Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of HZBio1 in Chinese Healthy Subjects: A Randomized Phase 1a Study.

INTRODUCTION: Polyethylene glycol-modified (PEGylated) recombinant uricase is a promising guideline-recommended treatment for hyperuricemia and gout. This first-in-human, single ascending dose, phase 1a trial evaluated the tolerability, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of HZBio1 in Chinese healthy subjects. METHODS: The present study enrolled healthy subjects (aged 18-45 years) between March 8, 2021 and January 14, 2022. Thirty subjects were randomly assigned into 5 HZBio1 cohorts (6 per dose cohort) following the dose escalation scheme, and 10 received placebo. Each subject received a single dose of HZBio1 (in the range 0.96-12 mg) or placebo, by intramuscular injection. RESULTS: All treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity during a 35-day follow-up period. The TEAEs and drug-related TEAEs incidences were 76.7% versus 60.0% and 73.3% versus 60.0% in the HZBio1 and placebo cohorts, respectively. HZBio1 exposure increased in a greater than dose-proportional manner following single-dose administration across the 3- to 12-mg range. Plasma uric acid levels decreased following a single dose of HZBio1 and reached the nadir at 144-192 h. The reduction in uric acid concentration was most pronounced in the 9- to 12 mg HZBio1 cohorts. HZBio1 administration elicited low-titer anti-PEG (IgG, IgM) antibodies, whereas antidrug antibodies were rarely detected, and no subjects developed neutralizing antibodies. CONCLUSION: HZBio1 at doses of 3-12 mg was well tolerated in healthy subjects, had an acceptable pharmacokinetics profile, and promising urate-lowering effect. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04765995.