Dusquetide, a First-in-Class Innate Defense Regulator: A Comprehensive Review of Its Mechanism of Action, Clinical Development, and Therapeutic Frontier in Inflammatory and Orphan Diseases

Abstract

Dusquetide, a synthetic five-amino-acid peptide, represents a first-in-class therapeutic agent belonging to the family of Innate Defense Regulators (IDRs). Unlike conventional immunomodulators that often target specific cytokines or receptors, dusquetide exerts a broad spectrum of biological effects by selectively binding to the ZZ domain of the sequestosome-1 (SQSTM1/p62) protein, a pivotal signaling hub that integrates cellular responses to stress, infection, and inflammation. This interaction modulates the innate immune system, effectively resetting the balance between pro-inflammatory pathways and resolution-phase activities such as tissue repair and bacterial clearance without directly activating autophagy. Preclinical models have validated its efficacy across a diverse range of pathologies, including chemotherapy-induced oral mucositis, colitis, bacterial infections, and macrophage activation syndrome. Clinically, dusquetide has been evaluated most extensively in the context of head and neck cancer, where a Phase 3 trial (DOM-INNATE) demonstrated a biologically meaningful reduction in the duration of severe oral mucositis, although the primary endpoint did not achieve statistical significance in the intent-to-treat population, a discrepancy that has spurred detailed post-hoc analyses. More recently, the therapeutic potential of dusquetide has been expanded into the realm of orphan auto-inflammatory diseases. A pilot Phase 2a study in Behçet’s Disease (SGX945) published in late 2025 reported clinically meaningful reductions in the number, duration, and pain of both oral and genital aphthous ulcers, with a favorable safety profile. This comprehensive review synthesizes the current understanding of dusquetide’s molecular pharmacology, critically evaluates the aggregate clinical data across its lead indications, and discusses the future trajectory of this unique compound in addressing significant unmet medical needs in oncology supportive care and rare inflammatory disorders.