Development and evaluation of a pegloticase biobetter for sustained suppressionof fructose-induced obesity

Project Summary Excessive fructose consumption from beverage consumption and processed food is a major driver of obesity and metabolic syndrome, largely due to increased uric acid (UA) levels from fructose metabolism in the liver. Elevated UA, majority of which is in the more soluble anionic form called urate, is directly linked to metabolic issues including leptin resistance (influencing satiety/hunter) and fat accumulation leading to non- alcoholic fatty liver disease. The link between UA and fructose-induced obesity highlights the potential of urate-lowering therapies (ULT) to mitigate fructose-induced obesity. Pegloticase is a PEGylated uricase enzyme clinically approved to treat tophaceous gout patients who do not respond to other ULT; it is the only treatment available for repeated dosing that can reduce serum UA by directly breaking down UA. Other ULT target pathways that either reduces UA synthesis, or induces greater renal clearance; thus, pegloticase’s ability to directly breakdown UA may offer superior efficacy in reversing fructose-induced obesity. However, pegloticase has not been tested to reverse fructose-induced obesity or metabolic syndrome, in part due to its safety profile. Pegloticase in its current form induces anti-PEG antibodies (APA) in nearly 90% of the subjects, leading to loss of efficacy in nearly 60% of the patients, and high incidence of allergic reactions culminating in a black box warning for anaphylaxis on its product label. While such safety profile may be acceptable for a highly debilitating and painful acute inflammatory conditions with no other treatments, it is unsuitable for use in obesity applications. To overcome the clinical shortcoming of pegloticase, Mucommune has licensed a technology that effectively overcomes pre-existing APA and mitigate APA induction, without requiring broad immunosuppression. The approach uses high molecular weight free PEG to saturate circulating APA and B-cell receptors on APA+ B-cells, thereby reducing the “hapten” effect of PEG-drugs. Our prior work shows that free PEG suppresses APA induction against pegloticase in animal models, restores drug circulation in the presence of high APA titers, and does not further induce APA. In highly sensitive swine models, free PEG completely eliminates hypersensitivity reactions to PEGylated drugs, greatly enhancing the safety and efficacy of PEGylated treatments. This proposal seeks to evaluate whether free PEG reformulated pegloticase (MM010) can be repeatedly dosed into animals to sustain ULT that safely and effectively block fructose-induced obesity. In Aim 1, we will produce and characterize pegloticase, which will be used in animal studies of fructose-induced obesity in Aim 2. We will file a pre-IND package (Aim 3) with the FDA to gain guidance on the anticipated preclinical and clinical development path. Successful completion of this project will position MM010 as a novel option in treating hyperuricemia and metabolic disorders, potentially benefiting millions with inadequate UA management.