Dev 2017 Jul;6(4):363-76.

an
22. Shen Z, Tieu K, Wilson D, Bucci G, Gillen M, Lee C, et al. Evaluation of

Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption

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Inhibitor, and Commonly Used Drugs for Gout Treatment. Clin Pharmacol Drug Dev 2017
ed

Jul;6(4):377-87.

*23. Fleischmann R, Kerr B, Yeh LT, Suster M, Shen Z, Polvent E, et al.

pt

Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant

administration of lesinurad and febuxostat in gout patients with hyperuricaemia.

ce

Rheumatology 2014 Dec;53(12):2167-74.

Ac

This phase IB study demonstrated the urate-lowering efficacy of combining lesinurad

400mg and 600mg with febuxostat. This study only used the higher non-FDA approved

doses of lesinurad.

*24. Perez-Ruiz F, Sundy JS, Miner JN, Cravets M, Storgard C, Group RS. Lesinurad in

combination with allopurinol: results of a phase 2, randomised, double-blind study in patients

19
 with gout with an inadequate response to allopurinol. Ann Rheum Dis 2016 Jun;75(6):1074-

80.

This 4-week phase II study randomized patients with gout on allopurinol to lesinurad

(200mg, 400mg, or 600mg daily) or placebo and assessed the serum urate response.

**25. Saag KG, Fitz-Patrick D, Kopicko J, Fung M, Bhakta N, Adler S, et al. Lesinurad

Combined With Allopurinol: A Randomized, Double-Blind, Placebo-Controlled Study in

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Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based

Study). Arthritis Rheumatol 2017 Jan;69(1):203-12.

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This 12-month US-based phase III study (CLEAR 1) randomised patients on background

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allopurinol to either lesinurad (200mg or 400mg daily) or placebo.

**26. Bardin T, Keenan RT, Khanna PP, Kopicko J, Fung M, Bhakta N, et al. Lesinurad in
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combination with allopurinol: a randomised, double-blind, placebo-controlled study in

patients with gout with inadequate response to standard of care (the multinational CLEAR 2
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study). Ann Rheum Dis 2017 May;76(5):811-20.

ed

This 12-month US and international phase III study (CLEAR 2) randomised patients on

background allopurinol to either lesinurad (200mg or 400mg daily) or placebo.

pt

**27. Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, et al. Lesinurad,

a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients

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With Tophaceous Gout: Findings of a Phase III Clinical Trial. Arthritis Rheumatol 2017
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Sep;69(9):1903-13.

In this 12-month phase III study (CRYSTAL), of patients with tophaceous gout, all

participants received febuxostat 80mg daily, and were randomized to either lesinurad

(200mg or 400mg daily) or placebo.

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 **28. Tausche AK, Alten R, Dalbeth N, Kopicko J, Fung M, Adler S, et al. Lesinurad

monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3

clinical trial and extension study. Rheumatology 2017 Sep 23; Epub ahead of print.

This paper described a 6-month phase III study (LIGHT) and open label extension study of

patients with intolerance or contra-indication to a xanthine oxidase inhibitor, randomised

to lesinurad 400mg daily monotherapy or placebo. Lesinurad is approved at a dose of

t
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200mg daily, for use only in combination with a xanthine oxidase inhibitor.

29. Stamp LK, Chapman PT, Barclay ML, Horne A, Frampton C, Tan P, et al. A

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randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve

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target serum urate in people with gout. Ann Rheum Dis 2017 Sep;76(9):1522-28.

30. Stamp LK, Chapman PT, Barclay M, Horne A, Frampton C, Tan P, et al. Allopurinol
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Rheum Dis 2017 Aug 22; Epub ahead of print.

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31. Spencer K, Carr A, Doherty M. Patient and provider barriers to effective management
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of gout in general practice: a qualitative study. Ann Rheum Dis 2012 Sep;71(9):1490-5.

32. Reinders MK, van Roon EN, Houtman PM, Brouwers JR, Jansen TL. Biochemical
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effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated

gout patients. Clin Rheumatol 2007 Sep;26(9):1459-65.

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33. Pui K, Gow PJ, Dalbeth N. Efficacy and tolerability of probenecid as urate-lowering
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therapy in gout; clinical experience in high-prevalence population. J Rheumatol 2013

Jun;40(6):872-6.

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 Table 1 Summary of the published phase II and phase III trials of lesinurad
Name Phase Design Participants Primary Primary endpoint outcome Percentage with 2x Kidney stone Adjudicated cardiovascular
endpoint increase in serum treatment emergent treatment emergent adverse
creatinine from baseline adverse events events
Perez-Ruiz, 2 All participants N = 227, all with Percent reduction -16% with 200mg 0% with 200mg Not reported Not reported
2016 24 received allopurinol inadequate from baseline lesinurad/allopurinol lesinurad/allopurinol
then randomised to response to serum urate at 4
lesinurad 200mg, allopurinol weeks. -22% with 400mg 5.1% with 400mg
400mg, or 600mg lesinurad/allopurinol lesinurad/allopurinol
daily, or placebo for 4

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weeks -30% with 600mg 9.1% with 600mg

rip
lesinurad/allopurinol lesinurad/allopurinol

+3% with 1.4% with

placebo/allopurinol placebo/allopurinol

c
CLEAR 1 25 3 All participants on N = 603, all with The proportion of 54% with 200mg 1% with 200mg 1% with 200mg 4% with 200mg
baseline allopurinol, inadequate patients with lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol

us
randomised to response to serum urate
lesinurad 200mg or allopurinol <0.36mmol/L at 59% with 400mg 6% with 400mg 2.5% with 400mg 4.5% with 400mg
400mg daily , or month 6. lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol
placebo for 12

an
months 28% with placebo/allopurinol 0% with 2% with 3.5% with placebo/allopurinol
placebo/allopurinol placebo/allopurinol
CLEAR 2 26 3 All participants on N = 610, all with The proportion of 55% with 200mg 2% with 200mg 0% with 200mg 3.9% with 200mg
baseline allopurinol, inadequate patients with lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol

M
randomised to response to serum urate
lesinurad 200mg or allopurinol <0.36mmol/L at 67% with 400mg 8% with 400mg 3% with 400mg 3.0% with 400mg
400mg daily , or month 6. lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol lesinurad/allopurinol
placebo for 12

d
months 23% with placebo/allopurinol 0% with 0.5% with 5.3% with placebo/allopurinol
placebo/allopurinol placebo/allopurinol
CRYSTAL 27 3 All participants N = 324, all with The proportion of 57% with 200mg 2.8% with 200mg 0.9% with 200mg 5.7% with 200mg
received 80mg
febuxostat, then
randomised to
tophaceous gout,
with serum urate
≥0.48mmol/L, or
te
patients with
serum urate
<0.30mmol/L at
lesinurad/febuxostat

76% with 400mg

lesinurad/febuxostat

5.5% with 400mg

lesinurad/febuxostat

1.8% with 400mg

lesinurad/febuxostat

3.7% with 400mg

ep
lesinurad 200mg or ≥0.36mmol/L on month 6 lesinurad/febuxostat lesinurad/febuxostat lesinurad/febuxostat lesinurad/febuxostat
400mg daily , or urate-lowering
placebo for 12 therapy 47% with placebo/febuxostat 0% with 3.7% with 1.8% with placebo/febuxostat
months placebo/febuxostat placebo/febuxostat
c

LIGHT 28 3 Randomised to N = 214, all The proportion of 30% with lesinurad 400mg 8.4% with lesinurad 1% with lesinurad 1% with lesinurad 400mg
lesinurad 400mg intolerant or with patients with 400mg 400mg (4.2% in open
Ac

daily or placebo as contra-indications serum urate 2% with placebo label extension phase) 1% with placebo
monotherapy for 6 to xanthine <0.36mmol/L at 0% with placebo
months, with open oxidase inhibitor month 6 0% with placebo
label extension of treatment
lesinurad 400mg
daily monotherapy

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Figure legend
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Figure 1. Two-dimensional structure of lesinurad

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