Targeted Treatment for Hyperuricemia: The Drug Pipeline.

Abstract

Gout is the most prevalent inflammatory arthritis worldwide and disproportionately affects older adults, who frequently have comorbid conditions such as chronic kidney disease and cardiovascular disease that lead to polypharmacy and complicate both urate-lowering therapy (ULT) and management of acute flares. Although treat-to-target ULT (lowering and maintaining serum uric acid levels below 6 mg/dL) remains the cornerstone of gout care, a subset of patients fail to achieve serum urate goals owing to intolerance, contraindications, or inadequate response with available agents. This narrative review summarizes current and emerging pharmacologic therapies for gout with a focus on ULT in clinical development and their relevance to aging populations. In addition to ongoing studies of novel xanthine oxidase inhibitors (XOI), the development of highly selective urate transporter 1 (URAT1) inhibitors underscores a renewed interest in uricosuric therapy. Agents such as dotinurad have demonstrated effective urate lowering with favorable renal and hepatic safety profiles in older individuals, including patients with chronic kidney disease, suggesting potential advantages in this higher-risk population. Likewise, novel uricase-based strategies, including immune-tolerizing platforms such as nanoencapsulated sirolimus plus pegadricase (NASP), aim to overcome immunogenicity and treatment burden associated with pegloticase. Novel agents targeting the NLRP3 inflammasome and IL-1β appear to have promise for anti-inflammatory prophylaxis and flare treatment that are integral to effective ULT. Currently, with several next-generation agents in late-phase trials, efforts will be needed to enhance the generalizability of these studies to older patients with comorbidity that are common to real-world gout care.