Tetrathiomolybdate (DB05088): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Tetrathiomolybdate (TM) is an investigational, orally bioavailable small-molecule therapeutic agent primarily characterized by its potent and highly specific copper-chelating properties.[1] Its principal mechanism involves the reduction of systemic "free" copper—the non-ceruloplasmin-bound, biologically active form of the metal—through a dual-action process of inhibiting gastrointestinal absorption and forming inert complexes in the bloodstream.[3] This core function has positioned TM as a promising therapy for Wilson's disease, a genetic disorder of copper overload. Pivotal clinical trials have demonstrated its superiority over standard-of-care agents, such as trientine, in preventing the initial, often irreversible, neurological deterioration that can occur upon treatment initiation in affected patients.[5]

Beyond its application in Wilson's disease, TM has been the subject of extensive investigation across multiple therapeutic areas, including oncology and fibrotic diseases. In these contexts, its mechanism is understood to extend beyond simple metal sequestration. By depleting copper, TM inhibits a range of copper-dependent enzymes and signaling pathways critical to pathogenesis, such as those involved in angiogenesis (e.g., VEGF, bFGF), extracellular matrix remodeling (e.g., lysyl oxidase), and inflammation (e.g., NF-κB).[1] This positions TM not as a conventional cytotoxic or debulking agent, but as a modulator of the pathological microenvironment. Promising clinical data has emerged from its use as an adjuvant therapy to prevent recurrence in high-risk breast cancer.[9] Furthermore, recent research has uncovered a novel property of TM as a slow-release donor of hydrogen sulfide (

H2​S), a gasotransmitter with cytoprotective effects, suggesting potential applications in conditions such as ischemia-reperfusion injury.[10]