PRECLINICAL DEVELOPMENT OF URICASE-PEG 20

Hyperuricemia (elevated serum uric acid) results in gouty arthritis and chronic renal disease. Severe hyperuricemia can occur following cancer chemotherapy (tumor lysis syndrome) and organ transplantation (most common in heart and kidney transplant patients) which may result in acute uric acid nephropathy with resultant metabolic disorders and death. Moreover, in addition to pain, hyperuricemia can result in destructive gouty arthritis, with concomitant permanent damage to joints and connective tissue. Elevated uric acid levels (hyperuricemia) do not develop in most mammals because they have the gene which encodes urate oxidase which metabolizes the less soluble uric acid into a much more soluble metabolite, allantoin. However, in humans, the urate oxidase gene has evolved to contain a nonsense codon which results in a complete loss of enzyme activity. Many different groups of investigators have administered uricase, purified from micro organisms, to patients. Although these treatments lower plasma uric acid levels, all of the enzymes used are highly immunogenic and cause allergic reactions and anaphylaxis. Formulation of other therapeutic proteins with polyethylene glycol (PEG) has been shown to reduce their anti-genicity and prolong their circulating half-life. We have initiated Phase I clinical testing of a PEG modified uricase termed Uricase-PEG20. In this proposal we seek funding to perform the additional studies requested by the FDA in order for this drug to move into Phase 2 human clinical testing. PROPOSED COMMERCIAL APPLICATIONS: This proposal focuses on performing the additional preclinical experiments requested by the FDA in order for this drug to enter Phase 2 human testing. Although non-PEG formulated uricase is used in Europe, it has not been approved in the USA because of the high incidence of allergic reactions associated with its use. uricase-PEG 20 is formulated with polyethylene glycol (PEG), a technology known to reduce the antigenicity of heterologous proteins.