Nanoencapsulated Sirolimus Plus Pegadricase (NASP) in Uncontrolled Gout: Current Status and Future Directions

Uncontrolled gout (UG) is a progressive arthropathy that develops as a consequence of sustained hyperuricemia. Recombinant uricases can profoundly lower serum urate (SU) and reverse the clinical manifestations of uncontrolled gout. However, therapeutic uricases are highly immunogenic and can provoke the development of anti-drug antibodies (ADAs), resulting in a loss of effect and potentially severe allergic reactions. Pegloticase is currently the only US Food and Drug Administration-approved uricase indicated for the treatment of UG. The Food and Drug Administration recently approved the co-administration of methotrexate with pegloticase to inhibit ADA formation and enhance the efficacy and tolerability of pegloticase. Nanoencapsulated sirolimus plus pegadricase (NASP) is a novel every-4-week treatment delivered as a sequential two-component infusion consisting of nanoencapsulated sirolimus immediately followed by pegadricase, a novel PEGylated uricase. NASP mitigates ADA formation by promoting uricase-specific immunotolerance, thereby obviating the need for systemic immunomodulatory drugs. Phase I trials demonstrated that NASP inhibited ADA development, allowing sustained pegadricase control and SU lowering for up to 30 days. The dose-finding (phase II) study showed NASP (nanoencapsulated sirolimus 0.1-0.15 mg/kg and pegadricase 0.2 mg/kg) reduced ADA development and supported durable SU lowering. The phase II COMPARE trial demonstrated that monthly NASP was as effective as twice-monthly pegloticase in achieving SU targets at 6 months. Combined phase III DISSOLVE trial data confirmed that NASP significantly lowered SU and increased SU responses in participants with UG. All phase I-III trials demonstrated that NASP was generally well tolerated with no specific safety signals. Overall, NASP has demonstrated robust and durable SU lowering, which ultimately reduced disease burden, supporting positive health-related quality-of-life outcomes. This review summarizes the clinical development of NASP with particular reference to the targeted immunotolerizing strategy that diminishes its immunogenicity. Video abstract available online. Video Abstract.