Background/Purpose: Pegloticase is a pegylated recombinant mammalian uricase approved for treatment of persons with chronic gout refractory to standard urate lowering therapy¹. Despite an initial profound reduction of serum urate, some patients may lose the urate-lowering effect of pegloticase owing to the development of anti-drug antibodies². The TRIPLE trial was undertaken to determine whether 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 and a more persistent urate lowering effect.

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

Results: Results are available for 50 subjects. There were 22 responders (44%), 21 nonresponders (42%) and 7 subjects who dropped out (14%). Responders had significantly higher trough levels of pegloticase than nonresponders 1 week after the initial infusion (Figure) that persisted throughout the trial. Pegloticase levels at 1 week post infusion predicted responsiveness. Fourteen of 19 subjects (73.7%) with trough pegloticase levels >1.22 mg/mL at 1 week were responders to treatment whereas only 6 of 19 patients (31.6%) with trough levels £1.22 mg/mL at 1 week were responders (Chi square test with continuity correction, P=0.023).

Conclusion: To date, the TRIPLE strategy of adding an additional tolerizing dose of pegloticase between the first and second biweekly administrations showed an overall response rate of 44%. Pegloticase serum levels after the initial dose may predict subsequent persistent responsiveness and provide guidance regarding adjustment/continuation of treatment.

References

1.    Sundy JS, et al. JAMA. 2011;306:711.

2.    Lipsky PE, et al. Arth Res Ther. 2014;16:R60.

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