Abstract
PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 ± 2.1 mg/dl (mean ± SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.
Highlights
By day seven after injection of PEGuricase, plasma uric acid concentration (pUAc) had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl
In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase
Attacks of inflammatory arthritis in patients with gout are triggered by monosodium urate crystals, which result from the low solubility and high levels of uric acid in plasma and extracellular fluids [1,2]
Summary
Attacks of inflammatory arthritis in patients with gout are triggered by monosodium urate crystals, which result from the low solubility and high levels of uric acid in plasma and extracellular fluids [1,2]. Gout can usually be controlled by maintaining serum urate below the limit of solubility (about 7 mg/dl, or 0.42 mM) with drugs that block urate synthesis by inhibiting xanthine oxidase, or that promote renal urate excretion [3]. For various reasons (noncompliance, intolerance, inadequate dosage, or inefficacy), therapy fails in a subset of patients, who may develop destructive arthropathy, widespread deposition of urate in tissues (tophi), and nephropathy [4]. At this chronic stage, urate deposits built up over decades are only slowly depleted by blocking the synthesis of urate, because the renal clearance of urate is often inefficient in these patients. In humans the uricase gene was inactivated by mutations during
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