Efficacy and Tolerability of Pegloticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment

Sundy, John S.; Baraf, Herbert S. B.; Yood, Robert A.; Edwards, N. Lawrence; Gutiérrez‐Ureña, Sergio; Treadwell, Edward L.; Vázquez‐Mellado, Janitzia; White, William Β.; Lipsky, Peter E.; Horowitz, Zeb; Huang, Wen; Maroli, Allan N.; Waltrip, Royce W.; Hamburger, Steven A.; Becker, Michael A.

doi:10.1001/jama.2011.1169

Cited by 422 publications

(296 citation statements)

References 33 publications

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“…The clinical benefits and risks of these very low serum urate levels are currently uncertain. Although both clinical trial data and observational studies have shown benefit in flare reduction and tophus regression with very low serum urate concentrations 16, 23, the European League Against Rheumatism has recommended against lowering UA to these levels for more than several years 2.…”

Section: Discussionmentioning

confidence: 99%

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Dalbeth

Jones

Terkeltaub

et al. 2017

Arthritis & Rheumatology

131

137

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ObjectiveTo investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12‐month phase III trial in patients with tophaceous gout.MethodsPatients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate‐lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data.ResultsPatients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg.ConclusionTreatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy.

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Section: Discussionmentioning

confidence: 99%

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Dalbeth

Jones

Terkeltaub

et al. 2017

Arthritis & Rheumatology

131

137

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“…Other qualitative and quantitative studies have covered an even wider range of gout-related issues including treatment, knowledge, disease monitoring, outcomes and patient and clinician perspective within each study [24,25,42]. The emergence of clinical trial and survey data showing QOL deficits in gout patients [18-23] indicates that we need a better understanding of the patient perspective of the impact of gout on their lives.…”

Section: Discussionmentioning

confidence: 99%

“…Gout has a significant negative effect on patient’s quality of life (QOL) [18-21] and effective treatment improves QOL [22,23]. Therefore, it is critical to understand the specific impact of gout on patients’ lives.…”

Section: Introductionmentioning

confidence: 99%

The impact of gout on patient’s lives: a study of African-American and Caucasian men and women with gout

Singh

2014

Arthritis Res Ther

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IntroductionThe aim of this study was to examine the impact of gout on quality of life (QOL) and study differences by gender and race.MethodsTen race- and sex-stratified nominal groups were conducted, oversampling for African-Americans and women with gout. Patients presented, discussed, combined and rank-ordered their concerns.ResultsA total of 62 patients with mean age 65.1 years, 60% men, 64% African-American, participated in 10 nominal groups: African-American men (n = 23; 3 groups); African-American women (n = 18; 3 groups); Caucasian men (n = 15; 3 groups); and Caucasian women (n = 6; 1 group). The most frequently cited high-ranked concerns among the ten nominal groups were: (1) effect of gout flare on daily activities (n = 10 groups); (2) work disability (n = 8 groups); (3) severe pain (n = 8 groups); (4) joint swelling and tenderness (n = 6 groups); (5) food restrictions (n = 6 groups); (6) medication related issues (n = 6 groups); (7) dependency on family and others (n = 5 groups); (8) emotional Impact (n = 5 groups); (9) interference with sexual function (n = 4 groups); (10) difficulty with shoes (n = 4 groups); and (11) sleep disruption (n = 4 groups). Compared with men, women ranked the following concerns high more often: problems with shoes (n = 4 versus n = 0 groups); dependency (n = 3 versus n = 2 groups); and joint/limb deformity (n = 2 versus n = 0 group). Compared with Caucasians, African-Americans ranked the following concerns high more often: dietary restrictions (n = 6 versus n = 0 groups); severe pain (n = 6 versus n = 2 groups); gout bringing the day to a “halt” (n = 2 versus n = 0 group); effect on emotional health (n = 4 versus n = 1 groups); and the need for canes/crutches during flares (n = 2 versus n = 0 group).ConclusionsGout has a significant impact on a patient’s QOL. Important differences in the impact of gout by gender and race were noted.

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“…Each uricase monomer has been conjugated with 10 ± 1 strands of 10-kDa monomethoxy-PEG (mPEG) to reduce its immunogenicity. [36] However, anti-PEG Abs have been detected since the early phase 1 trial: a single subcutaneous (SC) injection of pegloticase induced the generation of both anti-PEG IgM and IgG Abs in 5 out of 13 patients (38%). [37] These antibodies were associated with the quick drug clearance and three anti-PEG positive subjects had injection-site reactions at 8–9 days post-injection.…”

Section: Anti-peg Abs In the Clinicmentioning

confidence: 99%

“…Several subsequent trials also found high incidence rates of anti-drug antibodies (ADAs), but their specificity was not determined. [36, 39]…”

Section: Anti-peg Abs In the Clinicmentioning

confidence: 99%

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Zhang

Sun

Liu

et al. 2016

Journal of Controlled Release

486

360

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The technique of attaching the polymer polyethylene glycol (PEG), or PEGylation, has brought more than ten protein drugs into market. The surface conjugation of PEG on proteins prolongs their blood circulation time and reduces immunogenicity by increasing their hydrodynamic size and masking surface epitopes. Despite this success, an emerging body of literature highlights the presence of antibodies produced by the immune system that specifically recognize and bind to PEG (anti-PEG Abs), including both pre-existing and treatment-induced Abs. More importantly, the existence of anti-PEG Abs has been correlated with loss of therapeutic efficacy and increase in adverse effects in several clinical reports examining different PEGylated therapeutics. To better understand the nature of anti-PEG immunity, we summarize a number of clinical reports and some critical animal studies regarding pre-existing and treatment-induced anti-PEG Abs. Various anti-PEG detection methods used in different studies were provided. Several protein modification technologies beyond PEGylation were also highlighted.

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Efficacy and Tolerability of Pegloticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment

Abstract: clinicaltrials.gov Identifier: NCT00325195.

Cited by 422 publications

References 33 publications

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

The impact of gout on patient’s lives: a study of African-American and Caucasian men and women with gout

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

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