Background/Purpose: Pegloticase is a pegylated recombinant mammalian uricase approved for treatment of persons with chronic gout refractory to standard urate lowering therapy¹. Despite initial reduction of serum urate (sUA) to near 0 mg/dL, patients may lose the urate lowering effect of pegloticase owing to the development of anti-drug antibodies (ADA)², and as a result, only 42% of treated subjects had sustained urate lowering in the registration trials¹. In the absence of stopping rules, infusion reactions (IRs) occurred in 26% of patients in the biweekly dosing regimen compared to 5% of placebo-treated patients. Gout flares occurred in 74% of pegloticase treated subjects in the first 3 months of treatment compared with 51% receiving placebo. Examination of pegloticase pharmacokinetics (PK)² indicated that the biweekly regimen may not maintain high levels of drug during the first month of therapy, possibly contributing to the immunogenicity of pegloticase. PK modelling suggested that an additional dose of 8 mg of pegloticase 1 week after the initial dose and 1 week before the subsequent dose might be sufficient to maintain high serum pegloticase levels and contribute to the development of high zone tolerance with decreased ADA. The TRIPLE (Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect, NCT02598596) was designed to address this question.

Methods: is was a multi-center open label trial enrolling subjects with chronic gout whose sUA was not maintained at 6mg/dL or below. Background urate lowering therapy was discontinued and subjects were treated with 3 weekly doses of 8mg pegloticase followed by biweekly administration of 8 mg of pegloticase for a total of 10 doses over 17 weeks. SUA was measured immediately before each dose. After the first administration, dosing was only permitted if the sUA was 6 mg/dL or less. Standard infusion prophylaxis and gout flare prophylaxis was required. The primary outcome was the maintenance of sUA at 6 mg/dL or less throughout the treatment period.

Results: 47 subjects have been enrolled with a mean age of 62.0+/- 15.4 years, and BMI 0f 30.0+/-4.5. Subjects have received a total of 282 infusions to date. There has been a total of 2 IRs, both in the same subject (2.1% of subjects with IRs, 0.7% of infusions with IRs). None of these IRs met criteria of anaphylaxis and were thought to be mild/moderate. There have been 5 serious adverse events in 3 subjects, 4 of which were felt to be unrelated to pegloticase and 1 of which was a gout flare. A total of 24 subjects (51.1%) experienced gout flares with each experiencing a mean of 2.2 flares. A total of 5 (10.6%) discontinued treatment before completion of the study. Of the 36 subjects who have completed the treatment regimen, 19 (52.8%) were persistent responders.

Conclusion: The tolerization regimen of pegloticase treatment appears to improve outcomes and is well tolerated. Few IRs were noted as administration of pegloticase was avoided in those with a sUA > 6mg/dL . The tolerization regimen may also be associated with a somewhat higher frequency of subjects achieving a persistent urate lowering effect.

1. Sundy JS et al JAMA 2011,306:711-720
2. Lipsky, PE et al Arth Res Ther 2014, 16:R60

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/initial-results-of-a-clinical-study-to-determine-whether-a-tolerizing-regimen-of-pegloticase-can-increase-the-frequency-of-subjects-having-sustained-lowering-of-serum-urate/