The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform

Nicola Dalbeth - One of the best experts on this subject based on the ideXlab platform.

  • lesinurad monotherapy in gout patients intolerant to a Xanthine Oxidase Inhibitor a 6 month phase 3 clinical trial and extension study
    Rheumatology, 2017
    Co-Authors: Anne-kathrin Tausche, J. Kopicko, C. Storgard, Maple Fung, Nicola Dalbeth, R Alten, Scott Adler, N Bhakta, Scott Baumgartner, Kenneth G Saag
    Abstract:

    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 <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with lesinurad. A total of 143 patients (65 lesinurad, 78 placebo) enrolled in the extension study. Treatment with lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with lesinurad 400 mg, lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • SAT0313 Relationship Between Sustained Lowering of Serum Urate Levels and Improvements in Gout Flares and Tophus Area: Pooled Exploratory Analysis of Gout Subjects Receiving Lesinurad and Xanthine Oxidase Inhibitor Combination Therapy
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Robert Terkeltaub, J. Kopicko, C. Storgard, Maple Fung, Fernando Perez-ruiz, Nicola Dalbeth
    Abstract:

    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

Fernando Perez-ruiz - One of the best experts on this subject based on the ideXlab platform.

  • Reassessing the Safety Profile of Lesinurad in Combination with Xanthine Oxidase Inhibitor Therapy
    Rheumatology and Therapy, 2019
    Co-Authors: Fernando Perez-ruiz, Tim L. Jansen, Anne-kathrin Tausche, Pascal Richette, Frederic Liote, Austin Stack
    Abstract:

    Introduction The rate of adverse renal events has been shown to be higher in patients treated with lesinurad plus a Xanthine-Oxidase Inhibitor (XOI) than in patients treated only with a XOI. We reassessed the risks for various adverse renal events from a different perspective and devised a hypothesis to explain the results. Methods We used data from phase 3 trials that were publicly available from the full prescribing information document and estimated the relative risk and the number needed to treat for increased serum creatinine (sCri), renal failure, and renal lithiasis. We examined these risks for each treatment group and the risks stratified by estimated glomerular filtration rate (eGFR). Results Overall, the relative risk for sCri was > 1.0 with the 400 mg/day dose of lesinurad and higher with the 200 mg/day dose, but it was

  • Reassessing the Safety Profile of Lesinurad in Combination with Xanthine Oxidase Inhibitor Therapy.
    Rheumatology and therapy, 2019
    Co-Authors: Fernando Perez-ruiz, Anne-kathrin Tausche, Pascal Richette, Frederic Liote, T.l.th.a. Jansen, Austin G Stack
    Abstract:

    The rate of adverse renal events has been shown to be higher in patients treated with lesinurad plus a Xanthine-Oxidase Inhibitor (XOI) than in patients treated only with a XOI. We reassessed the risks for various adverse renal events from a different perspective and devised a hypothesis to explain the results. We used data from phase 3 trials that were publicly available from the full prescribing information document and estimated the relative risk and the number needed to treat for increased serum creatinine (sCri), renal failure, and renal lithiasis. We examined these risks for each treatment group and the risks stratified by estimated glomerular filtration rate (eGFR). Overall, the relative risk for sCri was > 1.0 with the 400 mg/day dose of lesinurad and higher with the 200 mg/day dose, but it was

  • International position paper on the appropriate use of uricosurics with the introduction of lesinurad
    Clinical Rheumatology, 2018
    Co-Authors: Tim L. Jansen, Fernando Perez-ruiz, Anne-kathrin Tausche, Pascal Richette
    Abstract:

    Over the last 70 years, pharmacotherapy in gout with urate-lowering drugs has consisted of four drugs only: In 1952, a mild uricosuric probenecid became available, the Xanthine Oxidase Inhibitor Allopurinol in 1964, and the latter became the most frequently used urate-lowering drug worldwide; in the Eurozone, the uricosuric benzbromarone was welcomed in 1977. Only in 2002, the potent non-purine Xanthine Oxidase Inhibitor febuxostat was introduced. In many countries, uricosurics such as probenecid and benzbromarone have not been available up to now, and these days, the new uricosuric lesinurad is the first uricosuric that may be introduced in these countries, which is the reason for describing the position this novel uricosuric deserves in treating gout. Recent literature will be shortly reviewed, and the current proposed position for lesinurad will be given as an aid for clinicians.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

Yi Dong - One of the best experts on this subject based on the ideXlab platform.

  • in vitro and in vivo studies on adlay derived seed extracts phenolic profiles antioxidant activities serum uric acid suppression and Xanthine Oxidase Inhibitory effects
    Journal of Agricultural and Food Chemistry, 2014
    Co-Authors: Mouming Zhao, Dongxiao Sunwaterhouse, Guowan Su, Xiao Wang, Yi Dong
    Abstract:

    This study aimed to explore the potential of polished adlay, brown adlay, adlay bran, and adlay hull to prevent and treat hyperuricemia. Brown adlay extract effectively decreased the serum uric acid levels of oxonate-induced hyperuricemic rats. Free and bound phenolic extracts from these materials contained significant amounts of phenolics, with free phenolics dominated by chlorogenic acid and p-coumaric acid while bound phenolics dominated by p-coumaric acid and ferulic acid. Free and bound phenolics of adlay bran exhibited significant Xanthine Oxidase inhibition activities, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities, oxygen radical absorbance capacities, and superoxide radical scavenging activities. Adlay bran phenolics could be effective Xanthine Oxidase Inhibitors and radical scavengers. p-Coumaric acid is a Xanthine Oxidase Inhibitor with strong superoxide radical scavenging activity. However, ferulic acid is a Xanthine Oxidase Inhibitor with weak superoxide radical scavenging...

  • in vitro and in vivo studies on adlay derived seed extracts phenolic profiles antioxidant activities serum uric acid suppression and Xanthine Oxidase Inhibitory effects
    Journal of Agricultural and Food Chemistry, 2014
    Co-Authors: Mouming Zhao, Dongxiao Sunwaterhouse, Xiao Wang, Dashuai Zhu, Lianzhu Lin, Yi Dong
    Abstract:

    This study aimed to explore the potential of polished adlay, brown adlay, adlay bran, and adlay hull to prevent and treat hyperuricemia. Brown adlay extract effectively decreased the serum uric acid levels of oxonate-induced hyperuricemic rats. Free and bound phenolic extracts from these materials contained significant amounts of phenolics, with free phenolics dominated by chlorogenic acid and p-coumaric acid while bound phenolics dominated by p-coumaric acid and ferulic acid. Free and bound phenolics of adlay bran exhibited significant Xanthine Oxidase inhibition activities, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities, oxygen radical absorbance capacities, and superoxide radical scavenging activities. Adlay bran phenolics could be effective Xanthine Oxidase Inhibitors and radical scavengers. p-Coumaric acid is a Xanthine Oxidase Inhibitor with strong superoxide radical scavenging activity. However, ferulic acid is a Xanthine Oxidase Inhibitor with weak superoxide radical scavenging activity. Chlorogenic acid is a superoxide radical scavenger with weak Xanthine Oxidase Inhibitory activity.

C. Storgard - One of the best experts on this subject based on the ideXlab platform.

  • lesinurad monotherapy in gout patients intolerant to a Xanthine Oxidase Inhibitor a 6 month phase 3 clinical trial and extension study
    Rheumatology, 2017
    Co-Authors: Anne-kathrin Tausche, J. Kopicko, C. Storgard, Maple Fung, Nicola Dalbeth, R Alten, Scott Adler, N Bhakta, Scott Baumgartner, Kenneth G Saag
    Abstract:

    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 <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with lesinurad. A total of 143 patients (65 lesinurad, 78 placebo) enrolled in the extension study. Treatment with lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with lesinurad 400 mg, lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • SAT0313 Relationship Between Sustained Lowering of Serum Urate Levels and Improvements in Gout Flares and Tophus Area: Pooled Exploratory Analysis of Gout Subjects Receiving Lesinurad and Xanthine Oxidase Inhibitor Combination Therapy
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Robert Terkeltaub, J. Kopicko, C. Storgard, Maple Fung, Fernando Perez-ruiz, Nicola Dalbeth
    Abstract:

    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

Maple Fung - One of the best experts on this subject based on the ideXlab platform.

  • lesinurad monotherapy in gout patients intolerant to a Xanthine Oxidase Inhibitor a 6 month phase 3 clinical trial and extension study
    Rheumatology, 2017
    Co-Authors: Anne-kathrin Tausche, J. Kopicko, C. Storgard, Maple Fung, Nicola Dalbeth, R Alten, Scott Adler, N Bhakta, Scott Baumgartner, Kenneth G Saag
    Abstract:

    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 <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with lesinurad. A total of 143 patients (65 lesinurad, 78 placebo) enrolled in the extension study. Treatment with lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with lesinurad 400 mg, lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • THU0537 Clinical Response of Tophus and Flares To Extended Use of Lesinurad in Combination with A Xanthine Oxidase Inhibitor in Patients with Gout
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Thomas Bardin, C. Storgard, Maple Fung, Robert Terkeltaub, J. Hu, Nicola Dalbeth, Fernando Perez-ruiz
    Abstract:

    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.

  • SAT0313 Relationship Between Sustained Lowering of Serum Urate Levels and Improvements in Gout Flares and Tophus Area: Pooled Exploratory Analysis of Gout Subjects Receiving Lesinurad and Xanthine Oxidase Inhibitor Combination Therapy
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Robert Terkeltaub, J. Kopicko, C. Storgard, Maple Fung, Fernando Perez-ruiz, Nicola Dalbeth
    Abstract:

    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