Efficacy and safety of PEGylated uricase in healthy adults and patients with hyperuricaemia: A phase I, randomized, double-blind, dose-escalation, placebo-controlled trial.

AIMS: This Phase I trial aimed to evaluate the tolerability, pharmacokinetics, pharmacodynamics (PK/PD), and immunogenicity of PEGylated uricase (PEG-UOX) in healthy adults and patients with hyperuricaemia.

METHODS

A total of 48 subjects-24 healthy adults and 24 patients with hyperuricaemia-were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation study. Participants received a single intravenous dose of PEG-UOX ranging from 0.5 to 8 mg. A sentinel dosing design was employed to allow for initial safety evaluation before dose escalation. Blood and urine samples were collected over a 21-day follow-up period to assess uric acid and allantoin levels. Safety was continuously monitored throughout the study.

RESULTS

PEG-UOX administration led to marked reductions in serum uric acid levels in both healthy and hyperuricaemic subjects, with the greatest efficacy observed in hyperuricaemic patients receiving the 8 mg dose. Urinary excretion of uric acid decreased, while allantoin levels increased, confirming the uricolytic activity of PEG-UOX. Immunogenicity analysis revealed a higher incidence of anti-PEG antibodies in healthy subjects than in patients with hyperuricaemia, suggesting differential immune responses. No serious adverse events (SAEs) were reported; most treatment-emergent adverse events were mild in severity, including transient, asymptomatic ST-T changes and Ventricular Premature Contractions(VPCs) classified as mild (Grade 1) by independent cardiologists.

CONCLUSIONS

PEG-UOX demonstrated favourable pharmacokinetics, urate-lowering effects, and tolerability over a 21-day observation period in both healthy adults and patients with hyperuricaemia. Its uricolytic mechanism offers a promising therapeutic alternative for managing hyperuricaemia, particularly in cases refractory to conventional urate-lowering therapies.

TRIAL REGISTRATION: Clinical trials, NCT05226013 (Registered 2 April 2022, retrospectively registered). ChinaDrugTrials (www.chinadrugtrials.org.cn), CTR20211801 (registered 27 July 2021).