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

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Mucommune LLC $719,216 on September 15, 2025, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to develop and evaluate a reformulated pegloticase biobetter for sustained suppression of fructose-induced obesity.

The project addresses a clinical safety barrier to applying pegloticase—a pegylated uricase enzyme approved for gout—to obesity intervention. Current pegloticase formulations induce anti-PEG antibodies in nearly 90 percent of subjects, resulting in loss of efficacy in approximately 60 percent of patients and high incidence of allergic reactions carrying a black box anaphylaxis warning. Mucommune has licensed a technology that overcomes pre-existing anti-PEG antibodies and mitigates anti-PEG antibody induction without requiring broad immunosuppression. Excessive fructose consumption elevates uric acid and urate levels, driving leptin resistance and fat accumulation including non-alcoholic fatty liver disease; pegloticase's ability to directly break down urate may offer superior efficacy in reversing fructose-induced obesity compared to alternative urate-lowering therapies targeting synthesis or renal clearance pathways.

Work is performed in Morrisville, North Carolina. The period of performance extends through August 31, 2027.

The University of North Carolina at Chapel Hill, through its Office of Sponsored Research, serves as sub-recipient and will conduct in vivo studies evaluating the safety and activity of MM010 (pegloticase reformulated with free PEG developed in the Lai Lab) in mouse models of fructose-induced obesity. The sub-recipient will evaluate sustained uric acid suppression from repeated injections in mice on high-fructose diet compared to placebo, assess optimal pegloticase dosing, compare intramuscular and subcutaneous injection efficacy versus conventional intravenous administration, and measure anti-PEG immunoglobulin levels across treatment groups.

Abstract

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.