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Objective To investigate the efficacy and safety of lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA

Objective To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12‐month phase III trial in patients with tophaceous gout.

ObjectivesDetermine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.MethodsPatients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of ResultsPatients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, pConclusionLesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.Trial registration numberNCT01493531.

Introduction Patients with gout have numerous comorbidities. We aimed to estimate the prevalence and incidence rates of renal and cardiovascular morbidities in trial-aligned patients with established gout in Germany (DE), the United Kingdom (UK), the United States (US), and France (FR). Methods This longitudinal cohort study used retrospective data from IMS Disease Analyzer™ (DE, FR), Clinical Practice Research Datalink–Hospital Episode Statistics (UK), and IMS’ PharMetrics Plus database linked with outpatient laboratory results (US). Included patients were ≥18 years at index date (January 1, 2010; all dates +1 year for FR), with continuous enrollment during the pre-index year, had “prevalent established gout” determined by data in the pre-index year, and ≥1 documented visit after index date; additional inclusion/exclusion criteria were aligned with recent gout clinical trials. Look-back for comorbidity prevalence extended to January 1, 2003 (US: January 1, 2009). Follow-up for incidence extended from index date to at most March 26, 2013 (FR: May 31, 2014). Events of interest were identified by diagnostic codes and/or laboratory data. Results The trial-aligned cohorts included 35,118 (DE), 24,607 (UK), 121,591 (US), and 17,338 (FR) patients. Among renal conditions, baseline diagnosis of chronic kidney disease/renal failure was most prevalent in the UK followed by DE; abnormal serum creatinine was most prevalent in the UK. Hypertension was the most prevalent cardiovascular diagnosis in all countries, followed by ischemic heart disease (IHD) and myocardial infarction. Incidence rates (per 100 patient-years) for new/worsening renal impairment ranged from 1.67 (DE) to 4.34 (US) and for nephrolithiasis diagnosis from 0.31 (FR) to 3.79 (US). The incidence rates for hypertension diagnosis were highest among cardiovascular-related events, ranging from 3.23 (UK) to 20.27 (US), followed by IHD. Conclusions Patients with established gout such as those included in gout trials have a high burden of established morbidity and new diagnoses of morbid events. Consideration of comorbidities, which greatly exacerbate disease burden, is important in gout management. Funding AstraZeneca. Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0346-1) contains supplementary material, which is available to authorized users.

ObjectivesTo assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol.MethodsPatients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200–600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout.ResultsPatients (n=208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (pConclusionsLesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone.Trial registration numberNCT01001338.

Zancong Shen, Colin Rowlings, Brad Kerr, Vijay Hingorani, Kimberly Manhard, Barry Quart, Li-Tain Yeh, Chris Storgard Ardea Biosciences, Inc. (a member of the AstraZeneca group), San Diego, CA, USA Abstract: Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration–time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. Arelative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated. Keywords: urinary excretion, urate lowering, URAT1, single and multiple doses, food effect, clearance&nbsp

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG.Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m(2)/day) and three-to-six-patient (≥25 mg/m(2)/day) cohorts according to a modified Fibonacci's schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed.Thirty-five patients were treated at doses ranging from 6 to 225 mg/m(2). A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m(2); shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m(2); extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m(2)) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m(2), with a dose-proportional increase in C max and AUC0-inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses83 mg/m(2).The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.

Objective Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12-month, multicenter, randomized, double-blind, placebo-controlled phase III trial, was conducted to investigate daily lesinurad (200 mg or 400 mg orally) added to allopurinol versus placebo plus allopurinol in patients with serum urate (UA) levels above a target of

Background Three randomized, double-blind, Phase III trials reported that greater proportions of patients treated with lesinurad 200 mg (LESU200) or 400 mg (LESU400), combined with the xanthine oxidase inhibitor (XOI) allopurinol (ALLO; CLEAR 1 and 2) or febuxostat (FBX; CRYSTAL), achieved serum uric acid (sUA) targets at 6 months versus xanthine oxidase inhibitor (XOI) + placebo (PBO). Objectives To evaluate the impact of long-term treatment with lesinurad + XOI on tophus and flares for at least 1 year and up to 2 years. Methods Patients completing 12 months in the core CLEAR and CRYSTAL studies could enroll in respective uncontrolled, open-label extension studies (NCT01808131; NCT01808144). Patients randomized to LESU200 + XOI or LESU400 + XOI in the core studies who continued on combination therapy in the extension studies were analyzed. Efficacy endpoints included: (1) proportions of patients with complete resolution (CR) of ≥1 target tophus (i.e. measurable tophus on hands/wrists and/or feet/ankles 5–20 mm in longest diameter), (2) percent reductions in the total area of all target tophi, and (3) proportions of patients experiencing gout flares requiring treatment (GFRT). Results A total of 239 (LESU200+ALLO) and 232 (LESU400+ALLO) patients continued in the CLEAR extension; 64 (LESU200+FBX) and 65 (LESU400+FBX) patients continued in the CRYSTAL extension. Proportions of patients with CR of ≥1 target tophus increased from end of core study (1 year) to 2 years: from 25.0% to 43.8% in LESU200+ALLO and 30.3% to 36.4% in LESU400+ALLO, and from 26.6% to 53.1% in LESU200+FBX and 35.4% to 58.5% in LESU400+FBX (LOCF). Percent reduction in the total area of all target tophi versus baseline changed from end of core study to 2 years: from 11.6% to 41.8% in LESU200+ALLO and 42.7% to 49.3% in LESU400+ALLO, and from 54.8% to 68.3% in LESU200+FBX and 58.6% to 72.4% in LESU400+FBX (LOCF). Proportions of subjects with a GFRT per month decreased during continued combination treatment in both extension studies (Figure). The proportions of patients with a GFRT during Months 1, 12, and 24 were, respectively, 16.3, 7.9, and 5.6 in LESU200+ALLO; 18.1, 6.9, and 3.0 in LESU400+ALLO; 26.6, 10.9, 6.3 in LESU200+FBX; and 36.9, 4.6, 1.9 in LESU400+FBX. Extended treatment with LESU + XOI did not result in increased exposure-adjusted incidence rates of adverse events (AEs), AEs leading to discontinuation of lesinurad, serious AEs, or clinical laboratory abnormalities. Conclusions The CLEAR and CRYSTAL extension studies showed that patients treated with lesinurad + XOI for up to 2 years exhibited continued increases in the rate of complete resolution of tophi and reduction in tophus area, as well as decreased rates of GFRT. Acknowledgement This study was funded by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and was funded by AstraZeneca. Disclosure of Interest T. Bardin Grant/research support from: Ipsen, Menarini., Consultant for: AstraZeneca, Ipsen, Menarini, Novartis, Savient, Sobi, Takeda, Cymabay., N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, Novartis., Consultant for: AstraZeneca, Fonterra, Pfizer, Takeda, Crealta, Cymabay., Speakers bureau: AstraZeneca, Teijin., R. Terkeltaub Consultant for: Ardea Biosciences, AstraZeneca, Takeda, Relburn, REVIVE., C. Storgard Employee of: Ardea Biosciences, a member of the AstraZeneca Group., M. Fung Employee of: Ardea Biosciences, a member of the AstraZeneca Group., J. Hu Employee of: Ardea Biosciences, a member of the AstraZeneca Group., F. Perez-Ruiz Consultant for: AstraZeneca, Menarini, Pfizer., Speakers bureau: AstraZeneca, Menarini, Pfizer.

Background Two replicate, randomized, core Phase III trials (CLEAR 1 and 2) reported significantly more subjects treated with lesinurad 200 mg (LESU200) or 400 mg (LESU400) combined with allopurinol (ALLO) achieved target sUA Objectives Assess long-term safety and efficacy of LESU+ALLO therapy in subjects enrolled in the CLEAR 1and 2 extension study (NCT01808131). Methods Efficacy was assessed for those completing the core study and either 1) continuing core LESU+ALLO treatment (200CONT, 400CONT) or 2) crossing over from core ALLO+PBO to either ALLO+LESU200 (200CROSS) or LESU400 (400CROSS). Core LESU200+ALLO or LESU400+ALLO subjects and 200CONT and 400CONT extension groups are reported for safety. Efficacy endpoints included proportions of subjects with target sUA Results For efficacy, the 200CONT (n=239) and 400CONT (n=232) groups receiving treatment for up to 24 months, and 200CROSS (n=121) and 400CROSS (n=122) groups, receiving treatment for up to 12 months, were analyzed. Proportions of subjects with sUA For safety, pooled analysis on a total of 405 and 401 subjects (LESU200, LESU400 respectively), from the core studies and 239 and 232 (200CONT, 400CONT, respectively) from the extension studies, was conducted. EAIRs (per 100-PY) of TEAEs and serious TEAEs at any time during core or extension studies were 54.2 and 5.8 for LESU200 and 57.2 and 8.3 for LESU400. EAIRs of renal-related TEAEs and serious renal-related TEAEs were 7.4 and 0.5 for LESU200 and 14.2 and 0.8 for LESU400. EAIRs of kidney stone incidence rates were 0.5 and 2.0 per 100-PY for LESU200 and LESU400, respectively. EAIRs of sCr elevations ≥1.5x baseline was 7.8 and 17.0 per 100-PY for LESU200 and LESU400, respectively; resolution of sCr elevations by analysis cutoff occurred in 91.7% and 87.8% of cases, respectively. Conclusions Subjects treated with LESU+ALLO therapy through 2 years continued to be at sUA target; those crossing over from ALLO monotherapy had increased proportions reach target. Safety during continued treatment was consistent throughout the core and extension studies. Acknowledgement This study was funded by Ardea Biosciences/AstraZeneca. Disclosure of Interest K. Saag Grant/research support from: Ardea Biosciences, Inc., a member of the AstraZeneca Group; Crealta, Takeda, Consultant for: Ardea Biosciences Inc., a member of the AstraZeneca Group; AstraZeneca; Takeda, M. Becker Consultant for: Ardea Biosciences Inc., a member of the AstraZeneca Group; AstraZeneca; Takeda; Crealta; CymaBay; BioCryst; Pfizer, C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, N. Bhakta Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, S. Adler Employee of: AstraZeneca, J. Hu Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, T. Bardin Grant/research support from: Ipsen; Menarini, Consultant for: AstraZeneca; Ipsen; Menarini; Novartis; Savient; Sobi; Takeda

Background Lesinurad (RDEA594) is a selective uric acid reabsorption inhibitor (SURI) being investigated for treatment of gout in combination with xanthine oxidase inhibitors. Objectives Assess efficacy and safety of lesinurad in combination with allopurinol (ALLO) in gout patients with inadequate response to standard of care (SOC) ALLO dosing (NCT01493531). Methods CLEAR 2 was a 12-month, randomized, double-blind, global phase III trial to evaluate lesinurad (200 mg or 400 mg oral, qd) in combination with ALLO vs ALLO+placebo (PBO). Patients were ages 18-85 yrs on stable, medically appropriate SOC ALLO doses ≥300 mg (≥200 mg in moderate renal impairment), as determined by investigator, with serum uric acid (sUA) ≥6.5 mg/dL at screening and ≥2 gout flares in prior 12 months. Primary endpoint was proportion of patients meeting sUA target of Results Patients (N=610) were mostly male (96.2%), mean ± SD age was 51.2±10.9 yrs, and duration since gout diagnosis was 11.5±9.3 yrs. Most patients (84.1%) received ALLO 300 mg (range: 200-900 mg) daily; 23.6% had tophi at screening (measurable target tophi at baseline, 15.9%) and baseline sUA was 6.90±1.19 mg/dL. Lesinurad at both doses in combination with ALLO significantly increased proportions of patients achieving sUA targets ( Conclusions Lesinurad (200 or 400 mg) in combination with ALLO significantly increased the proportion of patients achieving sUA target at 6 months, with more than twice as many patients reaching goal of Acknowledgements Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest T. Bardin Grant/research support from: Ipsen, Menarini, Consultant for: AstraZeneca, Ipsen, Menarini, Novartis, Savient, Sobi, Takeda, R. Keenan Consultant for: AstraZeneca, Crealta Pharmaceuticals, Takeda, P. Khanna Speakers bureau: Takeda, J. Kopicko Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., N. Bhakta Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., S. Adler Employee of: AstraZeneca Pharmaceuticals, C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., S. Baumgartner Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., A. So Consultant for: Novartis, AstraZeneca, Menarini

Background Hyperuricemia and gout are increasingly prevalent, and if not appropriately treated, may cause permanent joint destruction, bone erosion, and kidney damage. Patients typically have worse-than-normal pre-existing health status at diagnosis, and comorbidities such as chronic renal impairment and cardiovascular (CV) diseases are associated with gout. Objectives Estimate prevalence and incidence rates (IRs) of potential treatment- or disease-related renal and CV morbidities (pre-existing and new incident events) in patients with established gout in Germany (DE), the United Kingdom (UK), United States (US), and France (FR). Methods A longitudinal cohort study was conducted using retrospective data from IMS Disease Analyzer™ (DE & FR), Clinical Practice Research Datalink-Hospital Episode Statistics (UK), & IMS9 PharMetrics Plus database linked with outpatient laboratory results (US), from Jan 1, 2009 to Dec 31, 2011. Patients were required to have “prevalent established gout” (treated with urate-lowering treatment [ULT] or eligible for ULT based on ACR guidelines) between Jan 1, 2009 & Dec 31, 2009; age ≥18 yrs on index date (Jan 1, 2010); and ≥1 documented visit both prior to Jan 1, 2009 and after Jan 1, 2010. Variable follow-up extended from index date to Dec 31 2011 (all dates +1 yr for FR). Events of interest were identified based on diagnostic codes/laboratory data. Analyses are presented overall and stratified by type of 1st ULT regimen (allopurinol or febuxostat) after index, with follow-up until treatment discontinued. Results A total of 35,188 (DE), 24,607 (UK), 121,591 (US), and 17,388 (FR) patients were analyzed. Among renal conditions, baseline diagnosis of CKD/renal failure was most prevalent in the UK (10.9%) & DE (6.7%), whereas prevalence of abnormal serum creatinine (sCR) was most prevalent in the UK (30.6%). Hypertension was the most prevalent CV diagnosis in all 4 countries (59.5% [DE], 24.4% [UK], 52.4% [US], 31.2% [FR]), followed by ischemic heart disease and myocardial infarction (Table). IRs (per 100 patient-yrs) of new/worsening renal impairment ranged from 1.67 (DE) to 4.34 (US). IRs of nephrolithiasis diagnosis ranged from 0.31 (FR) to 3.79 (US). sCR elevations of 1.5x to Conclusions These findings show that gout patients have comorbid renal and CV disease and are at risk for and develop new renal and events. Comorbid illnesses greatly enhance the overall disease burden in this patient population. Awareness and consideration of these comorbidities are important in the medical management of gout patients. References Zhang W, Doherty M, Bardin T, et al. Ann Rheum Dis. 2011;70:563-570. Kuo CF, Grainge MJ, Mallen C, et al. Ann Rheum Dis. 2014 Nov 14. Grassi D, Ferri L, Desideri G, et al. Curr Pharm Des. 2013;19(13):2432-2438. Acknowledgements Funding for the study was provided by AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest J. Nuevo Employee of: AstraZeneca, F. Nyberg Employee of: AstraZeneca, L. Horne: None declared, R. Morlock Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., L. Aiyer Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., D. Hines Employee of: IMS Health, X. Ansolabehere Employee of: IMS Health, P. Chevalier Employee of: IMS Health

Background Lesinurad (LESU; RDEA594) is a selective uric acid reabsorption inhibitor (SURI) being investigated for the treatment of gout in combination with a xanthine oxidase inhibitor. Objectives The CRYSTAL study is a multinational, randomized, double-blind, placebo-controlled, phase III clinical trial of LESU in combination with febuxostat (FBX) to determine efficacy and safety of combination therapy compared with FBX monotherapy in patients with tophaceous gout (NCT01510769). Methods Patients with gout, ages 18-85 yrs, with serum uric acid (sUA) ≥8 mg/dL (≥6 mg/dL on urate lowering therapy) and ≥1 tophus were given FBX 80 mg qd for 3 weeks before randomization to LESU (200 mg or 400 mg oral, qd) in combination with FBX or placebo (PBO) + FBX. Primary endpoint was proportion of patients with sUA Results Patients (N=324) were white (79.9%) and male (95.4%) with mean ± SD age of 54.1±11.0 yrs and 14.7±10.9 yrs since gout diagnosis. sUA was 8.7±1.6 mg/dL at screening and 5.3±1.6 mg/dL on FBX at randomization (28% with sUA ≥6 mg/dL). More patients achieved sUA levels Conclusions In patients with tophaceous gout, LESU (200 or 400 mg) in combination with FBX increased the proportion of patients achieving sUA Acknowledgements Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, Novartis, Speakers bureau: Savient, Menarini, Novartis, Takeda, and Advisory Boards for AstraZeneca, Fonterra, Takeda, Metabolex, G. Jones Grant/research support from: Abbvie, Ardea, Novartis, Auxilium, Consultant for: Pfizer, Roche, Hospira and Janssen, Speakers bureau: UCB, Roche, Janssen, Abbvie, Novartis, Mundipharma, Amgen, BMS, Pfizer, R. Terkeltaub Consultant for: AstraZeneca, Takeda, Revive, Relburn, UCB, D. Khanna Grant/research support from: AstraZeneca, Consultant for: AstraZeneca, Takeda, J. Kopicko Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, N. Bhakta Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, S. Baumgartner Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, F. Perez-Ruiz Grant/research support from: Spanish Health Ministry, Spanish Rheumatology Foundation, and Cruces Hospital Rheumatologists Association, Consultant for: AstraZeneca, Menarini, Metabolex, Novartis, Pfizer, and SOBI, Speakers bureau: AstraZeneca and Menarini

Background Gout affects 1–4% of the population in developed Western countries. The goal of gout treatment is lowering serum uric acid (sUA) levels to treat and prevent urate crystal deposition, thereby improving signs and symptoms of gout, e.g., acute flares and tophus formation. Objectives Describe impact of current urate-lowering treatment (ULT) on sUA, gout flares and tophi in patients with established gout in France (Fr), Germany (DE), the United Kingdom (UK) and the United States (US). Methods A retrospective database analysis was conducted using Disease Analyzer database (Fr, DE), IMS9 PharMetrics Plus™ database linked with outpatient laboratory results (US), and Clinical Practice Research Datalink-Hospital Episode Statistics (UK) from Jan 1, 2009 to Dec 31, 2011. Patients were required to have evidence of “prevalent established gout” (ie, treated with or eligible for ULT based on ACR guidelines) between Jan 1, 2009 and Dec 31, 2009; be age ≥18 on index date (Jan 1, 2010); and have ≥1 documented visit prior to Jan 1, 2009 and ≥1 documented visit for gout after Jan 1, 2010. Follow-up extended from Jan 1, 2010 to Dec 31, 2011 (all dates +1 yr for France). Univariate descriptive statistics were conducted to describe elevated sUA occurrence (≥6 mg/dL), gout flares, and tophi by ULT (allopurinol [ALLO] and febuxostat [FBX]). Results A total of 22126 (Fr), 58672 (DE), 36188 (UK) and 169085 (US) patients met selection criteria. ALLO:FBX populations were 13995:1,785 (Fr), 36251:429 (DE), 21409:101 (UK), and 82415:3610 (US). Mean (SD) age 68.0 (12.3), 69.2 (11.0), 64.6 (12.3) and 54.5 (9.6) years, respectively. Most patients were male (Fr: 74.9%; DE: 70.3%; UK: 85.6%; US: 89.2%). Availability of sUA results varied by country, but was low, ranging from 2.4% (US) to 41.0% (DE). For sUA, study population included only patients with ≥1 sUA measure. Observed incidence rates of elevated sUA episodes (8 to 58 per 100 patient yrs), 1st gout flare during follow-up (1.1 to 60 per 100 patient yrs), and percentage of patients with reported tophus (up to 2.3%), by country and stratified by ULT, are provided (Figure). Conclusions Current ULT (eg, ALLO, FBX) often do not achieve recommended sUA goals and gout-related outcomes, with many patients experiencing elevated sUA levels. In this multinational database analysis of ULT-treated patients, high number of elevated sUA episodes, evidence of continued flares, and percentage of patients with reported tophus over the observation period present continued need for improvement in gout treatment. Notably, sUA testing rates were low ( References Soriano LC, Rothenbacher D, Choi HK, Rodriguez LAG. Arthritis Res Ther. 2011;13:R39-47. Zhang W, Doherty M, Pascual E et al. Ann Rheum Dis 2006;654:1301-1311. Roddy E, Doherty M. Arthritis Res Ther. 2010;12:223-233. Acknowledgements This study was funded by AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest J. Nuevo Employee of: AstraZeneca, F. Nyberg Employee of: AstraZeneca, L. Horne: None declared, R. Morlock Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, L. Aiyer Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, D. Hines Employee of: IMS Health, X. Ansolabehere Employee of: IMS Health, P. Chevalier Employee of: IMS Health

Background Previous studies have shown that long-term urate-lowering therapy is required for improvements in gout flare frequency and tophi reduction, and that lower serum uric acid (sUA) levels may result in greater benefit. However, optimal sUA levels to jointly achieve these outcomes within a year using single or combination oral therapies are uncertain. Objectives To assess the impact of sustained sUA lowering to determine if the magnitude of continual low sUA levels results in greater tophus size reduction and fewer patients experiencing gout flares requiring treatment (GFRT). Methods Patients, irrespective of treatment assignment, were combined from 3 Phase III clinical studies examining the efficacy of lesinurad, a selective uric acid reabsorption inhibitor (SURI), in combination with a xanthine oxidase inhibitor (allopurinol: CLEAR 1 [NCT01510158], CLEAR 2 [NCT01493531]), or febuxostat: CRYSTAL [NCT01510769]). For this analysis, GFRTs were assessed during the last quarter of study treatment (end of Month 9 to end of Month 12) and reduction in target tophus area (measured using Vernier calipers) was assessed over the duration of the study. Patients were categorized by on-study median sUA levels of ≥6, 5– Results In total, 1537 patients were eligible for analysis; 95% were male, 78% were white, and mean (SD) age was 42 (11) years. A total of 474 patients (30.8%) had ≥1 target tophi that were followed in the studies. A positive relationship between lower sUA and greater tophus area reduction and GFRT was observed. In patients with ≥1 target tophi at baseline in the 3 studies, those with lowest on-study median sUA levels achieved greatest reduction in tophus area (Fig. 1A). Patients with median sUA Similarly, those with lower sUA levels were less likely to have GFRT. During the last quarter of the study, 12.2% with median sUA Conclusions These findings demonstrate that degree of clinical benefit (reduction in GFRT or tophus area) within 12 months correlates with the magnitude of sustained sUA lowering using oral sUA-lowering therapy. The results provide additional confirmation of the validity of sUA lowering as a surrogate for clinically meaningful effects in gout patients and point to potential benchmarks. In this context, patients with median sUA Acknowledgements This study was funded by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and was funded by AstraZeneca. Disclosure of Interest R. Terkeltaub Consultant for: Ardea Biosciences, AstraZeneca, Takeda, Relburn, REVIVE, F. Perez-Ruiz Consultant for: Menarini, AstraZeneca, Pfizer, Speakers bureau: Menarini, AstraZeneca, Pfizer, C. Storgard Shareholder of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., J. Kopicko Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group., N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, Novartis, Speakers bureau: Savient, Menarini, Novartis, Teijin, and Advisory Boards for AstraZeneca, Fonterra, Takeda, Pfizer, Metabolex

Background Lesinurad (LESU; RDEA594) is a selective uric acid reabsorption inhibitor (SURI) being investigated for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI). Objectives LIGHT is a multinational randomized, double-blind, placebo-controlled, 6-month phase III clinical trial to determine the efficacy and safety of LESU 400mg monotherapy in patients intolerant to an XOI (NCT01508702). Methods Gout patients with intolerance/contraindication to XOI and serum uric acid (sUA) ≥6.5 mg/dL were randomized to LESU (400mg oral, once daily) or placebo (PBO). The primary endpoint was the proportion of patients with sUA Results Patients (LESU, 107; PBO, 107) were primarily white (81.8%) and male (91.1%) with mean ± SD age of 54.4±12.3 years, 11.2±8.7 years since gout diagnosis, 6.2±7.3 gout flares in past 12 months, tophi (25% of patients), renal impairment (58.9% with estimated creatinine clearance [eCrCL] Conclusions In this multinational study of gout patients with high sUA and intolerance/contraindication to an XOI, nearly one third of patients treated with LESU 400 mg achieved sUA Acknowledgements Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest A.-K. Tausche Consultant for: Menarini, Ipsen, Novartis, Savient, AstraZeneca, Speakers bureau: Menarini, Ipsen, Novartis, Savient, AstraZeneca, R. Alten Grant/research support from: AstraZeneca, N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, Novartis, Consultant for: AstraZeneca, Fonterra, Takeda, Metabolex, Speakers bureau: Savient, Menarini, Novartis, Takeda, J. Kopicko Employee of: Ardea Bisociences, Inc., a member of the AstraZeneca group, N. Bhakta Employee of: Ardea Bisociences, Inc., a member of the AstraZeneca group, C. Storgard Employee of: Ardea Bisociences, Inc., a member of the AstraZeneca group, S. Baumgartner Employee of: Ardea Bisociences, Inc., a member of the AstraZeneca group, K. Saag Grant/research support from: Ardea/AstraZeneca, Crealta, Takeda, Consultant for: Amgen, Ardea/AstraZeneca, CORONA, Crealta

Background Lesinurad (RDEA594) is a selective uric acid reabsorption inhibitor (SURI) being investigated for treatment of gout in combination with xanthine oxidase inhibitors. Objectives Investigate the efficacy and safety of lesinurad in combination with allopurinol (ALLO) in gout patients with inadequate response to standard of care (SOC) ALLO dosing (NCT01510158). Methods CLEAR 1 was a 12-month, randomized, double-blind, US phase III trial to evaluate lesinurad (200 mg or 400 mg oral, qd) in combination with ALLO vs ALLO+placebo (PBO). Patients were ages 18-85 yrs on stable, medically appropriate SOC ALLO doses ≥300 mg (≥200 mg in moderate renal impairment), as determined by investigator, with serum uric acid (sUA) ≥6.5 mg/dL at screening and ≥2 gout flares in prior 12 months. Primary endpoint was proportion of patients meeting sUA target of Results Patients (N=603) were primarily male (94.0%), mean ± SD age was 51.9±11.3 yrs, and duration since gout diagnosis was 11.8±9.4 yrs. Most patients (90.5%) received ALLO 300 mg (range: 200-600 mg) daily; 14.3% had tophi at screening (measurable target tophi at baseline, 9.0%) and baseline sUA was 6.94±1.27 mg/dL. Lesinurad at both doses in combination with ALLO significantly increased proportions of patients achieving sUA targets ( Conclusions Significantly greater proportions of patients responded to addition of lesinurad (200 or 400 mg), with approximately twice as many achieving sUA target at 6 months compared with patients treated with ALLO+PBO. Lesinurad was generally well tolerated, particularly at 200 mg, where AE profile was comparable to ALLO+PBO, with the exception of higher incidence of reversible 2.0x sCr elevations. Combination therapy with lesinurad+ALLO may represent a future option for gout patients who warrant additional therapy. Acknowledgements Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest K. Saag Grant/research support from: Ardea, Crealta, Takeda, Consultant for: Ardea/AstraZeneca, Takeda, D. Fitz-Patrick Grant/research support from: Takeda, CymaBay Therapeutics, Ardea, J. Kopicko Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, N. Bhakta Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, S. Adler Employee of: AstraZeneca Pharmaceuticals, C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, S. Baumgartner Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, M. Becker Consultant for: Ardea /AstraZeneca, BioCryst, Metabolex, Savient, Takeda, Pfizer

Background Gout is a common inflammatory arthritis and its worldwide prevalence is increasing. Serum urate (sUA) levels, tophi and flares have been associated with increasing disease burden among patients with gout. Objectives In a cohort of patients treated with xanthine oxidase (XO) inhibitors assess the relationship between sUA, flares, tophi, treatment duration and identify characteristics of patients with high levels of disease activity and impairment (patients with sUA > 6, multiple flares and tophi) despite active treatment. Methods Data were assessed from a quantitative survey of US physicians. Laboratory and clinical data were confirmed through chart audits using a structured case report form created by Bio-Trends. The sample was restricted to patients treated with XO inhibitor urate lowering therapy (ULT). Physician type (rheumatologist vs. primary care physician [PCP]), patient socio-demographics factors, flare rates (treatment and non-treatment related), treatment duration and time since initial diagnosis were recorded. Descriptive statistics were used to describe the relationship between sUA, flares, tophi, treatment duration and identify characteristics of patients with sUA > 6, multiple flares (2+) flares and tophi. Comorbidities were captured using chart review and analyzed as present or absent. A multivariate model was used to assess the impact of patient, clinician, and treatment variables on patients with dependent variable being patients who had sUA > 6, multiple flares, and tophi. Results The sample included 125 rheumatologists and 124 PCPs. Of the 1,245 patients with gout, 858 (69%) were treated with a XO inhibitor: 621 (72.4%) were treated with allopurinol and 237 (27.6%) were treated with febuxostat. Average sUA was positively correlated with tophi (r=0.18; p 6, multiple flares and tophi. These patients were more likely to be treated by a rheumatologist (69%) and had more comorbid conditions. A multivariate model controlling for patient and clinical covariates identified being treated by a rheumatologist (OR 1.62; p=0.03), use of febuxostat (OR 1.63; p=0.03), comorbid alcoholism (OR 2.62; p 6, multiple flares and tophi. For patients treated with allopurinol the average daily dose was approximately 300 mg per day and there was no difference in dosing by sUA level (p=0.9). Image/graph Conclusions In patients with gout, sUA levels were positively correlated with number of flares experienced in a 12 month period and the presence of tophi and negatively correlated with time on treatment. Patients with sUA > 6, multiple flares, and tophi were more likely to have comorbidities that limit treatment options. Disclosure of Interest P. Khanna Speakers bureau: Takeda, S. Baumgartner Employee of: Ardea Biosciences, D. Khanna Consultant for: Savient, Takeda and Ardea Biosciences, Speakers bureau: Savient, C. Storgard Employee of: Ardea Biosciences, R. Morlock Employee of: Ardea Biosciences

Background Allopurinol is the most commonly used urate lowering therapy in the world. Although allopurinol is EMEA authorized for up to 900 mg per day, the majority of patients receive 300 mg per day or less. Objectives To describe physician, patient and treatment characteristics in patients with gout treated with allopurinol. Methods Data from a quantitative survey of physicians were assessed and results confirmed through chart audits. Initial and current dose of allopurinol, presence of co-morbid conditions, use of prophylaxis for flare prevention, serum uric acid (sUA), physician subspecialty and patient factors were evaluated. Data on achieving target sUA were also collected. Results are presented as proportions or means and standard deviations (SD). Multivariate and descriptive statistics were used to describe patients with sUA ≤ 6 mg/dL. Results 126 rheumatologists and 126 primary care physicians were interviewed. Of 1260 patients, 816 (65%) were treated with allopurinol. Patient characteristics, treatment and percent with a sUA≤ 6 mg/dL are presented in Table 1. Across all countries, majority of patients were treated with 300mg or less of allopurinol per day. Less than 6.5% in France, Germany and Spain were given > 300mg whereas 10% in Italy and 34% in the UK achieved a daily dose above 300mg (p Image/graph Conclusions Allopurinol is the most widely used urate lowering therapy. Although it is approved for up to 900 mg the majority of patients are treated with 300mg or less per day. Less than 50% of patients achieve sUA Disclosure of Interest J. Singh Consultant for: URL pharmaceuticals, Savient, Takeda, Ardea, Regeneron, Allergan and Novartis, C. Storgard Employee of: Ardea Biosciences, S. Baumgartner Employee of: Ardea Biosciences, R. Morlock Employee of: Ardea Biosciences

Background Gout is a common inflammatory arthritis and its worldwide prevalence is increasing. EULAR and ACR Guidelines recommend a target serum urate (sUA) ≤ 6 mg/dL. For patients with significant crystal burden, sUA may need to be driven lower to reduce flares and decrease tophi as recommended by the ACR guidelines (2011). Objectives To describe physician, patient and treatment characteristics in patients treated with xanthine oxidase inhibitor (XOI) therapy that achieve sUA ≤ 6 mg/dL yet have 2 or more physician confirmed gout flares per year. Methods Data were assessed from a survey of US physicians about gout disease management. Patient results were confirmed through in-depth chart audits assessing diagnosis, comorbid conditions, disease severity and laboratory assessments. Disease severity was measured using a physician global assessment (mild, moderate or severe), flare counts, joint damage and presence of tophi. Type and dose of XOI, length of current treatment, compliance, physician type and patient socio-demographics factors were identified. Comorbidities were captured using chart review and analyzed as present or absent. Descriptive and multivariate statistics were used to describe patients having more than 2 flares per year (excluding treatment initiation flares) in patients achieving sUA ≤ 6 mg/dL. Results 125 rheumatologists and 124 primary care physicians were interviewed. Of 1245 patients with gout, 81% were male and the average age was 57 (sd=13). 858 (69%) patients were treated with an XOI inhibitor[others were not treated (29%) or treated with non-XOI(2%)], of these 355 (42%) had a least one assessment sUA ≤ 6 mg/dL. Of the 355 patients reaching sUA target, 122 (34%) reported 2 or more flares in the last year. On average, patients with 2 or more physician confirmed flares were treated for 36.8 months on their current ULT and patients with 1 or no flares were treated for 37.2 months (p=0.9). Patients reporting 2 or more flares a year were more likely to have tophi (31% vs. 19%; p Conclusions Less than 50% of patients treated with a XOI inhibitor alone reached sUA target. Of the patients achieving a sUA level of ≤ 6 mg/dL, over a third reported 2 or more flares in a 12-month period. Patients with multiple flares were more likely to have higher urate burden, chronic kidney disease and other comorbid conditions. Frequent flares and greater tophaceous burden may require treating to a sUA level of 5 mg/dL or lower as recommended by the ACR guidelines. Disclosure of Interest D. Khanna Consultant for: Savient, Takeda and Ardea Biosciences, Speakers bureau: Savient, P. Khanna Speakers bureau: Takeda, C. Storgard Employee of: Ardea Biosciences, S. Baumgartner Employee of: Ardea Biosciences, R. Morlock Employee of: Ardea Biosciences

2503 Background: BIIB021 is an oral fully synthetic Hsp90 inhibitor that is being developed for both solid and hematologic tumors. BIIB021 selectively and potently inhibits the molecular chaperone ...

3563 Background: Change in tumor size is commonly used as a surrogate endpoint for clinical outcome. Measurement of tumor volume, the gold standard for determining tumor size, is not clinically practical. The 2 most commonly used measurements of tumor size ie, longest diameter in axial plane (LD, used in RECIST) and cross product (CP) of LD and the longest perpendicular dimension in axial plane (used in WHO), are surrogates for tumor volume and assume simple tumor geometry. Since most tumors grow and regress irregularly, we determined which of these measurements most accurately reflects change in tumor volume by comparing change in tumor volume calculated using LD or CP with change in measured tumor volume. Methods: Computed tomography (CT) scans of the chest, abdomen, and pelvis were acquired at baseline and 8-week intervals during treatment in 22 patients (pts) enrolled in 2 first-in-human (FIH) clinical trials. CT scans were analyzed by a central reader to obtain LD, CP, and tumor volume. LD (assuming spherical tumor geometry) or CP (assuming spherical or elliptical tumor geometry) was used to calculate volume. The mean bias (μ: mean difference between measured and calculated percent change in tumor volume from baseline [%ΔVol]) and limits of agreement (μ ± 2s [s = standard deviation of difference]) from Bland-Altman analyses (used for assessing agreement between 2 measurement methods) were used for comparisons between measured and calculated %ΔVol. A nested effects model (tumor lesions considered as nested within pts) was used to test significance of differences between measured and calculated %ΔVol. Results: Bland-Altman analyses showed that μ ± 2s was -5% ± 70% for LD, 5% ± 38% for CP (spherical), and 7% ± 33% for CP (elliptical). Nested analyses indicated consistent results with an observed significant difference (p-value = 0.02) between measured and calculated %ΔVol using LD and non-significant differences (p-values = 0.28 and 0.05) using CP (assuming elliptical and spherical geometry respectively). Conclusions: In this diverse FIH population, 2-dimensional tumor measurements (using CP) are better than 1-dimensional tumor measurements (using LD) in representing changes in tumor volume and should decrease noise in the measurement of treatment response. No significant financial relationships to disclose.

14033 Introduction: AMG 386 is a selective angiopoietin 1 /2-neutralizing peptibody that inhibits angiogenesis by preventing interaction between angiopoietins and Tie2 receptors. This open-label study evaluated the safety, pharmacokinetics (PK), and antitumor activity of AMG 386 in combination with FOLFOX-4 (F), carboplatin + paclitaxel (CP), or docetaxel (D) in adult patients (pts) with advanced solid tumors. Methods: Three cohorts of 6–9 pts received 1 full cycle of chemotherapy (2 weeks of F or 3 weeks of D 75 mg/m2 or CP). Administration of AMG 386 10 mg/kg IV weekly was started on day 1 of cycle 2 for patients who did not experience a dose-limiting toxicity (DLT) to chemotherapy during cycle 1, and continued until disease progression or intolerance. Safety and tolerability, tumor response (RECIST every 8 weeks), PK profiles of AMG 386 and chemotherapy agents, and formation of antibodies to AMG 386 were assessed. Results: As of October 2, 2006, 16 pts have received AMG 386: 6 pts in the F cohort, 5 in CP, and 5 in D; 7 pts were men, median age 59.5 years (range, 44- 75 years). No AMG 386-related serious AEs or DLTs were reported. AEs related to chemotherapy + AMG 386 in = 2 pts were neutropenia (n = 3), thrombocytopenia (n=2), diarrhea (n=2), and vomiting (n=2). No neutralizing antibodies were observed. F, CP, and D coadministered with AMG 386 did not appear to affect the PK profile of AMG 386, and AMG 386 had no apparent effect on the PK profile of 5 FU, leucovorin, C, P, or D. Tumor response data are available for 6 pts. One pt receiving CP+ AMG 386 for bladder cancer refractory to gemcitabine/cisplatin had a complete response (CR) at week 8, confirmed at week 16. Stable disease in 4 pts and progressive disease in 1 pt were also observed. Conclusions: Weekly administration of AMG 386 in combination with F, CP, or D appears to be safe and well tolerated. A CR in bladder cancer suggests promising antitumor activity of AMG 386 in combination with chemotherapy. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted. [Table: see text]

3522 Introduction: AMG 386 is a selective angiopoietin1/2-neutralizing peptibody that inhibits angiogenesis by preventing interaction of angiopoietins with Tie2 receptors. This first-in-human study evaluated the safety, pharmacokinetics (PK), and tumor response of AMG 386 in adults with advanced solid tumors. Methods: Patients (pts) in sequential cohorts received weekly IV AMG 386 at 0.3, 1, 3, 10, and 30 mg/kg. Safety assessments were adverse events (AEs), laboratory data, vital signs, ECGs, and anti-AMG 386 antibodies. Tumor response was assessed via RECIST criteria, DCE-MRI, FDG-PET, and volumetric CT. Results: As of Oct. 2, 2006, enrollment is complete with 32 pts (15 men, mean [SD] age 58 [12] years). One dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest likely related to tumor burden, deemed possibly related to AMG 386. Other treatment-related toxicities were all = Grade 2; those observed in = 2 pts were fatigue (n=8), nausea (n=2), and peripheral edema (n=4). PK was dose-linear (mean terminal half-life, 3.1 to 6.3 days). AMG 386 appeared to reach a steady state after 3 doses, with minimal accumulation. Two pts developed binding antibodies to AMG 386; in 1 pt, they disappeared at wk 6. No neutralizing antibodies were seen. Sixteen pts had stable disease (4–52 wks, median 8 wks); 13 had progressive disease; 3 were not evaluable. One pt with ovarian cancer remains active at 52 weeks with 27% tumor shrinkage and investigator-reported reduction in serum CA-125 from 217 U/ml pretreatment to 73 U/ml (wk 4) and 31 U/ml (wk 48). A significant vascular effect (> 20% reduction) was seen by DCE-MRI in 7 of 12 (58%) evaluable subjects. Reduction in SUVmax (FDG-PET) accompanied reduction in IAUC (DCE-MRI) in 5 of 6 evaluable patients. Conclusions: Weekly administration of AMG 386 appeared to be generally well tolerated, with 1 AE > Grade 2 and no reports of the toxicities associated with VEGF blockade (hypertension, proteinuria, bleeding/clotting). Half of pts experienced stable disease; 1 has a sustained minor clinical response accompanied by a biologic response. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted. No significant financial relationships to disclose.

ObjectivesAllopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated allopurinol, particularly at doses >300mg/d. The objective of this open-label study was to investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses.MethodsLong-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate allopurinol doses to achieve target sUA < 6.0mg/dL. The primary objective was evaluation of the safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits. Secondary objectives included sUA-lowering efficacy and gout flare frequency.ResultsOf 1735 patients enrolled, 1732 received ≥1 allopurinol doses. The maximal daily allopurinol dose during study was 300mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving >300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the 300-mg categories, respectively. Rash incidence was low (1.5%) and allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA < 6.0mg/dL at month 6 was achieved by 35.9% of patients overall: 22.4%, 35.0%, and 48.3% in dosing categories 300mg, respectively.ConclusionsThis large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA.

The present study aimed to assess disease control, health resource utilization (HRU), and healthcare costs, and their predictors in gout patients across the USA, UK, Germany, and France.Data were extracted from the PharMetrics Plus (USA), Clinical Practice Research Datalink-Hospital Episode Statistics (UK), and Disease Analyzer databases (Germany and France) for adult gout patients over a 3-year period: 2009-2011 (all dates +1 year for France). Patients had "prevalent established gout" (i.e., were treated with urate-lowering therapy [ULT] or eligible for ULT based on American College of Rheumatology guidelines) in the preindex panel-year, with January 1 of the second study year as the study index date. Assessments of disease control (uncontrolled gout definition: ≥1 serum urate (sUA) elevation or ≥2 flares; analysis limited to the subpopulation with sUA) data, HRU, and costs were in the second post-index panel-year, while potential predictors (demographics and gout treatment characteristics) were identified in the first post-index panel-year.Treatment rates were high (70% with chronic urate-lowering treatment in all countries but France), while between 31.3% (France) and 62.9% (USA) of patients remained uncontrolled. Predictors of control included female gender and high adherence. In Germany, the UK, and France, lack of disease control predicted increased gout-attributed costs and increased HRU, both gout-attributed (also in the USA) and non-gout-attributed.Gout management remains suboptimal, as many patients remain uncontrolled despite using urate-lowering treatment. Effective and convenient treatment options are needed to improve disease control and minimize additional HRU and costs.AstraZeneca.