Gout is one of the most common inflammatory joint diseases worldwide, driven by chronically elevated levels of urate in the blood. When urate crystallizes in joints and soft tissues, it triggers excruciating attacks of arthritis and, over time, can produce tophi, the disfiguring deposits of urate crystals that characterize advanced disease. Most patients are managed with oral medications such as allopurinol or febuxostat, which reduce urate production, or uricosuric agents that increase its excretion through the kidneys. But a substantial minority of patients cannot reach target urate levels with these drugs, cannot tolerate them, or carry contraindications such as severe kidney impairment. For these individuals, guidelines in China, Europe, and elsewhere recognize an alternative approach: replacing the enzyme that humans lack.

Humans, unlike most other mammals, do not possess functional uricase, the enzyme that converts uric acid into the far more soluble compound allantoin, which is readily excreted by the kidneys. This evolutionary loss of uricase is thought to have been advantageous in our primate ancestors, possibly because uric acid acts as an antioxidant and may have helped maintain blood pressure on ancient low-salt diets. The trade-off is that humans are uniquely vulnerable to hyperuricemia. Recombinant uricase therapy restores the missing enzymatic activity pharmacologically. Rasburicase, a non-PEGylated uricase, is already used to prevent tumor lysis syndrome in oncology, while pegloticase, a PEGylated mammalian uricase, is approved for chronic refractory gout. PEGylation, the attachment of polyethylene glycol chains to a protein, extends the drug’s half-life and shields it from rapid immune clearance, but it also introduces its own immunological complications, since many people carry pre-existing antibodies against polyethylene glycol itself.

HZBio1, developed by Hangzhou Grand Biologic Pharmaceutical, is a PEGylated recombinant uricase produced in Escherichia coli. Each active enzyme molecule is a homotetramer, a four-subunit assembly in which every monomer consists of 298 amino acids. Lysine residues on the surface of the tetramer serve as convenient attachment points for polyethylene glycol modification, allowing the drug to be manufactured with a consistent architecture. The design goal is familiar to anyone following the biologics field: retain the catalytic power of the bacterial enzyme while disguising it long enough to circulate and work, and ideally with less immunogenicity than existing PEGylated uricases.

To test that concept, investigators at Peking Union Medical College Hospital in Beijing enrolled 40 healthy volunteers aged 18 to 45 years between March 2021 and January 2022. Thirty participants were randomly assigned to five dose-escalation cohorts of six subjects each, while ten received placebo. Every subject received a single intramuscular injection of either HZBio1, at doses ranging from 0.96 to 12 milligrams, or placebo. The trial was registered with ClinicalTrials.gov under identifier NCT04765995 and approved by the hospital’s ethics committee for drug clinical trials, and all participants provided written informed consent. The study followed each subject for 35 days after dosing, tracking safety, drug concentrations in plasma, uric acid dynamics, and antibody responses.

The safety picture was reassuring, if not entirely free of signals. Treatment-emergent adverse events occurred in 76.7 percent of HZBio1 recipients compared with 60.0 percent of placebo recipients, a gap that reflects the background noise of minor complaints common in any phase 1 population. Drug-related adverse events were reported in 73.3 percent of the active group versus 60.0 percent on placebo. Critically, every adverse event recorded during the follow-up period was grade 1 or grade 2 in severity, meaning mild to moderate, and the vast majority were described as mild and self-limiting. No severe events, dose-limiting toxicities, or safety signals requiring discontinuation emerged across the dose range explored.

The pharmacokinetic data revealed an intriguing property. Across the 3- to 12-milligram range, systemic exposure to HZBio1 increased in a greater than dose-proportional manner, meaning that doubling the dose more than doubled the drug’s presence in the bloodstream. Such super-proportional exposure can occur when a drug’s absorption or clearance pathways become saturated, and it has practical implications for dosing, since small increments in dose may produce disproportionately large changes in exposure. For a first-in-human program, characterizing this nonlinearity early is exactly what dose-escalation studies are designed to accomplish, and it will inform how future trials select and space doses.

The pharmacodynamic results were the trial’s headline attraction. A single injection of HZBio1 sent plasma uric acid concentrations falling, with levels reaching their nadir between 144 and 192 hours after dosing, roughly six to eight days. The reduction was most pronounced in the 9- and 12-milligram cohorts, and among subjects receiving 6 to 12 milligrams, participants achieved at least a 50 percent reduction in plasma urate over the 35-day observation period. A urate-lowering effect of that magnitude and duration, from a single intramuscular dose, is notable because it suggests the PEGylated enzyme remains active in circulation for an extended period, potentially allowing an infrequent dosing schedule that would be attractive for a chronic disease like gout.

Immunogenicity, the perennial concern with PEGylated proteins, was monitored with equal care. HZBio1 administration elicited low-titer antibodies against polyethylene glycol, of both the immunoglobulin G and immunoglobulin M classes. By contrast, antibodies directed against the drug protein itself were rarely detected, and no subject developed neutralizing antibodies, the kind that would inactivate the enzyme and potentially blunt or abolish its therapeutic effect. The distinction matters because neutralizing antidrug antibodies are the principal reason some patients lose response to pegloticase, and pre-existing or induced anti-PEG antibodies have been linked to infusion reactions with other PEGylated medicines. Whether the low-titer anti-PEG response observed here remains clinically silent with repeated dosing is a question only longer studies can answer.

The authors conclude that HZBio1 at doses of 3 to 12 milligrams was well tolerated in healthy subjects, showed an acceptable pharmacokinetic profile, and produced a promising urate-lowering effect. The trial was funded by Hangzhou Grand Biologic Pharmaceutical, with the funder reporting no role in the design, conduct, analysis, or reporting of the research; two authors are company employees and one is employed by Grand Life Sciences Group, while the academic investigators disclosed no conflicts of interest. As with any phase 1a study, the caveats are substantial: only 40 subjects were involved, all were young and healthy Chinese adults rather than patients with gout, and each received just one dose. The super-proportional exposure seen at higher doses will need careful management in patient trials, and the durability of the immune response under repeated administration remains untested. Nevertheless, the combination of mild adverse events, sustained urate suppression, and an apparently favorable antibody profile gives HZBio1 a credible foundation for advancing into phase 1b and phase 2 studies in the hyperuricemic and gout populations who most need a new enzymatic option.

Subject of Research: First-in-human phase 1a evaluation of the PEGylated recombinant uricase HZBio1 for hyperuricemia and gout

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

Article References: Liu, H., Zheng, X., Yang, C., Tian, W., Wan, R., Wang, Y., Yu, Y., Wang, Q., & Wang, H. (2026). Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of HZBio1 in Chinese Healthy Subjects: A Randomized Phase 1a Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03792-0

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03792-0

Keywords: HZBio1, PEGylated uricase, gout, hyperuricemia, phase 1a trial, pharmacokinetics, pharmacodynamics, immunogenicity, anti-PEG antibodies, urate-lowering therapy, biologics, first-in-human study