Lesinurad in Combination with Febuxostat in Patients With

Home , Lesinurad

Page 1of59 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/art.40159. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen MD Australia; Australia; 6 Nicola Dalbeth, MD, FRACP MD, Dalbeth, Nicola Clinical III APhase Gout: Tophaceous With Patients Inhib Reabsorption Acid Uric Selective a Lesinurad, Febuxos With Combination in Lesinurad head: Running 1 Novartis, Auxilium, and has served on advisory boar advisory on and served has Auxilium, Novartis, Jones r has G Crealta. and Cymabay, Pfizer, Takeda, andadvi Takeda, AstraZeneca, Menarini, for bureaus AstraZene from grantsupport received has Dalbeth N Disclosures Biosciences byArdea funded was study clinical This Spain 48903, Baracaldo sn, Cruces Arbor, Michigan, USA; Michigan, Arbor,

MS AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA; MD, Gaithersburg, Pharmaceuticals, AstraZeneca Zealand; New Auckland, Auckland, of University 4 5* Jeff Kopicko, MSPH Kopicko, Jeff Scott Baumgartner, MDScottBaumgartner, 3

AcceptedUS California, Diego, San California, University of Article 5 Ardea Biosciences, Inc., San Diego, CA, USA(*forme CA, Diego, San Inc., Biosciences, Ardea 5* This article isprotected by copyright. All rights reserved. Nihar Bhakta, MDBhakta, Nihar 1 Graeme Jones, Jones, MD Graeme 5* and Fernando Perez-Ruiz, MD, PhD MD, Perez-Ruiz, Fernando and Arthritis &Rheumatology

5 Scott Adler, ScottAdler, MD 2 Robert Terkeltaub, MDTerkeltaub, Robert 2 University of Tasmania, Hobart, TAS 7001, 7001, TAS Hobart, Tasmania, of University (a member of the AstraZeneca group). AstraZeneca the of member (a eceived grant support from Abbvie, Ardea, Ardea, Abbvie, from support grant eceived ds for Pfizer, Roche, Hospira, and Jannsen, andJannsen, Hospira, Roche, for Pfizer, ds itor, in Combination With Febuxostat in Febuxostat With Combination in itor, Trial sory boards for AstraZeneca, Fonterra, Fonterra, AstraZeneca, for boards sory ca and has participated on speaker speaker on andparticipated has ca

7 tat in Patients with Tophaceous Gout Tophaceous with Patients tat in Hospital Universitario Cruces, Pza Cruces, Universitario Hospital A; 6 Maple Fung,MDMaple 4 University of Michigan, Ann Ann Michigan, University of 7

3 Dinesh Khanna, MD, MD, Khanna, Dinesh r employee); r 5 Chris Storgard, Storgard, Chris

Target journal: Arthritis & Rheumatology Rheumatology Arthritis & journal: Target e former are Baumgartner and S Storgard, C Kopicko, SAdler is group. AstraZeneca the of member a Inc., andSOBI.N Pfizer, Novartis, Metabolex, Menarini, and Menar AstraZeneca for speaker bureaus on served Hospita Cruces and Foundation, Rheumatology Spanish gran received has F Perez-Ruiz Takeda. AstraZeneca, As grant from a research received has Khanna Dinesh AstraZe to consultant is a R Terkeltaub Pfizer. and Abbvie Jannsen, for UCB,Roche, speaker bureaus and

• • • •

(Current 4388) (Current through Introduction from words maximum 4200 Text: Tables and figures: maximum 6 (Current 6) 6(Current maximum and figures: Tables References: maximum 50 (Current 34)(Current 50 maximum References:

Accepted(Current permitted is material supplementary Online Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons neca, Takeda, Revive, Relburn, and UCB. and Relburn, Revive, Takeda, neca, Bhakta is an employee of Ardea Biosciences, Biosciences, Ardea of employee an is Bhakta an employee of AstraZeneca. M Fung, J Fung, M AstraZeneca. of employee an t support from the Spanish Health Ministry, Ministry, Health Spanish from the support t mployees of Ardea Biosciences, Inc. Biosciences, Ardea of mployees traZeneca and is a consultant for for aconsultant is and traZeneca , Novartis, Mundipharma, Amgen, BMS, Amgen, Mundipharma, Novartis, , ini, and advisory boards for AstraZeneca, AstraZeneca, for boards advisory ini, and l Rheumatologists Association. Hehas Association. lRheumatologists 7 7 files) Discussion Discussion 2 Page 2of59 Page 3of59 versus 28.3%, respectively, respectively, 28.3%, versus verarea tophi target reduced total febuxostat plus betwee notdifferent was resolution tophus Complete lesi the in patients significantly more timepoints, (76.1%; (76.1%; a with 6 Month sUAby target achieved patients more Objective ABSTRACT Results data. laboratory and adverseevents included in t change total percent included end points Other complete reso with patients of proportion was point sUA< achieving patients of was proportion endpoint 400mg ordaily) or (200 lesinurad to randomization febuxost weregiven tophus target measurable ≥1 and Methods phase a in12-month, gout tophaceous with patients

. Patients (N=324) were predominately male with mean with male predominately were (N=324) Patients P . <0.0001), but not 200mg (56.6%; 200mg(56.6%; not but <0.0001), . . Patients with serum urate (sUA) ≥8.0 mg/dl (≥6.0 m (≥6.0 mg/dl ≥8.0 (sUA) serum urate with Patients

Investigate efficacy and safety of lesinurad in com in lesinurad safety of efficacy and Investigate

Accepted Articlewords)(249

This article isprotected by copyright. All rights reserved. P <0.05). Safety was generally comparable with febuxo comparable generally wasSafety <0.05). Arthritis &Rheumatology John Wiley& Sons P =0.13), versus febuxostat alone (46.8%). At alloth At alone(46.8%). febuxostat versus =0.13), nurad 200mg group achieved sUA target. sUA target. achieved group 200mg nurad sus febuxostat alone (50.1% and 52.9% 52.9% (50.1%and alone febuxostat sus arget tophi area. Safety assessments assessments Safetyarea. arget tophi placebo added to febuxostat. Primary Primary febuxostat. to added placebo lution of ≥1 target tophus (month 12). 12). (month tophus target ≥1 of lution 5.0 mg/dl (month 6). Key secondary end end secondary 6). (month Key mg/dl 5.0 IIItrial. ddition to febuxostat of lesinurad 400mg 400mg lesinurad of febuxostat to ddition n groups. Lesinurad (200mg and 400mg) and400mg) (200mg Lesinurad groups. n at 80mg daily for 3 weeks before weeks before 3 for daily 80mg at bination with febuxostat in with febuxostat bination g/dl on urate-lowering therapy) therapy) on g/dl urate-lowering age 54.1 years. Significantly Significantly years. age54.1 stat alone, alone, stat er 3 additional therapy. additional p 200mg in lesinurad with safety profile acceptable relclinically with alone, febuxostat with compared Conclusion 400mg. lesinurad reversible predominately rates of higher for except

. .

Accepted Article demonstrat febuxostat with combination Lesinuradin

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons evant added impact on tophi and an onand tophi impact added evant serum creatinine elevation, particularly with with particularly elevation, creatinine serum atients with tophaceous gout warranting warranting gout tophaceous with atients ed superior sUA lowering lowering sUA superior ed 4 Page 4of59 Page 5of59 levels than febuxostat alone (12). The aims of theaims of (12). The alone febuxostat than levels febuxo plus lesinurad study Ibof clinical phase A (13,14). urate reducing production and acid lowerto action of mechanism a dual provides XOI an (12 sUA lowers and uric of excretion acid increases the renal from anion of urate most reabsorption for ur inhibits the (10). XOI Lesinurad an on target at comb gout in of treatment the Europe for and States reabsor anion urate selective novel is a Lesinurad (1,2). a withuricosuric XOI an includes re guidelines XOI,of treatment dose appropriate an month consecutive sustain3 for it able to were 48% 8). With febuxostat 80 mg daily, 67–75% of patients of67–75% mg80daily, febuxostat With 8). only about 40% of patients treated with allopurinol with treated patients 40%of about only inhibit (1,2),to febuxostat or allopurinol either (ULT) therapy urate-lowering first-line recommended through a combination of lifestyle management and and p management lifestyle of combination a through in mg/dl pa <5.0or mg/dl <6.0 (sUA) serum urate of

Accepted Articletreat long-term for guidelines rheumatology Current

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons urate production (4). However, in clinical trials, trials, clinical inHowever,(4). production urate ic acid transporter URAT1 that is responsible is responsible that URAT1 transporter ic acid current phase III study (CRYSTAL) were to (CRYSTAL)were IIIstudy phase current ). Therefore, lesinurad in combination with combination in lesinurad ).Therefore, 300 mg daily achieved sUA <6.0 mg/dl(5 achieved<6.0 sUA mg daily 300 commend combination therapy that therapy combination commend tubule (11). By inhibiting URAT1, lesinurad lesinurad URAT1, Byinhibiting (11). tubule achieved sUA <6.0 mg/dl (5,7 sUA mg/dl <6.0 achieved tients with greater gout disease severity severity gout disease greater with tients s (8). If target sUA cannot be achieved with achieved be cannot sUA If(8).target s stat demonstrated greater reduction in sUA sUA in reduction greater stat demonstrated ination with an XOI for those patients not not patients those for XOI an with ination sUA by increasing renal excretion of uricof excretion renal increasing by sUA ption inhibitor approved in the United United the in approved inhibitor ption is a xanthine oxidase inhibitor (XOI), inhibitor oxidase xanthine a is harmacotherapy (1 harmacotherapy ment of gout recommend maintenance maintenance recommend gout of ment – 3). The The 3). – 9) ,only but 9) – 5 Zealand, included an approximate 35-day screening p screening 35-day approximate an included Zealand, N in conducted study, NCT01510769).The Identifier: with combination in versus placebo mg 80 febuxostat mg(200 lesinurad safety of and efficacy evaluating multinationa multicenter, double-blind, randomized, Feb and Lesinurad with Gout Tophaceous Subcutaneous with febuxostat 80 mg in patients with tophaceous g tophaceous with in mg patients 80 febuxostat with (200 mg lesinurad of risks and benefits the examine Trial design. design. Trial andgout. hyperuricemia similar t to andare 1 Table Material Supplementary c inclusion/exclusion Complete criterion. exclusion weight ideal body using formula Cockcroft-Gault via creatinin estimated anincluded criteria Exclusion (16). Vernier calipers using measured mm ≥5 feet/ankles and/or the hands/wrists on tophus ULT. onPatient for those mg/dl ≥6.0 ULT and taking werere levels sUA a ULT. never taken had who those inclu patients wereeligible.Eligible gout(15) of Patients. Patients.

Accepted Article index mass body years; 85 to 18 (ages women or Men Treatment Treatment procedures.

This article isprotected by copyright. All rights reserved. PATIENTS AND METHODS METHODS AND PATIENTS Arthritis &Rheumatology John Wiley& Sons The Combination Treatment Study in Subjects with in Subjects Study Treatment Combination The ded those on ULT currently or in the past and and the inpast currently or ULT on dedthose riteria are provided in the Online the in provided are riteria or 400 mg oral) in combination with combination in oral) 400 mg or hose of recent trials for the treatment of the treatment for trials recent of hose or 400 mg oral, once daily) in combination combination in once oral, daily) mg 400 or s were also required to have ≥1 measurable measurable ≥1 have to required werealsos . History of kidney stones was not an not was stones kidney of History . orth America, Europe, Australia, and New andNew Europe,Australia, America, orth out. out. l, placebo-controlled, combination study combination l, placebo-controlled, e clearance (eCrCl) <30 ml/min calculated calculated ml/min <30 (eCrCl) clearance e quired to be ≥8.0 mg/dl for patients not patients for mg/dl ≥8.0 be quired to eriod (including a run-in period of run-in period a (including eriod febuxostat 80 mg (ClinicalTrials.gov (ClinicalTrials.gov mg 80 febuxostat and ≤20 mm in the longest diameter, diameter, inlongest the mm and ≤20 uxostat (CRYSTAL) was a phase III, phase a was (CRYSTAL) uxostat <45 kg/m <45 2 ) with a diagnosis a diagnosis with ) 6 Page 6of59 Page 7of59 time. The study was conducted between February 2012 between conducted studywas The time. to were permitted Patients requirements. regulatory Helsink of Declaration the (GCP), Practice Clinical Indepen with accordance in conducted studywas The was re use medication visit.Concomitant study each packag medication returned of the verification with asse was medication study with Compliance (1). gout of College Rhe American with agreement in hydrated, dri to wereencouraged Patients water. of cup 1 and were taplacebo or lesinurad, of febuxostat, Doses System. Web Response System/Interactive acentral used sites allstudy at Randomization mg. 80 +febuxostat mg 200 lesinurad (febuxostat), 80mg werer patients mg, 80 febuxostat on 3weeks After to toxicity intolerant developed or became patients prophyl Goutflare colchicine. to /contraindication drug antiinflammatory a ornonsteroidal available) (0.50 or colchicine of consisted prophylaxis flare w ULTsolealong the as dailymg 80once febuxostat of Regardless Figure 1). (Supplemental months ≤3.5 tre double-blind 12-month days), a 21 approximately

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons .6 mg once daily, per protocol and as locally as and per protocol once .6 daily, mg i (October 2008), and all applicable local allapplicable 2008),and i (October axis was continued through month 5 unless month 5 unless through continued was axis ized Interactive Voice Response Response Voice Interactive ized (NSAID) if patients had an intolerance intolerance had an patients if (NSAID) prophylaxis. ing and any remaining medication during during remaining anymedication and ing ith gout flare prophylaxis on Day −21. Gout Gout −21. Day on goutflare prophylaxis ith nk 2 liters of fluid/day and to remain well remain to and of 2fluid/day liters nk ULT type at screening, all patients began began patients all screening, at ULTtype corded at each study visit. each at corded withdraw from treatment or study at anystudyat or from treatment withdraw mg, or lesinurad 400 mg + febuxostat 80 80 + febuxostat mg 400 lesinurad mg, or atment period, and a follow-up period of of period a follow-up and atmentperiod, ssed by medication dispensing records, dispensing bymedication ssed umatology guidelines for management of management for guidelines umatology ken once daily in the morning with food food with morning the in daily once ken andomized 1:1:1 to placebo + febuxostat +febuxostat placebo to 1:1:1 andomized and April April 2014. and dent Ethics Committee (IEC) E6, Good Good (IEC)E6, Committee Ethics dent 7 every 3 months for tophi measurements. measurements. tophi months for 3 every 2 1),week (day baseline at wereassessed Patients flare. the treat to medication warmth,sw of presence of extent pain, and duration e daily a on reported Goutflares were month 12. of goutf rate of mean and the month each at treatment the includedproportion endpoints secondary Other measurement. longest the capture both to calipers digital using alltarget of areas the of insum the baseline from toph additional An12. month by resolution area) in t target ≥1 on response best tophus a with patients tophtarget ≥1 of a oftophus) inarea the decrease of pati the proportion were endpoints secondary Key <5.0 sUA with sUAmg/dl >5.0 baseline with patients sUA median 3) and visit; monthly each at mg/dl <3.0 mont all3 atof mg/dl <5.0 sUA 1) with patients of sensitivity visit. Prespecified each at levels sUA 6.Secondary month sUAby <5.0 mg/dl an with group Evaluations.

Accepted Article The primary efficacy endpoint was the proportion of proportion the was endpoint efficacy primary The

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons and supportive analyses included the proportion includedproportion the analyses supportive and diameter and longest perpendicular perpendicular andlongest diameter tophi at each visit. Tophi were measured measured were visit. Tophi each at tophi hs 4, 5, and 6; 2) sUA levels <5.0, <4.0, and <4.0, sUA<5.0, levels 2) 6; 5,and hs 4, us by month 12 and the proportion of and the12proportion month us by and months 1–6, 8, 10, and 12 for sUA and sUA for 1210, 1–6, and 8, months and ophus of complete or partial (≥50% decrease (≥50%decrease partial or complete of ophus us endpoint was the mean percent change mean waspercent the endpoint us lectronic patient diary (e-diary) that elicited that (e-diary) diary patient lectronic <5.0 mg/dl, as well as the proportion of of proportion asthe well mg/dl,as <5.0 mg/dl by month 6. 6. month mg/dl by elling, and tenderness, and any changein any and and tenderness, elling, ents with complete resolution (100% (100% complete resolution entswith lares from the end of month 6 to the the end 6to month end of from the lares sUA efficacy endpoints included mean mean included endpoints efficacy sUA of patients with gout flares requiring gout flares with of patients patients in each treatmenteach in patients 8 Page 8of59 Page 9of59 Statistical analyses. Statistical the do completing of days within 14 visit follow-up who diPatients febuxostat. plus lesinurad of study treatment double-blind the completed who Patients (19). 3) Table Supplementary (MACE)a event CV adverse major into categorization p assessed for routinely (CEAC).AEs were Committee independen an by safetywas CV conducted of Review creatinine to protein (sCr),urine creatinine serum Table 2), Supplementary (Online TEAEs stone kidney r of Assessments kidneyin function. changes and/or (18),which system the and/or urinary tubules renal t the potential have excretion acid uric urinary in uric increased the due interest to special of also in comorbidity common is a impairment renal because saf (CV) cardiovascular and renal included interest and (ECG), electrocardiogram examination, physical [MedDR Activities Regulatory for Dictionary Medical primary endpoint was the proportion of patients of wit patients proportion was the endpoint primary end secondary key 6and month at evaluated endpoint Safety assessments included treatment-emergent adv treatment-emergent included assessments Safety

Accepted Article The study consisted of a 12-month treatment period, atreatment 12-month consisted of The study This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons acid excretion that lesinurad causes. Increases Increases causes. lesinurad that excretion acid o induce microcrystallization of uric acid in acid uricof microcrystallization induce o ratio (PCR), and eCrCl. eCrCl. and (PCR), ratio ety. Renal safety assessments were included included were assessments safety Renal ety. d not enter the extension study completed a a completed study extension the notenter d uble-blind treatment. treatment. uble-blind could manifest clinically as kidney stones clinicallykidney as manifest could enal safety included renal-related and and renal-related safetyincluded enal A] version 14.0), clinical laboratory data, data, laboratory clinical version 14.0), A] vital signs. Adverse events (AEs) of special (AEs) special of events signs.Adverse vital h sUA <5.0 mg/dl by month 6. All 6.All mg/dl by month <5.0 sUA h and clinical laboratory data including including data laboratory clinical and nd non-MACE endpoints (Online (Online endpoints non-MACE nd otential CV relationship, with CVrelationship, otential patients with gout (17). Renal safety is Renal gout(17). with patients points evaluated at month 12. The 12. month at evaluated points were eligible to enroll in an extension an extension in enroll to eligible were t Cardiovascular Events Adjudication Adjudication Events Cardiovascular t erse events (TEAEs events erse ; with the primary primary the with coded by by codedthe 9

All other efficacy endpoints were evaluated at α=0at wereevaluated endpoints efficacy other All 0.025. of level alpha endpoints secondary thekey of testing hierarchical fo endpoint primary for the hypothesis the null If nonresponders. considered who were patients where method analysis primary the difference between response rates, and rates,and response between difference adjust corresponding asproportions, expressed were alph an at placebo with comparisons 2 treatment the correction w Bonferroni A mg/dl). <6.0 versus (≥6.0 ml/m ≥60 (eCrCl renal–7function by day stratified Cochran-Mant the using wereperformed group placebo b levels sUA onbased rates response of Comparisons p the primary (ITT) population, intent-to-treat the randomi of dose ≥1 received who patients randomized ra to length exposure of and level sUA and function gout f of rates Mean response). (tophus CMH test or b were analyzed endpoints Secondary allvisits. for o analyses the primary adjustment. For multiplicity

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons P -values. Nonresponder imputation (NRI) analysis was analysis (NRI) imputation Nonresponder -values. opulation for efficacy and safety assessments. safetyassessments. and efficacy for opulation y negative binomial regression (gout flares) regression binomial negative y in versus <60 ml/min) and sUA level at day -7 day sUAat level ml/min) and <60 versus in f response rates at each level, NRI was used used was atNRI level, rates each response f for the surviving dose was performed at anat dose performed was surviving for the as used for the primary endpoint for each of each for endpoint the primary for used as ndomized study medication. study medication. ndomized lares were adjusted for day –7 renal –7 day for adjusted were lares r 1 dose was rejected at the 0.025 level, 0.025 atlevel, rejected the was r1 dose etween each lesinurad group and the and group lesinurad each etween ed 95% confidence intervals (CIs) of (CIs)the of intervals 95%confidence ed response sUA for Results 0.025. aof level .05 (nominal .05 zed study medication were included in wereincluded medication study zed missing their month 6 sUA result were result 6sUA month their missing el Haenszel (CMH) test statistic, statistic, test (CMH) Haenszel el P -value), 2-sided without without 2-sided -value), 10

Page 10of59 Page 11of59

lesinurad 200mg + febuxostat (25.5%), and lesinurad and (25.5%), + febuxostat 200mg lesinurad studyprior the from withdrew who (22.8%) patients of dose ≥1 received patients of 324 A total other. t 48criteria, 168 to exclusion criteria, inclusion t consent. Of withdrew 48 who patients and failures prior werewithdrawn patients 715 remaining The 1). Patient disposition. disposition. Patient wit multiplicity for adjusting test, exact Fisher’s ha groups lesinurad rate the and a40% response had betwe rate response in a difference to detect power This sam group. treatment each to 105 approximately recr be to wereplanned patients 315 Approximately baseline. ≤1.2x to returned Resolution (20,21). assessment relevant clinically baseline the ≥1.5x≥2.0x (i.e., sCr inand increase pri days within 14 value highest as the defined was studymedication, relation to severity, incidence, class and organ system by coded were TEAEs testing. and groupnot bywerelisted treatment data Safety

Accepted Article Of 1,045 patients screened, 330 were randomized at wererandomized 330 screened, patients Of1,045 This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons RESULTS RESULTS o both inclusion/exclusion criteria, and 8to and criteria, inclusion/exclusion o both h an alpha level of 0.025, 2-sided, for each test. each for test. 2-sided, 0.025, of level alpha h an level at any time) was selected as the most themost as selected was time) any at level and relation to discontinuation. Baseline sCr Baseline discontinuation. to relation and of sCr elevation was defined as an sCr value value sCr an as defined was elevation sCr of randomized study medication. There were74 There studymedication. randomized or to first dose of study medication. Relative studymedication. of dose to first or he screen failures, 443 were related to related to 443were screen failures, he en treatment groups if the placebo group the ifplacebo groups treatment en 400mg + febuxostat (22.9%). The most (22.9%). The 400mg + febuxostat to completion: febuxostat (20.2%), febuxostat completion: to preferred term and listed according to according listed and term preferred to randomization, including 667 screen screen 667 including randomization, to d response rates as low as 65% using using low as 65% rates as dresponse ple size was calculated to provide >90% provide to calculated was size ple subjected to statistical hypothesis hypothesis statistical to subjected uited, for an allocation of allocation an for uited, 102 sites (Figure (Figure sites 102 11

Study medications. medications. Study months12 the in (8.2) gout flares (SD)6.7 of mean Efficacy assessments. assessments. Efficacy respectiv groups, febuxostat mg + 400 lesinurad and thein and feb 92.7% 97.2%, were99.1%, medications

of tophi was 1.8 (1.2) and area of target tophi was tophi target of andarea (1.2) 1.8 was tophi of on weeks febuxo 3 after (baseline) randomization at were8.7 levels years. sUA (10.9) 14.7 of diagnosis (SD)ag a mean (79.9%),with white and (95.4%) male grou treatment between similar were characteristics history. clinical and demographics Baseline respectively. 12 at69.7% months, and 71.7%, and 80.7% 82.1%, 86.2%, completed was by medication and noncompliance (10.5%) TEAEs were reasons common significant for the lesinurad 200 mg + febuxostat g mg+ febuxostat 200 lesinurad the for significant primary endpoint compared with febuxostat ( with febuxostat compared endpoint primary wit treated patients more Significantly 2). (Figure and +76.1 FBX mg 200 inlesinurad the 56.6% group, mg/dl <5.0 sUA achievedwho patients of proportion group by Month 6, superior treatment effects wereo effects treatment 6,superior by Month group diffe statistically not was the difference Although

Accepted Article Overall proportions of patients exhibiting ≥80% com ≥80% exhibiting patients of proportions Overall This article isprotected by copyright. All rights reserved. Primary endpoint of sUA response and secondary sUA sUA responsesecondary and sUA of Primaryendpoint Arthritis &Rheumatology John Wiley& Sons P P < 0.0001), while the difference was notwas difference while the < 0.0001), Demographics and baseline disease disease and baseline Demographics h lesinurad 400 mg + febuxostat achieved the the achieved febuxostat mg + 400 lesinurad h rent for the lesinurad 200 mg + febuxostat +febuxostat mg 200 thelesinurad for rent (1.6) mg/dl at screening and 5.3 (1.6) mg/dl (1.6) 5.3 and screening at mg/dl (1.6) 293.6 (234.6) mm(234.6) 293.6 roup ( roup prior to study entry. study entry. to prior stat 80 mg. At baseline, mean (SD) number (SD)number mean baseline, At mg. 80 stat ely. ely. ps (Table 1). Patients were predominately predominately were Patients 1). ps(Table % in the lesinurad 400 mg + febuxostat +febuxostat 400 mg lesinurad the in % e of 54.1 (11.0) years and time since gout since time (11.0)years and 54.1 of e by month 6 was 46.8% in the febuxostat the febuxostat in 46.8%6was month by bserved for this group at all other time all other atgroup this for bserved uxostat, lesinurad 200 mg + febuxostat, +febuxostat, mg 200 lesinurad uxostat, of patients at 6 months and 76.1%, and 76.1%, months at 6 patients of P P /protocol violation (9.0%). Study (9.0%).Study violation /protocol = 0.13). = 0.13). 2 . Patients self-reported a self-reported Patients . pliance with study study with pliance endpoints. The The 12 Page 12of59 Page 13of59

Key secondary and secondary endpoints: tophusreso endpoints: secondary and secondary Key month 12, but the differences were not significant. were not differences 12, the but month compar groups (51.4%) +febuxostat mg 400 lesinurad the inl greater numerically wasalso tophus target P 400 mg + febuxostat (56.9%, mg+ febuxostat 400 febuxostat group (21.1%) although the differences w the differences although (21.1%) group febuxostat febu mg + 400 lesinurad (25.5%) and febuxostat + mg nu was tophus target ≥1 of resolution complete with sUA <4.0 mg/dl by month 6 with lesinurad 200 mg + f mg+ 200 lesinurad 6with month mg/dlby <4.0 sUA (Suppleme points all time atgroup alone febuxostat les both ingreater was sUA mg/dl <5.0 achieved who 400 mg + febuxostat ( mg+ febuxostat 400 m 200 lesinurad with 44.1% alone, febuxostat with 6 subgrou In this 49.7%). (n=161, febuxostat on weeks subgr the was analyses theinprespecified Included 12). 6 and showsmonths (Figure 2 mg/dl median a and 6), 4, 5 (Months months consecutive 3 incThese2). Figure (Supplemental alone febuxostat favoring differences analyses showed supportive and points (Months 1, 2, 3, 4, 5, 8, 10, and and 12; 8,10, 1,2,3, 4,5, (Months points

Accepted of wi patients proportion The respectively). =0.11, Article P =0.024 and <0.0001 versus febuxostat alone). The alone). pr febuxostat versus and <0.0001 =0.024 This article isprotected by copyright. All rights reserved. P <0.0001) than with febuxostat (7.8%). with febuxostat than <0.0001) Arthritis &Rheumatology John Wiley& Sons P -values ≤0.0281). In addition, prespecified sensiti prespecified addition, In -values≤0.0281). esinurad 200 mg + febuxostat (49.1%) and and (49.1%) +febuxostat mg 200 esinurad

th complete or partial resolution of ≥1 of resolution partial or complete th oup of patients with sUA ≥5.0 mg/dl after 3 mg/dlafter sUAwith≥5.0 patients of oup luded achieving sUA <5.0 mg/dL for each of each for sUAmg/dL <5.0 achieving luded ntal Figure 3). Also, more patients achieved achieved patients more Also, 3). Figure ntal p, 23.5% of patients were at goal by month month by goal at were patients of 23.5% p, g + febuxostat, and 70.6% with lesinurad lesinurad with 70.6% and +febuxostat, g merically greater in both the lesinurad 200 200 lesinurad both ingreater the merically ere not statistically significant ( significant statistically not ere lesinurad 200 mg + febuxostat versus + febuxostat 200 mg lesinurad sUA <5.0 mg/dL, and an sUA <4.0 and <3.0 and <3.0 <4.0 sUA an and sUAmg/dL, <5.0 inurad + febuxostat groups than in the than +febuxostat groups inurad ebuxostat (28.8%, (28.8%, ebuxostat xostat (30.3%) groups compared with the (30.3%)compared groups xostat ed with the febuxostat group (45.9%) at (45.9%) group the febuxostat with ed lution. lution. The proportion of subjects of proportion The P =0.005) and lesinurad andlesinurad =0.005) oportion of patients patients of oportion P =0.45 and =0.45 vity 13 Secondary endpoint: gout flares requiring treatment requiring flares gout endpoint: Secondary

febuxostat alone (28.3%), alone febuxostat 400 lesinurad mg and +febuxostat mg 200 lesinurad tarin reduction 52.9% aand 50.1% month 12, At 4). when tophi alltarget for the areas of sum the for a had groups high febuxostat mg + 400 lesinurad and measured were tophi when and12 3,6,9, months At Safety assessments. assessments. Safety 6.0%). febuxostat, 200 mg lesinurad 9.2%; (febuxostat, 12 month of end loweswith thestudy, throughout declined generally patient of proportion The (17.4%). group febuxostat (200 m groups febuxostat + lesinurad both in higher requir gout flares with patients of proportion The alone). febuxostat each group had TEAEs with maximum severity of grade severity of maximum with TEAEs had group each grou mg+ febuxostat 400 the inlesinurad 82.6% and t in82.1% group, the infebuxostat was 72.5% study febuxostat, and lesinurad 400 mg + febuxostat group mg+ febuxostat 400 lesinurad and febuxostat, m 6 per patient (1.2) per and 0.7 (2.5), 1.4 (2.7), fromen period 6-month the over treatment requiring

Accepted Article

Adverse events. events. Adverse This article isprotected by copyright. All rights reserved. P -values of 0.01 and 0.005, respectively. 0.005, respectively. and 0.01 of -values Arthritis &Rheumatology John Wiley& Sons The proportion of patients with TEAEs throughout th throughout TEAEs with of patients The proportion onths in the febuxostat, lesinurad 200 mg + mg+ 200 lesinurad the infebuxostat, onths compared with the febuxostat group (Figure (Figure group the febuxostat with compared he lesinurad 200 mg + febuxostat group, mg + febuxostat 200 lesinurad he get tophi area was observed with the was observed area tophi get g, 25.5%; 400 mg, 35.8%) than the mg,35.8%)than 400 25.5%; g, s with gout flares requiring treatment treatment requiring goutflares with s t proportions at the end of month 11 to 11 the month of the end at proportions t p (Table 2). The majority of patients in ofmajority patients The 2). p(Table + febuxostat groups compared with compared groups febuxostat + er mean percent reduction from baseline from baseline reduction percent ermean s, respectively ( s, respectively ing treatment at the end of month 1 was month 1 theend atof treatment ing + febuxostat, 10.1%; lesinurad 400 mg + mg 400 10.1%; lesinurad febuxostat, + . . d of month 6 to end of month 12 were 1.2 were 1.2 12 month endof month 6 ofto d The mean (SD) rates of gout flares gout flares of (SD) rates mean The 1 or 2, based on Rheumatology Rheumatology on 2, orbased 1 , the lesinurad 200 mg + febuxostat febuxostat 200 mg + lesinurad , the P =0.55 and 0.04 versus 0.04 =0.55and e 14 Page 14of59 Page 15of59

Renal safety analyses (Table 2). (Table analyses safety Renal failure. heart congestive to t in and one arrest cardiac due to group febuxostat One dea patient. >1in occurred serious TEAE single theinlesinura andgroup,8.3% mg+ febuxostat 200 inpatients of 9.2% in werereported TEAEs Serious back and 8.3%), (3.7%, 5.7%, pain extremity 5.5%), ( hypertension 9.4%,13.8%), (8.3%, nasopharyngitis 400 lesinurad mg and +febuxostat, mg 200 lesinurad in common most The respectively. groups, febuxostat lesinurad infebuxostat, of the patients 13.8% and discont to led TEAEs Criteria(22). Toxicity Common patients in the febuxostat, lesinurad 200 mg + + febu200 mg lesinurad the in febuxostat, patients ( 2.8% in occurred baseline ≥1.5x sCr of Elevation respectively. w TEAEs stone Kidney studymedication. to unrelated wereconsidered All seriousAEs. renal-related had (0.9%) 1 patient and chronic) failure renal acute; lesinur the in 2 patients while serious AE, related lesin the in group. patients No mg+ febuxostat 400 mg + fe 200 lesinurad the in 8.5% group, febuxostat

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Renal-related TEAEs occurred in 5.5% of patients in of patients 5.5% in occurred TEAEs Renal-related Arthritis &Rheumatology John Wiley& Sons ad 400 mg + febuxostat group (renal failure failure (renal group mg+ febuxostat 400 ad in the febuxostat group (renal failure acute) acute) (renal group failure the febuxostat in 200 mg + febuxostat, and lesinurad 400 mg + + 400 mg lesinurad and +febuxostat, mg 200 by the investigator to be unlikely related or related or beto unlikely theinvestigator by he lesinurad 400 mg + febuxostat group due +febuxostat mg 400 lesinurad he pain (4.6%, 7.5%, 5.5%). (4.6%, 7.5%, pain xostat, and lesinurad 400 mg + febuxostat mg + febuxostat 400 lesinurad and xostat, the febuxostat group, 5.7% in the lesinurad lesinurad the group,in 5.7% the febuxostat inuation of study medication in 8.3%, 8.5%, 8.5%, 8.3%, in medication study of inuation urad 200 mg + febuxostat group had a renal- groupa had mg+ febuxostat 200 urad th was reported in the lesinurad 200 mg + 200 mg inlesinurad reported wasthe th buxostat group, and 10.1% in the lesinurad lesinurad and the in group,10.1% buxostat 7.3%,5.7%, 11.0%), headache (7.3%, 9.4%, 11.0%), headache 7.3%,5.7%, d400 mg + febuxostat group (Table 2). No No (Table 2). group + febuxostat mg d400 n=3), 4.7% (n=5), and 10.1% (n=11) of and(n=11) 10.1%(n=5), 4.7% n=3), + febuxostat groups, respectively, were were groups, respectively, febuxostat + ere reported by 0.9%, 1.8%, and 3.7%, 3.7%, and 1.8%, by 0.9%, reported ere dividual TEAEs in the febuxostat, in TEAEs the febuxostat, dividual the 15

and urinalysis, assessed over time, demonstrated no time, demonstrated assessed over urinalysis, and r (excluding parameters chemistry serum hematology, signs. vital and tests clinical laboratory Other group. any inparameters ECG in baseline res (3events), andpatients events), 2 (2 patients Non-M mg+ febuxostat. 400 inlesinurad the events) theinlesi (2events) 2 patients group, febuxostat wereme MACE criteria for that CEAC determined The and/o CVcomorbidity ≥1 had baseline events CV with ev seriousCV with respectively, groups, febuxostat 200 lesinurad m the infebuxostat, patients of 3.7% analyses. safety Cardiovascular Table 4). Material (Supplemental PCR clin wereno There respectively. groups, febuxostat 200lesinurad theinfebuxostat, (0.21)mg/dl –0.09 last and baseline between (SD)sCr mean in Changes last atgroups st febuxostat mg + 400 lesinurad and elevation 1unresolved was There only respectively. occu baseline ≥2.0x elevation sCr medication. study and 85. 60%, 100%, A of total respectively. groups,

Accepted Article

This article isprotected by copyright. All rights reserved. TEAEs classified as CV events were reported in 1.8% in werereported events asclassified CV TEAEs Arthritis &Rheumatology John Wiley& Sons pectively. There were no notable changes from from changes notable were no There pectively. nurad 200 mg + febuxostat, and 2 patients (4 (4 and 2 patients mg+ febuxostat, 200 nurad Clinical laboratory test results, including including test results, laboratory Clinical 7% of cases resolved without interruption in withoutinterruption casesresolved of 7% mg + febuxostat, and lesinurad 400 mg + 400 mg lesinurad and +febuxostat, mg ents in 0.9%, 2.8%, and 3.7%. All patients patients All and 3.7%. in2.8%, 0.9%, ents g + febuxostat, and lesinurad 400 mg + mg+ 400 lesinurad and febuxostat, + g assessment. udy ically meaningful changes in mean eCrCl or eCrCl changesmean in meaningful ically rred in 0.0%, 2.8% (n=3), and 5.5% (n=6), 5.5% (n=3), 2.8% and 0.0%, in rred in both the lesinurad 200 mg + febuxostat mg+ febuxostat 200 lesinurad both in the notable differences between treatment treatment between differences notable ACE CV endpoints were reported in 0, 0, 2 in werereported endpoints ACE CV r CV disease history. history. CV disease r enal laboratory results reported above), above), reported results laboratory enal value were 0.00 (0.19), 0.03 (0.18), and and (0.18), 0.03 (0.19), were 0.00 value t by 1 patient (1 event)thein (1 by t1 patient , 5.7%, and 5.7%, , 16 Page 16of59 Page 17of59

blood pressure, in any group. any in pressure, blood baseline changes from notable wereno There groups. these levels for more than several years (2). years several than more for levels these r has EULAR (16,23), concentrations urate serum low inr flare benefit shown have studies observational currently uncertain are levels urate serum low very mg/dL.<3 sUA studyachieved the in patients Some t in approved febuxostat dose of mg, the highest 80 opt treatment additional greatest for need the with meaningful clinically is This a 6. Month including sUA mg/d <5 achieve more to patients mgenabled 200 of weeks 3 after target at (ie,not those mg/dL ≥5 of analysis inprespecified the importantly, More gett in effective was +febuxostat mg 200 lesinurad additional However, 400 mg group. lesinurad the for The diffe alone. febuxostat with compared endpoint) achievi patients of the proportions increased 80mg, mgor 200 Lesinurad gout. tophaceous with patients le safety of and efficacy the investigated CRYSTAL

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons DISCUSSION result because this is the group of patients patients of is the group this because result febuxostat alone), the addition of lesinuradof addition alone), the febuxostat eduction and tophus regression with very very with regression and tophus eduction ing more patients to target sUA. target more to patients ing . Although both clinical trial data and and clinicaldata trial both Although . ions, as they failed to respond to febuxostat febuxostat to to failed asrespond they ions, ng sUA <5.0 mg/dl by month 6 (the primary 6(the primary mg/dl by month <5.0 sUA ng he United States. United he prespecified analyses showed that showed analyses prespecified 400 mg, in combination with febuxostat febuxostat with combination in 400mg, ecommended against urate lowering to lowering to urate against ecommended the subset of patients with a baseline sUA sUA a withbaseline patients of subset the rence in proportions was significant only only significant was proportionsin rence sinurad in combination with febuxostat in febuxostat combination inwith sinurad during the study in vital signs, including including signs, in vital study the during

L at all timepoints through Month 12, Month through alltimepoints at L The clinical benefits and risks of these of risks these and benefits clinical The 17

groups. Patients treated with lesinurad 400 mg in 400 mg c lesinurad with treated Patients groups. withdrawal ledstudy to that and AEs,TEAEs serious ofmajority eve the alone, febuxostat with compared mg a 200 lesinurad with was TEAEs higher overall of particular tolerated, well generally was Lesinurad demo to particularly tophi, baseline dissolve to as n may be treatment Longer-term (5,6,8). allopurinol that to o similar weeks, over 52 declined treatment The propor alone. febuxostat of that to similar was r whereas alone,the with febuxostat compared group by nearly 50% reduced was month 612 through month i treatment requiring goutflares of meanrate The t of month 12 by in regression tophus benefits show alone.T with febuxostat compared groups febuxostat 200 m lesinurad with area tophi target in reduction month 12. by tophus target ≥1 of resolution partial noted for was trend significant, statistically not sta werenot differences but alone, febuxostat with resolution complete with of patients proportion the febux with combination mgin 400 200 and Lesinurad

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons the proportion of patients with complete or complete of with patients theproportion nstrate treatment effect differences (24,25). (24,25). differences effect treatment nstrate tion of patients with gout flares requiring goutrequiring flares with patients of tion However, there was an almost 50% greater 50%greater almost anwas there However, ombination with febuxostat had a higher a higher had febuxostat with ombination g + febuxostat and lesinurad 400 mg + mg+ 400 lesinurad and febuxostat + g bserved in other studies with febuxostat or febuxostat with studies other in bserved tistically significant. A similar positive, but but positive, similar A significant. tistically were comparable across the 3 treatment 3treatment the across comparable were nd 400 mg in combination with febuxostat febuxostat combinationwith mg in 400 nd compared 12 bytophus month ≥1 of target eeded to further reduce gout flares, as well well as gout flares, reduce to eeded further herapy. nts were grade 1 or 2, and incidence of incidence 2,orand grade 1 were nts ly at the 200 mg dose. Although incidence incidence Although mgdose. 200 the at ly his is the first study of an oral agent to agentoral an study first of is the his n the 6-month period from the end of the end from period 6-month n the ate with lesinurad 200 mg + febuxostat mg + febuxostat 200 lesinurad with ate in the lesinurad 400 mg + febuxostat +febuxostat mg 400 lesinurad the in ostat resulted in numerical increases in increases numerical in resulted ostat 18 Page 18of59 Page 19of59

gout typically present with comorbidities, may also may comorbidities, with present typically gout should take physicians lesinurad, prescribing When reporte previously kidneys, as the by excreted acid ura decreasing through febuxostat, that the fact by werereporte TEAEs stone kidney Few (18,26). stones assoc have URAT1 been inhibit that therapies Other clinical t controlled randomized a in characterized xan a with combination in mg daily 200 lesinurad of febuxostat alone, febuxostat higherat occurred sCr elevations alone. febuxostat renal-relat of incidence had higher febuxostat with le with treated analyses, patients safety renal In febuxostat or with combination in mg 200 lesinurad study med randomized led that to TEAEs of incidence safety by this subgroup did not demonstrate notable notdemonstrate did subgroup this by safety (approximately low was use colchicineand tolerate wereall NSAIDs renal inacidtubules. uric urinary increased due mayto be but elucidated, completely unde mechanism The study. the during function renal studym randomized of withoutinterruption resolved resolved elevations sCr majority The of treatment.

Accepted Article

particularly with lesinurad 400 mg, which is not a is not which 400 mg, lesinurad with particularly

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons owed as prophylaxis for subjects not able able to not for subjects as prophylaxis owed rial with a planned duration of 2 years. 2 of aduration withplanned rial d for XOI therapies (27,28). (27,28). XOI therapies d for ed TEAEs compared with those treated with with treated those compared TEAEs ed by the time of the next assessment; most most nextassessment; the of by the time rates in the lesinurad groups versus versus the groups inlesinurad rates be taking other renal-acting medications, medications, renal-acting other taking be te production, reduces the amount of uric uric amount of the reduces production, te thine oxidase inhibitor is being further is being inhibitor oxidase thine sinurad 200 mg or 400 mg in combination combination mg in mg 400 or 200 sinurad 17% of patients). Evaluation of CV and renal andrenal CV of Evaluation patients). of 17% febuxostat alone. alone. febuxostat excretion and microcrystallization of microcrystallization and excretion treatment differences. treatment d during the study and may be explained explained maybe study and the during d ication discontinuation, compared with compared discontinuation, ication edication and without adverse impact on adverseimpact without and edication rlying sCr elevation has not been not elevation has sCr rlying into consideration that patients with patients thatconsideration into iated with development of kidney kidney of development with iated n approved dosage for dosage approved n

The safety profile safetyprofile The 19

much longer treatment, longer than 12 months, was n months, 12 than longer treatment, longer much studies Previous goutflares. in anddecline tophi of length short alone. The relatively febuxostat to th increased febuxostat mg) + 400 or (200 lesinurad of patients analysis However, febuxostat. on weeks sUA achieved whoalready had patients of percentage numbersmallof the include CRYSTAL of Limitations (30,31). placebo versus andsimil (29) initiation XOIof therapy on risk CV group.Data + lesinuradfebuxostat each in patients in occurred MACE Independently-adjudicated history. had ≥ All patients groups. treatment lesinurad the risk CV po high this in low at frequencies observed baseline, reflecting the high rates of CV disease i CVofdisease rates high reflecting the baseline, risk fa and CVcomorbidities analyses, safety CV In <45 mL eCrCl with in started patients notbe should symptoms and signs for and evaluate value, starting <60 mLeCrCl with patients in particularly therapy, renal functio monitor should physicians that states maintain appropri and and water with food lesinurad informa prescribing The poorly hydrated. be may and

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons n gout patients. ngout ar risks of CV AEs for allopurinol and febuxostat andfebuxostat allopurinol AEsfor CV of risks ar with febuxostat or allopurinol showed that showedthat allopurinol or febuxostat with the study limited the amount of resolution of resolution of the amount limited study the ctors were present in 74% of patients at patients 74%of in were present ctors /min or with sCr elevations 1.5 to 2 times the the 2times to 1.5 elevations sCr with or /min pulation, with small increases in rates with rates in increases smallwith pulation, 1 baseline CV comorbidity or CV disease CVdisease or comorbidity CV baseline 1 n before starting and during lesinurad andduring starting n before base analyses have indicated no change in change no indicated have analyses base /min. /min. e percentage of patients at goal compared compared goal at of patients epercentage not at goal at randomization showed that showed that randomization atgoal at not of acute uric acid nephropathy. Lesinurad Lesinurad nephropathy. acid uric acute of ate hydration via daily water intake. It also Italso intake. daily via water ate hydration tion (10) recommends patients take take patients (10) recommends tion 1 patient in the febuxostat group and 2 and group infebuxostat the 1patient <5.0 mg/dl at randomization after 3 after randomization mg/dlat <5.0 eeded to show a treatment difference difference showa totreatment eeded women in the study and the high high and the study the in women

Nonserious CV TEAEs were TEAEs CV Nonserious 20 Page 20of59 Page 21of59

production, and production, addressingbo mechanism, a dual provides febuxostat alone.XOI sUAan on target notat for XOI those an approved inhibitor reabsorption acid uric selective recommended, o dose appropriate an on uncontrolled patients For and decline tophi of resolution for up follow year been recently has of CRYSTAL extension An (24,25). febuxostat who warrant additional therapy. therapy. additional warrant who febuxostat

Accepted Article

there is a need for additional treatment options. L options. treatment additional afor need is there

may represent a treatment option for patients with for patients option a treatment represent may

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons in gout gout flares. in for treatment of gout in combination with combination goutin of for treatment Combination therapy with lesinurad and lesinurad with therapy Combination completed that included an additional one one additional an included that completed th uric acid excretion and urate and urate excretion acid uric th f an XOI for whom a uricosuric is is a whomuricosuric for XOI fan esinurad 200 mg is a mgnovel is esinurad 200 tophaceous gout gout on tophaceous 21 Chris Storgard: 1a, 1b, 1c, 2, 1c,2, 3 1b, 1a, Storgard: Chris 2,3 1c, 1b, Fung: Maple 2, 3 1b, 1c, Adler: Scott 2,3 1c, 1b, Bhakta: Nihar 3 1c, 2, 1b, Kopicko: Jeff 2,3 1b, 1c, Khanna: Dinesh 3 1c,2, 1b, Terkeltaub: Robert 1c, 2, 3 1b, Jones: Graeme 3 1c,2, 1b, 1a, Dalbeth: Nicola

Author contributions Author AstraZeneca. Tom Cla by was provided manuscript this for support revie and data; of the interpretation and analysis, conduct and the design role in a sponsor had study Biosciences byArdea funded was study clinical This Acknowledgments • • •

Criterion 3: Final approval of the version of the a the versionof the of approval Final 3: Criterion Criterion 1: a) Substantial contributions to study to Substantialcontributions a) 1: Criterion analysis and interpretation of data interpretation and analysis a data; of acquisition to contributions Substantial

Acceptedcrit revising or the article Drafting 2: Criterion Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons w and approval of the manuscript. Editorial Editorial manuscript. of approval the and w (a member of the AstraZeneca group). The AstraZeneca the of member (a of the study; collection, management, collection,management, study; of the us, PhD, of PAREXEL, which was funded by funded was which PAREXEL, of PhD, us, itically for important intellectual content intellectual important for itically rticle to be published be to rticle conception and design; and/or and/or b) and design; conception nd/or c) Substantial contributions to contributions c)Substantial nd/or 22 Page 22of59 Page 23of59

2,3 1c, 1b, 1a, Perez-Ruiz: Fernando 3 1c, 2, 1b, 1a, Baumgartner: Scott

Accepted Article

5. Becker MA, Schumacher Becker HR, Jr.,Wortmann RL, Ma 5. 4. Pacher P, PacherNivorozhkinA, TherapeuticC.Szabo 4. Richette BarskovaP, M,DohertyV, Pascual E, 2. Fitzgerald KhannaD, JD, KhannaBaeSin S,PP, 1. 6. Becker MA, Schumacher Becker HR, Espinoza LR,WellsA 6. Smolen U, BardinJ, Kiltz SA, T, Cohen Dalbeth 3.

half a centuryafterhalf a the discoveryallopurinol. of 2012;64:1431-46. pharmacologic therapeutic approaches hyperuricemto guidelines Rheumatology for gout. managementof Par CONFIRMS trial. Arthritistrial. CONFIRMS ResTher 2010;12:R63. andloweringsafetyefficacy offebuxostat inthe t

Accepted2005;353:2450-61. compared Febuxostat with inpatients allopurinol wi forrecommendationsgout. Ann Rheum Dis 2016;76:632 2017;76:29-42. recommendationsEULAR evidence-based for the manage Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons References N, DohertyN, al. M, et Treat-to-target (T2T) Becce F, Becce Castaneda-Sanabria J,al. et updated2016 ghMK, T, etAmericanNeogi 2012al. ofCollege effects of xanthine effects inhibitors:oxidaseof renaissance PharmacolRev 2006;58:87-114.

F, MacDonaldP, Lloyd et Theal. E, urate- reatmenthyperuricemia ofthe gout: of the cDonaldPA,Eustace D, Palo etal. WA, th andgout.hyperuricemia N EnglJMed t 1: systematic1: nonpharmacologict and ia. Arthritisia. Care Res(Hoboken) -8. ment of gout. Annof mentgout. Rheum Dis 24

Page 24of59 Page 25of59 HR, Schumacher Jr.,Becker MA, WortmannRL,Ma 8. MA, Fitz-Patrick Becker HK, D, Choi Dalbeth N, 7. 10. Zurampic (lesinurad). Zurampic Available at: 10. NL. Edwards Treatment-failure a gout: moving t 9. 15. Wallace SL, Robinson Wallace H, JL,Masi AT, Decker M 15. SL, Graham Stocker GG, McLachlan AJ,Williams 14. 12. Fleischmann R, Fleischmann Kerr B, Suster Yeh Shen LT, M, 12. 13. Iwanaga T, T, Iwanaga KobayashiHirayama D, M,Maeda T, 13. 11. Yeh L, Shen Z, Yeh Kerr RDEA594:B. a URAT1potent 11. 83. studymonth ofallopurinol inThegout: safety LASS Arthritis Rheum Arthritis 2008;59:1540-8. andgout:hyperuricemia a phase 28-week, III,rando febuxostat versusallopurinol andplacebo inreduci classificationthe acute arthritisof ofprimarygo Rheumatol 2011;38:904-10. pharmacodynamicinteraction between allopurinol and febuxostat ingout febuxostat patients hyperuricaemia. with Rh pharmacokineticandtolerability evaluation conc of agent, benzbromarone. agent, DrugDispos Metab 2005;33:179 renal increased clearance xanthine ofthe i oxidase renal transporters,renal andOAT1[abstract]. Ann OAT3 R

Accepted2017. Articlehttp://www.azpicentral.com/zurampic/zurampic.pdf#pa

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons Z, Polvent etal. E, Pharmacodynamic, Storgard Cravets C, M, et Anal. open-label, 6- cCarty Yu DJ, PreliminaryTF. criteria for the RO.Day KM, Pharmacokinetic and arget. arget. Rheum Arthritis 2008;58:2587-90. inhibitor affectingwithout important other ut. Arthritisut. Rheum1977;20:895-900. TamaiI.Involvement ofaciduric intransporter nhibitor inducedoxypurinol by uricosuric a cDonaldHuntB, PA, Streit etJ, ofEffectsal. Ostudy. Semin Arthritis Rheum 2015;45:174- ngurate in serum subjectswith omitantadministration oflesinurad and eumatology(Oxford) 2014;53:2167-74. mized,double-blind, parallel-group trial. heum Dis 2009;68:320. probenecid inpatients probenecid withJ gout. 1-5. ge=1 . AstraZeneca.. Accessed January 6, 25 Richette F, P, Perez-Ruiz DohertyJansen M, T 17. F, Perez-Ruiz Calabozo M, JI,Herrero-Pijoan 16. 20. Bellomo R, R, C, Bellomo Ronco JA,Kellum RL,MehtaPale 20. 22. Woodworth T, Woodworth Furst AltenDE,Bingham R, C, Yo 22. RL,JA, Mehta ShahKellum Molitoris BA, SV, R 21. 19. White Faich White BorerWB, G, CardiJS,Makuch RW. 19. F, Perez-Ruiz Hernandez-Baldizon Herrero-BS, 18. 3 SundyHS,YoodJS, Baraf RA, NL, Edwards Guti 23. 60. the therapy velocityon ofsize reduction oftophi 2007;11:R31. reportinitiativeanNetwork: of improveto outcome 2004;8:R204-R212. Care International ConsensusConference Acute of the Dia animal measures, fluid models, andinformat therapy cyclooxygenase-2 the inhibitor celecoxib. Am JCard gout. Arthritis gout. Care Res(Hoboken) 2010;62:1299-305 associated renal with lithiasis during uricosuric t outcomesandrenal ingout: what should we target? Toxicity CriteriaToxicityJRheumatol v.2.0. 2007;34:1401-1 adverse and reporting inrheumatology effects of cl

conventionaltreatment:randomized two controlled t pegloticase tolerability forof the treatment of ch Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons BeitesAM, RuibalA. ofEffecturate-lowering L,NukiG, Improvingal. Pascual E, et cardiovascul onco C, onco DG,et Acuteal.Warnock KidneyInjury errez-UrenaTreadwell SR, EL,et al. andEfficacy eitesGonzalez-Gay AM, MA. Risk factors vskyrenalP. definition,Acute - failure outcome cum etStandardizingal.cum V, D, Sloan assessment ovasculareventsthrombotic inarthritis trials of reatmentofhyperuricemia inpatients with ronic gout inpatients ronic refractorygout to inchronic gout. Arthritis Rheum 2002;47:356- 4. inicalII: trials the RheumatologyCommon iol2003;92:411-8. s injury. inacute kidney Crit Care NatRheumatolRev 2014;10:654-61. lysisQualityInitiative (ADQI) Crit Group. iontechnologyneeds: Second the . rials. JAMArials. 2011;306:711-20. 26 ar ar Page 26of59 Page 27of59 25. Schumacher HR, Schumacher Jr.,Becker E,MA, Lloyd MacDo 25. 27. Ettinger B, A, Tang Ettinger LivermoreCitronB, JT, W 27. Simkin MH, Bach Uricosuric PA. thedrugs: onc 26. 29. Kim SC, Schneeweiss Kim ChoudhryS, GlyJ, Liu N, 29. DS, Goldfarb MacDonald PA,Gunawardhana L, Ch 28. JH, Tayar Lopez-Olivo MA, Suarez-Almazor ME. 31. Singhingout: JA. Advances someanswers, mor 30. MA, Schumacher Becker HR, MacDonald PA,Lloyd 24. Rheumatol Rheumatol 2009;36:1273-82. successful longterm of urate lowering febuxost with 2009;48:188-94. oftreatmentfindingsgout: the5-yr FOCUS of effic OpinRheumatol 2014;26:169-75. and calcium andcalcium ClinJstones.Am SocNephrol 2013;8:19 febuxostat of versusallopurinol orplacebo inindi calcium prevention calculi.of oxalate NEnglJMed

AcceptedSystRevDatabase 2012;11:CD008653. 2015;128:653. oninhibitors cardiovascular disease inpatients wi Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons illiams T. Randomizedallopurinol trial of inthe nnSolomonRJ, Effects DH. of xanthineoxidase e andfuture e therapy forhyperuricemia? Curr e questions. e Arthritis ResTher 2010;12:136. Febuxostatfortreating chronic gout. Cochrane naldPA,Lademacher FebuxostatC. inthe vidualshigher urinary with uric excretionacid thcohort a gout:study. Am J Med efo McLean S,Randomized L. controlledtrial E, E, Lademacher ClinicalefficacyC. andsafety acystudy.and safety Rheumatology (Oxford) 1986;315:1386-9. atallopurinol insubjectsor withJ gout. 60-7. 27

LESU = lesinurad; FBX = febuxostat; PBO = placebo; = placebo; PBO FBX = febuxostat; lesinurad; = LESU 1. Figure legends Figure population) (safety events adjustment. <0.0#P < †P0.01; mulplicity; for adjustment aer Table 1. Table legends Table Figures and Tables Table 2. Table Figure 2 Figure studymedication. randomized signing an informed consent form. form. consent informed an signing imputation. PBO = placebo; LESU = lesinurad; FBX =f FBX lesinurad; LESU= =placebo; PBO imputation. achieving patients of proportion endpoint: Primary (ITT12 andmonth at6 month mg/dl and<3.0 mg/dl,

Demographic and baseline characteristics of patien of characteristics and baseline Demographic Overall summary of treatment-emergent adverse even adverse treatment-emergent summaryof Overall . Proportion of patients achieving serum uric acid serumacid achieving uric patients of . Proportion

Accepted disposition. Patient Article

† Arthritis &Rheumatology

Completed the study with or without completing withoutcompleting or studywith the Completed John Wiley& Sons 001 versus PBO + FBX without multiplicity withoutmultiplicity FBX + PBO versus 001 sUA <5.0 mg/dl at month 6 – nonresponder –nonresponder month at6 mg/dl <5.0 sUA qd = once daily. * daily. = once qd ebuxostat. *ebuxostat. population). population). (sUA) targets of <5.0 mg/dl, <4.0 mg/dl, <4.0 of (sUA) <5.0 targets ts – Intent-to-treat population population –Intent-to-treat ts ts and renal-related adverse adverse and renal-related ts P <0.0001 versus PBO + FBX FBX + PBO versus <0.0001

Screened was defined as defined was Screened 28 Page 28of59 Page 29of59

Figure 3. Figure + FBX, ** FBX, + observation carried forward; PBO = placebo; SE = SE= st placebo; = PBO forward; carried observation intent- = ITT SE.febuxostat; FBX ± = mean are Data (ITTPopulation). imputation LESU + FBX groups, all time points are points all time groups, FBX + LESU LESU FBX = febuxostat; = placebo; PBO baseline; = B mg + FBX, FBX, + mg Figure 4. Figure Mean serum urate levels by visit – observed cases cases – visitobserved by levels urate serum Mean Percent change in sum of the areas for all target alltarget for areas of sum the changein Percent P

P P < 0.01 versus PBO + FBX. + PBO versus < 0.01

Accepted Article = 0.0002).

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology P P John Wiley& Sons < 0.0001 versus baseline (except month 6 for LESU20 6 for (except month baseline versus 0.0001 < to-treat; LESU = lesinurad; LOCF = last =last LOCF =lesinurad; LESU to-treat; andard error of the the mean.*of error andard = lesinurad. Data are mean (SE). For the the For(SE). are mean Data lesinurad. = tophi (mm tophi (ITT population). (ITTpopulation). 2 ) by visit – LOCF – visit by ) P < 0.05 vs. PBO PBO vs.< 0.05 0 0 29

years (SD) (SD) years gout diagnosis, since Duration Age, years (SD) 54.6 (10.9) 54.2 (11.0) 53.3 (11.2) 53.3 (11.0) 54.2 (10.9) 54.6 (SD) years Age, 1. Table oa rao agttpia 211 1. 279 2 (227.9) 310.1 291.1 at tophi target of area Total (SD) baseline at of tophi target Number kg/m index, mass Body (9 309 (93.6) 102 Other (94.3) 100 White (98.2) 107 American Black/African Asian (%) n Race, (%) n Male,

Not Hispanic/Latino Hispanic/Latino Not Hispanic/Latino (%) n Ethnicity, Body weight, kg 99.4 (21.0) 110.3 (19.5) 98.8 (21.4 98.8 (19.5) 110.3 (21.0) 99.4 kg weight, Body

Accepted Article patien of characteristics and baseline Demographic 2 32.0 (5.6) 32.4 (5.6) 31.6 (5.7) 32.0 (5.6) 32.0 (5.7) 31.6 (5.6) 32.4 (5.6) 32.0 This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology 15.2 (10.9) 15.8 (11.0) 13.2 (10.6) 14.7 (10.9) 14.7 (10.6) 13.2 (11.0) 15.8 (10.9) 15.2 PBO + FBX + PBO 100 (91.7) 100 94 (86.2) 94 1.9 (1.3) 1.8 (1.3) 1.8 (1.2) 1.8 (1.2) (1.2) 1.8 (1.2) 1.8 (1.3) 1.8 (1.3) 1.9 n = = 109 n John Wiley& Sons 1 (0.9) (0.9) 1 (7.3) 8 (5.5) 6 9 (8.3) (8.3) 9

LESU200 + FBX + LESU200 80 (75.5) 80 (13.2) 14 99 (93.4) 99 n = = 106 n 4 (3.8) (3.8) 4 (7.5) 8 7 (6.6) (6.6) 7

ts – Intent-to-treat population population –Intent-to-treat ts

LESU400 + FBX + LESU400 80.3 (230.3) 293.6 293.6 (230.3) 80.3 104 (95.4) 104 85 (78.0) 85 (11.9) 13 n = = 109 n 5 (4.6) (4.6) 5 (5.5) 6 5 (4.6) (4.6) 5

) 99.5 (20.6) 99.5 ) 54.1 (11.0) 54.1

259 (79.9) 259 303 (93.5) 303 35 (10.8) 35 N = 324 = N 20 (6.2) 20 10 (3.3) 10 21 (6.5) 21 TOTAL TOTAL

5.4) 5.4) 30

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NSAID NSAID Colchicine n(%) baseline, at prophylaxis flare Gout (SD) months – 12 goutflares of past Number baseline, mm baseline, baseline baseline screening mg/dl sUA, n(%) baseline, at diuretic Thiazide/thiazide-like eCrCl <60 <60 eCrCl 60–<90 eCrCl ≥90 eCrCl (%) n mL/min, baseline, at function Renal Diabetes mellitus, n (%) mellitus, n Diabetes (%) n Hyperlipidemia, (%) n Hypertension, (%) (combined)*, n history CVordisease comorbidity CV Any

Accepted Article (246.4) (SD)

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology 11 (10.1) 15 (14.2) 18 (16.5) 44 (13.6) 44 (16.5) 18 (14.2) 15 (10.1) 11 22 (20.2) 22 (79.8) 87 25 (22.9) 25 (48.6) 53 (28.4) 31 17 (15.6)17 (42.2) 46 (59.6) 65 (73.4) 80 6.1 (5.1) 6.9 (11.2) 7.0 (7.4) 6.7 (8.2) (8.2) 6.7 (7.4) 7.0 (11.2) 6.9 (5.1) 6.1 5.2 (1.5) (1.5) 5.2 (1.5) 8.8 John Wiley& Sons

95 (89.6) 95 28 (26.4) 28 (38.7) 41 (34.9) 37 21 (19.8) 21 (39.6) 42 81 (76.4) 81 70 (66.0)70 5.4 (1.7) (1.7) 5.4 (1.6) 8.7 9 (8.5) (8.5) 9

22 (20.2) 22 (41.3) 45 (38.5) 42 15 (13.8) 15 (86.2) 94 14 (12.8) 14 (45.9) 50 (56.9)62 79 (72.5) 79 5.3 (1.6) (1.6) 5.3 (1.8) 8.6

139 (42.9) 139 (34.0) 110 276 (85.2) 276 138 (42.6) 138 240 (74.1) 240 197(60.8) 75 (23.1) 75 46 (14.2) 46 52 (16.0)52 5.3 (1.6) (1.6) 5.3 (1.6) 8.7 (234.6) (234.6)

disease, stroke, and transient ischemic attack. ischemic and transient stroke, disease, ang infarction, myocardial stones, kidney mellitus, (10.1) 11 (hypercholes hyperlipidemia hypertension, *Includes acid. (14.2) 15 7 =estima eCrCl therapy; ULT= urate-lowering drugs; (14.7) 16 lesinurad; LESU = = febuxostat; FBX placebo; = PBO (4.7) 5 nor (SD) (%) mean are Data (6.4) 7 stones, n(%) Kidney (%) infarction, n Myocardial

Accepted Article

Table 2. Table Serious renal-related AEs 1 (0.9) 0 (0) 2 (2.8) (2.8) 2 (10.1) 11 (0) 0 (8.5) 9 (0.9) 1 (5.5) 6 renal-relatedSerious AEs (0.9) 1 Anyrenal-related AEs Renal-relatedadverse events (0.9) 1 (8.3) 9 withdrawal AnyTEAEleading to study 0 (5.7) 6 medication discontinuation randomizedstudy (9.2) 10 AnyTEAEleading to Anyfatal TEAE AnyTEAE serious medication randomizedstudy related AnyTEAEpossibly to Grade4 3 or AnyTEAERCTCwith toxicity adverse events(TEAE) Anytreatment-emergent

Accepted Article even adverse treatment-emergent summaryof Overall

This article isprotected by copyright. All rights reserved. 22 (20.2) 25 (23.6) 28 (25.7) 28 (23.6) 25 (10.1) 11 (20.2) 22 (10.4) 11 (11.9) 13 79 (72.5) 87 (82.1) 90 (82.6) 90 87 (82.1) (72.5) 79 n = = 109 n 4 (3.7) 7 (6.6) 7 (6.4) (6.4) 7 (6.6) 7 (13.8) 15 (3.7) 4 (8.5) 9 (8.3) 9 Arthritis &Rheumatology John Wiley& Sons

LESU200 + FBX + LESU200 n = = 106 n ts and renal-related adverse adverse and renal-related ts LESU400 + FBX + LESU400 n = = 109 n 33

Kidney stones 4 (3.7) 1 (0.9) 2 (1.8) (1.8) 2 (0.9) 1 (3.7) 4 elevationsCr ≥1.5x baseline stones Kidney laststudyassessment elevationsCr cases unresolvedat Renal failure chronic Renal failure acute b a Criteria. lesinurad; LESU = = febuxostat; FBX placebo; = PBO (%). n are Data

sCr elevation ≥ 2.0x baseline 0 (0) 3 (2.8) 6 (5.5) 6 (2.8) 3 laststudyassessment (0) 0 elevationsCr cases unresolvedat elevationsCr ≥2.0x baseline All ≥ 2.0x baseline elevations captured in ≥ ≥ in1.5x e captured elevations baseline ≥ 2.0x All

Accepted returnin sCr elevation asan defined resolution sCr Article b a,b

This article isprotected by copyright. All rights reserved. a 3 (2.8) 5 (4.7) 11 (10.1) 11 (4.7) 5 (2.8) 3 Arthritis &Rheumatology John Wiley& Sons 1 (0.9) (0.9) 1 0 0 0 1 1 1 1 0 0 1 1 1 1 0 levations. levations. g to ≤ 1.2x baseline. ≤1.2x to g RCTC = Rheumatology Common Toxicity Toxicity Common Rheumatology = RCTC 0 0 0 1 (0.9) (0.9) 1 (0.9) 1

34 Page 34of59 Page 35of59

Figure 1 Figure

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Figure 2 Figure

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36 Page 36of59 Page 37of59 Figure3

Accepted Article

37 Figure4

Accepted Article

38 Page 38of59 Page 39of59 years (SD) (SD) years gout diagnosis, since Duration Male, n (%) 107 (98.2) 100 (94.3) 102 (93.6) 309 (9 309 (93.6) 102 Other (94.3) 100 White (11.2) 53.3 (98.2) 107 American Black/African (11.0) 54.2 (10.9) 54.6 Asian (%) n Race, (%) n Male, (SD) years Age, 1. Table baseline, mm baseline, at tophi target of area Total (SD) baseline at of tophi target Number kg/m index, mass Body

Not Hispanic/Latino Hispanic/Latino Not Hispanic/Latino (%) n Ethnicity, Body weight, kg 99.4 (21.0) 110.3 (19.5) 98.8 (21.4 98.8 (19.5) 110.3 (21.0) 99.4 kg weight, Body Demographic and baseline characteristics of patien of characteristics and baseline Demographic

(SD) Accepted Article 2 32.0 (5.6) 32.4 (5.6) 31.6 (5.7) 32.0 (5.6) 32.0 (5.7) 31.6 (5.6) 32.4 (5.6) 32.0 This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology 15.2 (10.9) 15.8 (11.0) 13.2 (10.6) 14.7 (10.9) 14.7 (10.6) 13.2 (11.0) 15.8 (10.9) 15.2 PBO + FBX + PBO 100 (91.7) 100 94 (86.2) 94 1.9 (1.3) 1.8 (1.3) 1.8 (1.2) 1.8 (1.2) (1.2) 1.8 (1.2) 1.8 (1.3) 1.8 (1.3) 1.9 n = = 109 n (246.4) (246.4) John Wiley& Sons 1 (0.9) (0.9) 1 (7.3) 8 (5.5) 6 9 (8.3) (8.3) 9 291.1 291.1

LESU200 + FBX + LESU200 310.1 (227.9) 280.3 (230.3) 293.6 293.6 (230.3) 280.3 (227.9) 310.1 80 (75.5) 80 (13.2) 14 99 (93.4) 99 n = = 106 n 4 (3.8) (3.8) 4 (7.5) 8 7 (6.6) (6.6) 7

ts – Intent-to-treat population population –Intent-to-treat ts

LESU400 + FBX + LESU400 104 (95.4) 104 85 (78.0) 85 (11.9) 13 n = = 109 n 5 (4.6) (4.6) 5 (5.5) 6 5 (4.6) (4.6) 5

) 99.5 (20.6) 99.5 ) 54.1 (11.0) 54.1

259 (79.9) 259 303 (93.5) 303 35 (10.8) 35 N = 324 = N 20 (6.2) 20 10 (3.3) 10 21 (6.5) 21 (234.6) (234.6) TOTAL TOTAL

5.4) 5.4)

NSAID NSAID Colchicine n(%) baseline, at prophylaxis flare Gout months (SD) months – 12 goutflares of past Number baseline baseline screening mg/dl sUA, n(%) baseline, at diuretic Thiazide/thiazide-like eCrCl <60 <60 eCrCl 60–<90 eCrCl ≥90 eCrCl (%) n mL/min, baseline, at function Renal Myocardial infarction, n (%) infarction, n Myocardial (%) mellitus, n Diabetes (%) n Hyperlipidemia, (%) n Hypertension, (%) (combined)*, n history CVordisease comorbidity CV Any

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology 11 (10.1) 15 (14.2) 18 (16.5) 44 (13.6) 44 (16.5) 18 (14.2) 15 (10.1) 11 22 (20.2) 22 (79.8) 87 25 (22.9) 25 (48.6) 53 (28.4) 31 17 (15.6) 17 (42.2) 46 (59.6) 65 (73.4) 80 6.1 (5.1) 6.9 6.9 (5.1) 6.1 5.2 (1.5) (1.5) 5.2 (1.5) 8.8 John Wiley& Sons 7 (6.4) (6.4) 7

95 (89.6) 95 28 (26.4) 28 (38.7) 41 (34.9) 37 21 (19.8) 21 (39.6) 42 (66.0) 70 (76.4) 81 5.4 (1.7) (1.7) 5.4 (1.6) 8.7 9 (8.5) (8.5) 9 5 (4.7) (4.7) 5 ( 11.2)

22 (20.2) 22 (41.3) 45 (38.5) 42 15 (13.8) 15 (86.2) 94 14 (12.8) 14 (45.9) 50 (56.9) 62 (72.5) 79 7.0 (7.4) 6.7 (8.2) (8.2) 6.7 (7.4) 7.0 5.3 (1.6) (1.6) 5.3 (1.8) 8.6 7 (6.4) (6.4) 7

139 (42.9) 139 (34.0) 110 276 (85.2) 276 138 (42.6) 138 (60.8) 197 (74.1) 240 75 (23.1) 75 46 (14.2) 46 52 (16.0) 52 5.3 (1.6) (1.6) 5.3 (1.6) 8.7 19 (5.9) 19

Page 40of59 Page 41of59 disease, stroke, and transient ischemic attack. ischemic and transient stroke, disease, ang infarction, myocardial stones, kidney mellitus, (10.1) 11 (hypercholes hyperlipidemia hypertension, *Includes acid. (14.2) 15 =estima eCrCl therapy; ULT= urate-lowering drugs; (14.7) 16 lesinurad; LESU = = febuxostat; FBX placebo; = PBO nor (SD) (%) mean are Data stones, Kidney n(%)

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons ina pectoris, heart failure, peripheral vascular peripheral failure, heart pectoris, ina NSAID = nonsteroidal antiinflammatory antiinflammatory =nonsteroidal NSAID ted creatinine clearance; sUA = serum uric serumuric = sUA clearance; creatinine ted terolemia, hypertriglyceridemia), diabetes diabetes hypertriglyceridemia), terolemia, 42 (13.0) 42 Adverse event category PBO + FBX FBX + PBO category event Adverse population) (safety events adverse events(TEAE) Anytreatment-emergent 2. Table Any renal-related AEs 6 (5.5) 9 (8.5) 11 (10.1) 11 (8.5) 9 (5.5) 6 Renal failure acute renal-relatedSerious AEs (0.9) 1 Anyrenal-related AEs Renal-relatedadverse events (0.9) 1 (8.3) 9 withdrawal Any TEAEtoleading study 0 (5.7) 6 medication discontinuation randomizedstudy (9.2) 10 Any TEAEtoleading Anyfatal TEAE AnyTEAE serious medication randomizedstudy Anyrelated TEAEpossibly to Grade4or 3 AnyTEAERCTCwith toxicity

Accepted Article even adverse treatment-emergent summaryof Overall

This article isprotected by copyright. All rights reserved. 79 (72.5) 87 (82.1) 90 (82.6) 90 (82.1) 87 (72.5) 79 22 (20.2) 25 (23.6) 28 (25.7) 28 (23.6) 25 (10.1) 11 (20.2) 22 (10.4) 11 (11.9) 13 n = = 109 n 4 (3.7) 7 (6.6) 7 (6.4) (6.4) 7 (6.6) 7 (13.8) 15 (3.7) 4 (8.5) 9 (8.3) 9 Arthritis &Rheumatology John Wiley& Sons 1 (0.9) (0.9) 1 (0.9) 1

LESU200 + FBX + LESU200 n = = 106 n 0 (0) 0 0 0 ts and renal-related adverse adverse and renal-related ts LESU400 + FBX + LESU400 n = = 109 n 1 (0.9) (0.9) 1 (2.8) 2 Page 42of59 Page 43of59 Kidney stones 4 (3.7) 1 (0.9) 2 (1.8) (1.8) 2 (0.9) 1 (0.9) 1 0 (3.7) 4 0 elevationsCr ≥1.5x baseline stones Kidney Renal failure chronic b a Criteria. lesinurad; LESU = = febuxostat; FBX placebo; = PBO (%). n are Data sCr elevation ≥ 2.0x baseline 0 (0) 3 (2.8) 6 (5.5) 6 (2.8) 3 studylast assessment (0) 0 elevationsCr cases unresolvedat elevationsCr ≥2.0x baseline last studylast assessment elevationsCr cases unresolvedat All ≥ 2.0x baseline elevations captured in ≥ ≥ in1.5x e captured elevations baseline ≥ 2.0x All

Accepted returnin sCr elevation asan defined resolution sCr Article b a,b

This article isprotected by copyright. All rights reserved. a 3 (2.8) 5 (4.7) 11 (10.1) 11 (4.7) 5 (2.8) 3 Arthritis &Rheumatology John Wiley& Sons 0 1 1 1 1 0 0 1 1 1 1 0 levations. levations. g to ≤ 1.2x baseline. ≤1.2x to g RCTC = Rheumatology Common Toxicity Toxicity Common Rheumatology = RCTC

Accepted Article

Page 44of59 Page 45of59

AcceptedProportionachieving patients serumof uric (sacid Article

This article isprotected by copyright. All rights reserved. at month 6 month month 12(ITTand at population) Arthritis &Rheumatology 86x50mm (300 x 300 DPI) (300 30086x50mm DPI) x John Wiley& Sons UA) targets of <5.0 mg/dl, mg/ <5.0 mg/dl,<3.0 of targets <4.0 and UA)

Accepted Article

Mean serum urate levels serumurate Mean byvisit observed– ( cases

ITT population) ITT

Page 46of59 Page 47of59

Accepted the of forinall sum t target areas change Percent Article

2 ) by visit – LOCF imputation Population) (ITT ) byvisit LOCF –

Inclusion criteria Inclusion 1. Table Supplemental Material Supplemental Online etal. Dalbeth,

1. 1. NSAID) ±PPI. NSAID) colchic with prophylaxis gout flare take to Able 7. 6. Meets one of the following criteria: criteria: the onefollowing of Meets 6. Gout. Primary of Arthritis Acute of Classification American the as per gout of diagnosis the Meets 5. contraception. potent childbearing of female female; or male Is 4. age.yearsof and ≤85 years ≥18 Is 3. schedule thevisit/protocol to adhere to Willing 2. act studyrelated first the before consent informed Able to understand the study procedures, the risks the study procedures, the understand to Able • •

must have an sUA value ≥6.0 mg/dL. sUAan value ≥6.0 have must dose appropriate a study on medically the Entering Accepteds have an ULTmust approved an taking currently Not Article Complete inclusion/exclusion criteria CRYSTAL criteria for inclusion/exclusion Complete This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons ine or NSAID (including Cox-2 selective selective Cox-2 (including NSAID or ine s. ial who agrees to use non-hormonal non-hormonal use to agrees who ial ivity. ivity. Rheumatism Association Criteria for the Criteria for Association Rheumatism involved and willing to provide written provide andto willing involved of febuxostat orallopurinol orallopurinol febuxostat of UA value ≥8 mg/dL.≥8 value UA 1 Page 48of59 Page 49of59 Exclusion criteria Exclusion

11. 8. 9. 10. 7. 1. 2. 3. 9. Body mass index (BMI) < 45 kg/m45 index< (BMI) mass Body 9. diameter. longest the an hands/wrists on the tophus measurable ≥1 With 8. 4. 5. 6.

Positive test for active hepatitis B or hepatitis C hepatitisor B active hepatitis test for Positive History of myositis/myopathy or rhabdomyolysis rhabdomyolysis or myositis/myopathy of History (e.g., azathioprine, 6-mercaptopurine, cyclosporine 6-mercaptopurine, azathioprine, (e.g., immunosuppressive mayrequire systemic or Requires Known or suspected human immunodeficiency virus (HIvirus immunodeficiency human suspected or Known History or suspicion of drug abuse within the withinthe past abuse of suspicion drug or History Known hypersensitivity or allergy to febuxostat to allergy or hypersensitivity Known screening visit. screening (e.g., urico gout of treatment for the indicated is other medication urate-lowering approved any Taking Previously received pegloticase pegloticase received Previously received active treatment or placeboor active treatment received involvi study clinical a in participated Previously Pregnant or breastfeeding or Pregnant

Acceptedl hard of ml] [45 oz beer, 1.5 orof ml][360 oz 12 week alcohol per (eof drinks more14 than Consumes Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology 2 John Wiley& Sons . infection ng lesinurad (RDEA594) or RDEA806 and RDEA806 or (RDEA594) lesinurad ng iquor) suric agent) within 8 weeks of the weeks of within 8 agent) suric d/or feet/ankles ≥5 mm and ≤20 mmin ≤20 and mm ≥5 feet/ankles d/or 5 years 5 ) .g., 1 drink = 5 oz [150 ml] of wine, wine, of ml][150 5 oz = drink 1 .g., than allopurinol or febuxostat that that febuxostat or allopurinol than or immunomodulatory treatment treatment immunomodulatory or V) infection V) 2

12. 13. 14. 15. 16. 19. 17. 20. 18. 23. 21. 22.

dysplasia or treated in situ Grade 1 cervical cance 1cervical situ in Grade treated or dysplasia with evidence no treated beenhas that cancer skin 5yearsw the previous within malignancy of History receiving anticoagulants in last 12 months12 last in anticoagulants receiving thromvenous deep or stroke, infarction, myocardial (NYHA) Association York New Heart angina, Unstable mmHg on repeat measurements on two separate visits separate twovisits on repeat measurements on mmHg above (systolic pressure hypertension Uncontrolled using ideal body weight weight ideal body using calcu 2.5 x ULN at any time during the the S during time any atULNx >2.5 kinase Creatine of normal (ULN) at any time during the Screening Screening Pe the during time any at (ULN) normal of amin aspartate or (ALT) aminotransferase alanine An Active peptic ulcer disease requiring treatment requiring disease ulcer peptic Active Gamma glutamyl transferase (GGT) >3 x ULN at any ti anyatx ULN >3 (GGT) transferase glutamyl Gamma hydrolase hydrolase othor acid, valproic progabide, valpromide, Taking History of xanthinuria; subject with active liver d liver active with subject xanthinuria; of History

Acceptedo 325 thanmg more with treatment chronic Receiving Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons isease or hepatic dysfunction hepatic orisease r er known inhibitors of epoxide of inhibitors epoxide erknown at any time during the the Screening during time any at creening Period Period creening of recurrence, treated cervical cervical treated recurrence, of non-melanoma of exception the ith 160 or diastolic pressure above above 95 pressure diastolic or 160 riod riod bosis (DVT); or subjects currently currently subjectsor (DVT); bosis lated by the Cockcroft-Gault formula formula Cockcroft-Gault bythe lated otransferase (AST) >2.0 x upper limit limit upper x(AST) >2.0 otransferase me during the Screening Screening Period the during me class III or IV heart failure, failure, heart IV IIIor class f salicylates per day per fsalicylates during the screening period) screening the during 3 Page 50of59 Page 51of59

24. 25.

used in clinical trials. clinicalin used include not does Visit; this Screening the to prior weeks within 8 therapy investigational an Received

Accepted Articlerequi protocol complythe to with ability patient’s risk to create undue might Monitor, Medical and/or which condition, psychological or medical other Any

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons febuxostat or locally marketed products products marketed locally or febuxostat rements, or to complete the study complete the toor rements, or 5 half-lives (whichever is longer) longer) is (whichever 5 half-lives or in the opinion of the Investigator Investigator the ofopinion the in the patient or interfere with the the with interfere or patient the 4 Nephropathy toxic Nephropathy Nephropathy clearance decreased renal Inulin abnormal clearance renal Inulin Hypercreatininemia ratedecreased filtration Glomerular rateabnormal filtration Glomerular increasedC Cystatin abnormalC Cystatin decreased renalclearance Creatinine abnormal renalclearance Creatinine ratio increased urea nitrogen/creatinine Blood increased urea Blood abnormal urea Blood increased creatinine Blood abnormal creatinine Blood Azotemia Anuria failure prerenal Acute TEAEs Renal-related 2. Table Supplemental

5 Page 52of59 Page 53of59 Calculus urethral Calculus ureteric Calculus bladder Calculus TEAEs Stone Kidney output decreased Urine clearance decreased renal Urea nephropathy Urate necrosis tubular Renal disorder tubular Renal atrophy tubular Renal necrosis papillary Renal injury Renal impairment Renal abnormal test function Renal chronic failure Renal acute failure Renal failure Renal necrosis cortical Renal failure Postrenal Oliguria uropathy Obstructive

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons 6 analysis stone Urinary removal calculus Urinary Ureterolithotomy removal calculus Ureteric calculus horn Stag removal stone Renal Nephrolithiasis urinary Calculus

Accepted Article

This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons 7 Page 54of59 Page 55of59 Major adverse cardiovascular events(MACE) cardiovascular adverse Major Non-major adverse cardiovascular events (non-MACE) cardiovascular adverse Non-major

Supplemental Table 3. Table Supplemental

• • • • • • • • •

Hospitalized congestive heart failure failure heart congestive Hospitalized All deaths (both CV and non-CV deaths) CV and non-CV (both deaths All Arrhythmias not associated with ischemiawith associated not Arrhythmias Nonfatal myocardial infarction myocardial Nonfatal Unstable angina with urgent coronary revascularizat coronary with urgent angina Unstable ischemia) ischemia) thromb dissection, arterial thrombosis, venous deep thrombotic vascular arterial and peripheral Venous Nonfatal stroke stroke Nonfatal Transient ischemic attack ischemic Transient

Accepted and non-electi (elective revascularization Cerebral Article Major and non-major adverse cardiovascular events cardiovascular adverse non-major and Major This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons ve) events (e.g. pulmonary embolism, embolism, pulmonary (e.g. events ion osis and peripheral arterial arterial and peripheral osis

8 eCrCl, ml/min 5.79 (9.70) 5.79 ml/min eCrCl, 4. Table Supplemental ratio. cle creatinine eCrCl,estimated (SD). mean are Data (10.11) 4.88 ml/min eCrCl, (0.08) 0.02 mg/mg PCR, PBO + FBX FBX + PBO protein/cr theinurinary month 12 to baseline from

Accepted Article n = = 109 n Change from baseline to month 12 (or to last value) last(or to12 to baseline month from Change n=106 n=106 n=87 n=87 n=78 n=78 This article isprotected by copyright. All rights reserved. Change from baseline to Last Value to baseline Last from Change Change from baseline to month 12 to baseline month from Change Arthritis &Rheumatology LESU200 + FBX + LESU200 John Wiley& Sons ─0.34 (10.77) ─0.34 1.08 (10.49) 1.08 0.13 (0.78) 0.13 n = = 106 n n=103 n=103 n=79 n=79 n=74 n=74 arance; PCR, urinary protein to creatinine to protein urinary PCR, arance; eatinine ratio. ratio. eatinine LESU400 + FBX + LESU400 ─0.20 (9.48) ─0.20 ─0.01 (0.13) ─0.01 −0.26 (9.40) −0.26 n = = 109 n n=106 n=106 n=84 n=84 n=79 n=79 in eCrCl and change andchange eCrCl in 9 Page 56of59 Page 57of59

Accepted Article Figure 1.Supplemental

Supplemental Figure Figure 2.Supplemental interval. confidence lesin LESU, acid; sUA,serum uric forward; carried NRI, nonres + febuxostat. placebo over febuxostat +

Accepted Article Summary of analyses showing a response that favors response that a showing analyses of Summary This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons urad; PBO, placebo; FBX, febuxostat; CI, FBX,febuxostat; placebo; PBO, urad; ponder imputation; LOCF, last observation observation LOCF, last imputation; ponder lesinurad 200 mg mg 200 lesinurad 11

Page 58of59 Page 59of

Figure 3.Supplemental imputation (ITT population subgroup with baseline s baseline with subgroup (ITTpopulation imputation lesinurad. lesinurad. serumacid uric = sUA FBX. PBO versus + proportions

Accepted Article Proportion of patients with a sUA <5.0 mg/dl by vi mg/dl by <5.0 a withsUA patients of Proportion This article isprotected by copyright. All rights reserved. Arthritis &Rheumatology John Wiley& Sons UA ≥5.0 mg/dl). * mg/dl). UA ≥5.0 ; PBO = placebo; FBX = febuxostat; LESU = LESU= febuxostat; = FBX = placebo; PBO ; P ≤ 0.025 for difference in in difference ≤ for 0.025 sit – Nonresponder – Nonresponder sit 12