Plitidepsin (Aplidin®): A Comprehensive Monograph on a Marine-Derived Agent from Multiple Myeloma to COVID-19

Executive Summary

Plitidepsin is a first-in-class, synthetically produced cyclic depsipeptide, originally discovered as a natural product isolated from the marine tunicate Aplidium albicans.[1] Marketed under the brand name Aplidin®, this small molecule has traversed a complex and challenging developmental pathway, marked by a novel mechanism of action, contentious clinical trial results, a paradoxical global regulatory history, and an emergent, compelling potential in antiviral therapy.

The core pharmacological activity of Plitidepsin is its high-affinity binding to the host protein eukaryotic Elongation Factor 1A2 (eEF1A2), a protein isoform overexpressed in various malignancies.[3] Rather than inhibiting the canonical function of protein synthesis, Plitidepsin's primary anticancer effect stems from the disruption of eEF1A2's non-canonical, pro-oncogenic roles. This unique interaction triggers a cascade of downstream events, including the induction of oxidative stress and a rapid, caspase-dependent apoptotic program in tumor cells, representing a novel therapeutic strategy in oncology.[5]

Clinically, Plitidepsin has a single approved indication: the treatment of relapsed and refractory multiple myeloma (RRMM), in combination with dexamethasone, exclusively in Australia.[1] This registration was granted by the Therapeutic Goods Administration (TGA) based on the results of the pivotal Phase III ADMYRE trial. The study met its primary endpoint, demonstrating a statistically significant, albeit modest, improvement in Progression-Free Survival (PFS) for the combination therapy compared to dexamethasone alone.[8]