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]

This approval stands in stark contrast to the drug's regulatory journey in other major markets. The European Medicines Agency (EMA) issued a negative opinion, concluding that the marginal clinical benefit did not outweigh the significant risks and added toxicity.[1] This decision precipitated a multi-year legal challenge by the developer, PharmaMar, which resulted in the annulment of the EMA's decision on procedural grounds related to a conflict of interest. Following a court order for re-evaluation, PharmaMar ultimately withdrew its European marketing application in 2025, a strategic move likely reflecting the unchanged underlying clinical data.[1] In the United States, Plitidepsin holds an Orphan Drug Designation for multiple myeloma but is not approved by the FDA.[12]

More recently, Plitidepsin has garnered significant attention for its potent antiviral properties. Its host-targeted mechanism of action is directly applicable to virology, as many viruses, including SARS-CoV-2, co-opt the host eEF1A protein for their replication. Preclinical studies demonstrated superior potency against SARS-CoV-2 compared to remdesivir, and early clinical data showed promising viral load reduction.[1] While a Phase III trial in moderate COVID-19 was terminated early due to declining hospitalization rates, the strong biological rationale positions Plitidepsin as a promising candidate for a broad-spectrum, host-directed antiviral agent.[15]

In conclusion, Plitidepsin represents a fascinating case study of a novel marine-derived therapeutic. Its journey is defined by a compelling and unique biological mechanism that has struggled to translate into a clear, clinically meaningful benefit in oncology sufficient for widespread regulatory acceptance. Its current role remains confined to a niche indication in a single country, while its future potential may pivot decisively toward the field of virology, where its host-targeting mechanism could address the persistent challenge of viral resistance and emerging pandemic threats.

Compound Profile and Pharmaceutical Data

Discovery and Chemical Identity

The discovery of Plitidepsin is a testament to the potential of marine biodiversity as a source of novel therapeutic agents.[17] It was originally isolated as a natural product from

Aplidium albicans, a species of marine tunicate (or sea squirt) found in the Mediterranean Sea.[1] The developer, PharmaMar, has noted that this invertebrate is found in the waters surrounding the island of Es Vedrà in the Balearic Islands, Spain.[19]

Chemically, Plitidepsin is classified as a cyclic depsipeptide and is structurally related to the didemnin family of compounds, particularly dehydrodidemnin B.[1] While its origins are in a natural product, the active pharmaceutical ingredient used in the commercial formulation, Aplidin®, is produced via total chemical synthesis. This approach ensures a consistent, scalable, and pure supply of the drug, overcoming the inherent limitations and variability of natural sourcing.[2]

The compound is identified by a comprehensive set of names and registry numbers essential for unambiguous scientific and regulatory communication.

• Generic Name: Plitidepsin [3]
• Brand Name: Aplidin® [1]
• Synonyms: Aplidine, dehydrodidemnin B [1]
• Systematic IUPAC Name: (2S)-N--11-hydroxy-3-[(4-methoxyphenyl)methyl]-2,6,17-trimethyl-20-(2-methylpropyl)-1,4,8,13,16,18,21-heptaoxo-15-(propan-2-yl)docosahydro-15H-pyrrolo[2,1-d]dioxatetraazacyclotricosin-7-yl}carbamoyl)-3-methylbutyl]-N-methyl-1-(2-oxopropanoyl)pyrrolidine-2-carboxamide [1]
• CAS Number: 137219-37-5 [1]
• DrugBank ID: DB04977 [1]
• PubChem CID: 9812534 [1]

Its fundamental physicochemical properties have been well-characterized:

• Molecular Formula: C57​H87​N7​O15​ [3]
• Molecular Weight:
• Average: 1110.34 Da [18]
• Monoisotopic: 1109.626015129 Da [3]

Formulation, Administration, and Stability

The pharmaceutical development of Plitidepsin was constrained by its inherent physicochemical instability. The molecule shows substantial degradation under heat and light stress when in a solubilized state, which necessitated its development as a lyophilized dosage form.[2] The commercial product is supplied as a sterile, lyophilized powder containing 2 mg of Plitidepsin per vial.[2]

Reconstitution of this powder requires a specific solvent mixture due to the drug's poor aqueous solubility. The optimal reconstitution solution was identified as a 15/15/70% (v/v/v) mixture of polyoxyl 35 castor oil, ethanol, and water for injection.[2] Reconstituting the 2 mg vial with 4 mL of this solution yields a clear, colorless to slightly yellow solution with a final Plitidepsin concentration of 0.5 mg/mL.[2] This reconstituted concentrate must then be further diluted with either 0.9% sodium chloride or 5% glucose infusion solution prior to patient administration.[2]

The standard administration protocol for the approved multiple myeloma indication is a 3-hour intravenous infusion, typically administered on Days 1 and 15 of a 28-day (4-week) treatment cycle.[7]

Strict storage and handling conditions are required to maintain the drug's integrity. Both the lyophilized powder vials and the ampoules of reconstitution solution must be stored under refrigeration between 2°C and 8°C.[2] Once reconstituted, the solution is chemically and physically stable for up to 28 hours at temperatures up to 25°C under normal light conditions. After final dilution for infusion, this stability window shortens to 24 hours at up to 25°C. Despite these stability data, immediate preparation and use are strongly recommended.[2]

The choice of polyoxyl 35 castor oil (a formulation excipient also known as Cremophor EL) as a solubilizing agent is a critical aspect of the drug's formulation. While effective for poorly soluble compounds, this excipient is well-documented in pharmaceutical science to be associated with a risk of infusion-related hypersensitivity reactions. This known property of the vehicle, rather than the active drug itself, provides a direct pharmacological rationale for the mandatory clinical risk mitigation strategy employed with Plitidepsin. To prevent such reactions, patients must receive premedication with intravenous ondansetron, ranitidine, and an antihistamine before each infusion.[8]

Preclinical and Clinical Pharmacology

Primary Mechanism of Action in Oncology: Targeting eEF1A2

The anticancer activity of Plitidepsin is mediated through a novel and distinct mechanism of action that sets it apart from traditional cytotoxic agents. Its primary intracellular target is the eukaryotic Elongation Factor 1 alpha 2 (eEF1A2).[3] eEF1A is a highly abundant GTPase whose canonical function is essential for protein biosynthesis, specifically the delivery of aminoacyl-tRNA to the A-site of the ribosome during the elongation phase of translation.[5] Mammalian cells express two isoforms, eEF1A1 and eEF1A2, which share high homology but have mutually exclusive expression patterns, suggesting distinct functions.[4]

Plitidepsin demonstrates high-affinity and specific binding to the eEF1A2 isoform, with a measured dissociation constant (KD​) of approximately 80 nM and a target residence time of about 9 minutes.[4] Molecular modeling and experimental data indicate that the drug binds snugly at the interface between domains 1 and 2 of the eEF1A2 protein. This interaction stabilizes the GTP-bound conformation of eEF1A2, which in turn prevents the necessary GDP/GTP exchange cycle, ultimately arresting ribosomal translocation and inhibiting protein synthesis.[4]

However, the central element of Plitidepsin's mechanism is not the simple inhibition of protein synthesis. The eEF1A2 isoform, unlike the ubiquitously expressed eEF1A1, is overexpressed in a range of human tumors and has been shown to possess distinct, non-canonical "moonlighting" functions that are pro-oncogenic.[4] It is the specific disruption of these non-canonical activities that drives Plitidepsin's potent antitumor effects.[6] Key pro-survival functions of eEF1A2 that are inhibited by Plitidepsin include:

• Inhibition of Apoptosis: eEF1A2 can suppress programmed cell death, contributing to tumor cell survival.[4]
• Regulation of Proteostasis: It is involved in the control of unfolded protein degradation and the cellular heat shock response.[4]
• Suppression of Pro-Apoptotic Signaling: eEF1A2 directly interacts with and inactivates the pro-apoptotic double-stranded RNA-dependent protein kinase (PKR). The binding of Plitidepsin to eEF1A2 disrupts this complex, disengaging and liberating active PKR. The reactivated PKR can then initiate extrinsic apoptosis through the activation of MAPK and NF-κB signaling cascades.[5]

The binding of Plitidepsin to eEF1A2 initiates a cascade of downstream cellular events that culminate in cell death. The drug is a potent inducer of apoptosis, a process mediated through multiple pathways, including the triggering of mitochondrial cytochrome c release, activation of the Fas/CD95 death receptor pathway, sustained activation of the c-Jun N-terminal kinase (JNK) pathway, and subsequent activation of executioner caspase-3.[18] Concurrently, Plitidepsin causes cell cycle arrest at the G1 and G2 checkpoints, effectively halting tumor cell proliferation.[17] A very early event following drug exposure is the induction of potent oxidative stress, characterized by an increase in intracellular reactive oxygen species (ROS) and a corresponding reduction in reduced glutathione (GSH) levels. This oxidative imbalance contributes to endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR), further pushing the cell toward an apoptotic fate.[4]

Secondary Pharmacodynamic Effects

Beyond its direct effects on tumor cells, Plitidepsin exhibits additional pharmacodynamic activities that contribute to its overall antitumor profile, particularly in the context of multiple myeloma.

One significant secondary effect is its anti-angiogenic activity. Preclinical studies have shown that Plitidepsin can inhibit multiple steps in the angiogenic cascade, which is the process by which tumors form new blood vessels to support their growth.[18]

In vitro experiments demonstrated that Plitidepsin inhibits the proliferation, migration, and invasiveness of endothelial cells, even in the presence of potent pro-angiogenic stimuli like Vascular Endothelial Growth Factor (VEGF) and Fibroblast Growth Factor 2 (FGF-2). Furthermore, in vivo studies using the chick chorioallantoic membrane (CAM) assay confirmed that Plitidepsin inhibits both basal physiological angiogenesis and angiogenesis induced by tumors.[18]

Another crucial activity, highly relevant to the pathophysiology of multiple myeloma, is its potent anti-resorptive effect on bone. Multiple myeloma is characterized by the formation of osteolytic lesions, where malignant plasma cells stimulate osteoclasts—the cells responsible for bone breakdown—leading to skeletal destruction, pain, and fractures. Plitidepsin has been shown to directly affect osteoclasts, markedly decreasing the number of osteoclast precursors, inhibiting their differentiation into mature cells, and reducing the bone resorption activity of already-matured osteoclasts.[1] This provides a powerful dual mechanism of action in myeloma: it not only kills the tumor cells directly but also mitigates one of the disease's most debilitating clinical consequences by protecting the skeleton. This combination of direct cytotoxicity, anti-angiogenic action, and anti-resorptive bone protection creates a multifaceted attack on the disease, providing a strong therapeutic rationale for its use.

Pharmacokinetics: ADME Profile

The pharmacokinetic profile of Plitidepsin in humans has been characterized in several Phase I and II clinical trials. As the drug is administered exclusively by intravenous infusion, the absorption phase is bypassed, and 100% of the dose is bioavailable systemically. Across various dosing schedules and infusion durations, its pharmacokinetics have been demonstrated to be linear and time-independent, with dose-proportional exposure observed up to 8.0 mg/m².[20]

Distribution:

Plitidepsin is extensively distributed throughout the body. This is evidenced by a very large apparent volume of distribution at steady state (Vss​), which has been reported to range from 500 to 1,350 L.20 A key and somewhat unusual feature of its distribution is its significant partitioning into red blood cells. Mass balance studies using radiolabeled drug revealed that total radioactivity levels were approximately 3.7 times higher in whole blood than in plasma, indicating that red blood cells serve as a major distribution compartment and drug reservoir.30 This implies that measuring plasma concentrations alone may significantly underestimate the total drug exposure within the body. In the plasma compartment, Plitidepsin is highly bound to proteins, with approximately 97.3% of the drug being protein-bound.20

Metabolism:

The metabolism of Plitidepsin is considered moderate.20 The primary enzyme system involved in its metabolism is cytochrome P450 3A4 (CYP3A4).8 This reliance on a major drug-metabolizing enzyme makes Plitidepsin susceptible to clinically significant drug-drug interactions with potent inhibitors or inducers of CYP3A4.

Excretion:

The primary route of elimination for Plitidepsin and its metabolites is hepatobiliary excretion into the feces. A comprehensive mass balance study in cancer patients using $^{14}$C-labeled Plitidepsin provided definitive data on its excretion pathways. Over a 20-day collection period, a mean of 77.4% of the administered radioactive dose was recovered. The vast majority of this, 71.3%, was found in the feces, while only a small fraction, 6.1%, was recovered in the urine.30 Further analysis revealed that the radioactivity excreted in feces consisted predominantly of metabolites, with very little unchanged parent drug. In contrast, the small amount of drug-related material found in the urine was mostly in the form of unchanged Plitidepsin.30

Plitidepsin is characterized by low plasma clearance, with mean values ranging from 45 to 49 L/h, and a long terminal half-life.[20] Mean half-life values in plasma and whole blood have been reported in the range of 21 to 44 hours, while a population pharmacokinetic model estimated a terminal half-life of up to 12 days, consistent with its slow clearance and large volume of distribution.[20]

Parameter	Value / Description	Source(s)
Administration Route	Intravenous Infusion	20
Volume of Distribution (Vss​)	500 – 1,350 L	20
Plasma Protein Binding	~97.3%	20
Blood to Plasma Ratio	~3.7	30
Clearance (Plasma)	45 – 49 L/h	20
Terminal Half-life	21 – 44 hours (plasma/blood); up to 12 days (population PK model)	20
Primary Elimination Route	Biliary / Fecal (~71% of dose)	30
Key Metabolizing Enzyme	Cytochrome P450 3A4 (CYP3A4)	8

Clinical Efficacy in Relapsed/Refractory Multiple Myeloma

Early Phase Development and Rationale

The clinical development of Plitidepsin for multiple myeloma was predicated on strong preclinical evidence of its activity. In vitro studies demonstrated potent cytotoxic effects against a broad panel of multiple myeloma cell lines, including those that had developed resistance to standard-of-care agents such as bortezomib and thalidomide derivatives.[28] This suggested that Plitidepsin's unique mechanism of action could overcome existing resistance pathways, making it a promising candidate for the relapsed/refractory setting.

These preclinical findings were explored in a multicenter Phase II clinical trial (NCT00229203) involving patients with heavily pretreated RRMM. In this study, 51 patients received Plitidepsin as a 3-hour infusion every two weeks. The results showed modest but clear signs of clinical activity in this difficult-to-treat population. As a monotherapy, Plitidepsin achieved an overall response rate (ORR) of 15% among 47 evaluable patients.[32] The protocol was later amended to allow the addition of dexamethasone for patients with a suboptimal response. In the subset of patients who received the combination, the ORR improved to between 19% and 22%.[32] The addition of dexamethasone also appeared to prolong disease control, with the median time to progression (TTP) increasing from approximately 2.3–3.0 months with monotherapy to 3.8–4.7 months with the combination.[8] While modest, these signals of efficacy in a patient population that had exhausted many other options provided the necessary rationale to advance Plitidepsin into a pivotal Phase III registration study.

The Pivotal ADMYRE Phase III Trial (NCT01102426): A Critical Analysis

The ADMYRE study was the definitive trial designed to establish the efficacy and safety of Plitidepsin for regulatory approval. It was a large, international, multicenter, open-label, randomized Phase III trial that enrolled 255 patients with RRMM.[21] Eligible patients were heavily pretreated, having received at least three but no more than six prior lines of therapy, and must have been previously exposed to both a proteasome inhibitor (like bortezomib) and an immunomodulatory drug (like lenalidomide).[9]

Patients were randomized in a 2:1 ratio to receive either the experimental treatment of Plitidepsin (5 mg/m² IV on Days 1 and 15) plus weekly dexamethasone (40 mg) or the control treatment of dexamethasone alone, administered in 4-week cycles.[21] A critical feature of the trial's design was the provision for patients in the dexamethasone-alone arm to cross over and receive the Plitidepsin-dexamethasone combination upon confirmed disease progression.[21] This design element, while ethically sound, would later prove to be a major confounding factor in the analysis of overall survival.

Primary Endpoint: Progression-Free Survival (PFS)

The ADMYRE trial successfully met its primary endpoint, demonstrating a statistically significant improvement in PFS for the Plitidepsin combination arm compared to the control arm.9 However, the magnitude of this benefit became a central point of regulatory debate.

• The assessment by an Independent Review Committee (IRC), the most stringent measure, found a median PFS of 2.6 months for the combination arm versus 1.7 months for the dexamethasone-alone arm. This represented a statistically significant 35% reduction in the risk of progression or death (Hazard Ratio = 0.65; p=0.0054), but an absolute median benefit of only 0.9 months.[8]
• The investigator assessment reported a larger benefit, with a median PFS of 3.8 months versus 1.9 months.[14]

Secondary Endpoint: Overall Survival (OS)

The analysis of overall survival was complicated by the high rate of patient crossover.

• In the primary intention-to-treat (ITT) analysis, there was no statistically significant difference in OS between the two arms. The median OS was 11.6 months for the Plitidepsin-dexamethasone group versus 8.9 months for the dexamethasone-alone group (HR = 0.797; p=0.1261).[8]
• This lack of significance was heavily influenced by the fact that 44% of patients (37 of 84) in the control arm crossed over to receive the Plitidepsin combination after their disease progressed.[8] This crossover effectively provided the control group with the active therapy, masking any potential survival difference.
• To account for this confounding effect, post-hoc statistical analyses using methods like the Rank Preserving Structural Failure Time (RPSFT) model and the two-stage method were performed. These adjusted analyses demonstrated a statistically significant survival benefit. The two-stage method, for instance, estimated a median OS of 11.6 months for the combination arm versus a modeled 6.4 months for the control arm had they not crossed over (HR = 0.622; p=0.0015).[8]

Other Endpoints

The objective response rate (ORR) as assessed by the IRC was relatively low at 13.8% for the combination arm. However, for those patients who did respond, the response was durable, with a median duration of 12 months.36 Furthermore, the study showed a benefit in terms of quality of life, as the median time to deterioration in patient performance status was more than doubled in the Plitidepsin arm (4.6 months) compared to the control arm (2.3 months).36

The results of the ADMYRE trial created a classic regulatory dilemma, pitting statistical significance against clinical meaningfulness. The study technically succeeded by meeting its primary endpoint with a p-value of 0.0054. However, the absolute clinical benefit in terms of PFS was less than one month. The key secondary endpoint of overall survival, arguably the most important outcome for patients, was not met in the primary analysis and could only be demonstrated through complex statistical modeling to correct for the high crossover rate. This fundamental disconnect—a statistically robust but clinically marginal PFS benefit paired with a modeled but not directly observed OS advantage—became the crux of the divergent opinions of global regulatory bodies, ultimately shaping Plitidepsin's limited market access.

Endpoint	Plitidepsin + Dexamethasone Arm	Dexamethasone Alone Arm	Hazard Ratio (95% CI)	p-value	Comments
PFS (IRC Assessment)	2.6 months	1.7 months	0.65 (0.48–0.89)	0.0054	Primary endpoint met; statistically significant but modest absolute benefit.
PFS (Investigator Assessment)	3.8 months	1.9 months	Not Reported	<0.05	Larger benefit observed by investigators.
OS (ITT Analysis)	11.6 months	8.9 months	0.797 (0.59–1.07)	0.1261	Not statistically significant; confounded by crossover.
OS (Adjusted for Crossover)	11.6 months	6.4 months	0.622 (0.45–0.86)	0.0015	Statistically significant benefit demonstrated after modeling.
Objective Response Rate (IRC)	13.8%	Not Reported	Not Applicable	Not Reported	Low overall response rate.
Median Duration of Response (IRC)	12.0 months	Not Reported	Not Applicable	Not Reported	Durable responses in the small subset of responders.

Data sourced from.[8]

Safety, Tolerability, and Risk Management

Comprehensive Adverse Event Profile

The safety profile of Plitidepsin has been established through its clinical trial program, primarily in a heavily pretreated population of patients with advanced malignancies where adverse events (AEs) are common.[8] The addition of Plitidepsin to a dexamethasone backbone resulted in an increased incidence and severity of specific AEs compared to dexamethasone alone.[21]

Most Common Adverse Events:

The most frequently reported AEs associated with Plitidepsin treatment are:

• Gastrointestinal: Nausea is the most common AE, affecting approximately 37% to 42% of patients, followed by vomiting (~16%) and diarrhea (~14%).[21]
• Muscular: Muscular events are a characteristic toxicity of Plitidepsin. Myalgia (muscle pain) is common, and elevations in serum creatine phosphokinase (CPK) are frequently observed. In the ADMYRE trial, Grade 3-4 CPK increase occurred in 20% of patients in the combination arm, compared to 0% in the control arm.[36] These muscular events are generally manageable and reversible with dose modification or treatment discontinuation.[2]
• Constitutional: Fatigue is a very common and often significant side effect, reported in over 36% of patients and contributing to a decreased quality of life.[21]
• Hepatic: Transient, asymptomatic elevations in liver transaminases (ALT and AST) are a known effect. In the ADMYRE study, Grade 3-4 elevations of ALT and AST were reported in 14% and 9% of patients on the combination arm, respectively, with no such events in the dexamethasone-alone arm.[21]

Hematologic Toxicity:

Compared to many conventional chemotherapeutic agents, Plitidepsin is considered to have relatively low hematological toxicity.2 While Grade 3-4 events of anemia, thrombocytopenia, and neutropenia were observed in the ADMYRE trial, the rates of severe anemia (31%) and thrombocytopenia (22%) in the combination arm were notably similar to or even lower than those in the dexamethasone-alone arm (35.4% and 27.9%, respectively).36 Severe neutropenia was more common with the combination (16% vs. 5.1%).36

Cardiac Safety:

A comprehensive analysis of pooled data from clinical trials concluded that single-agent Plitidepsin has a generally safe cardiac profile.40 The most frequently reported cardiac adverse events were rhythm abnormalities, with atrial fibrillation/flutter being the most common, occurring in approximately 2.6% of patients.40 In the ADMYRE trial, atrial fibrillation was noted more frequently in the combination arm than in the control arm, leading to its identification as a potential risk.8

Hypersensitivity/Infusion Reactions:

There is a known risk of severe hypersensitivity reactions associated with the infusion of Plitidepsin. This risk is managed through mandatory premedication protocols.8

System Organ Class	Adverse Event (Grade 3/4)	Plitidepsin + Dexamethasone (N=171) %	Dexamethasone Alone (N=84) %
Investigations	CPK Increase	20%	0%
	ALT Increase	14%	0%
	AST Increase	9%	0%
Blood/Lymphatic	Anemia	31%	35.4%
	Thrombocytopenia	22%	27.9%
	Neutropenia	16%	5.1%
General Disorders	Fatigue	18% (drug-related)	Not specified
Musculoskeletal	Myalgia	5% (drug-related)	0%

Data compiled from ADMYRE trial results and safety summaries.[32] Note: Fatigue and Myalgia percentages are for "drug-related" events from a Phase II summary, while other data is from the Phase III ADMYRE trial.

Drug-Drug Interactions and Contraindications

The metabolism of Plitidepsin via the CYP3A4 enzyme pathway is the basis for its most significant drug-drug interactions.

• CYP3A4 Inhibitors and Inducers: Co-administration of Plitidepsin with strong inhibitors of CYP3A4 (e.g., azole antifungals like itraconazole, macrolide antibiotics like clarithromycin, and grapefruit juice) is not recommended, as this can increase Plitidepsin plasma concentrations and the risk of toxicity. Conversely, co-administration with strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, and the herbal supplement St. John's wort) should be avoided, as this can decrease Plitidepsin exposure and potentially reduce its efficacy.[8]

Key contraindications and situations requiring caution include:

• Hepatic Impairment: Plitidepsin is not recommended for use in patients with impaired liver function due to its hepatic metabolism and potential for hepatotoxicity.[8]
• Cardiac Conditions: Unstable atrial fibrillation is a contraindication for its use.[8] Caution is advised in patients with pre-existing cardiac conditions.
• Toxicity Management: Dose interruptions or reductions are recommended for patients who experience significant toxicities, including Grade ≥3 hematologic events, elevated liver enzymes, or clinically significant increases in creatine kinase.[21]

Risk Mitigation Strategies

To manage the known risks associated with Plitidepsin administration, specific mitigation strategies are mandated. The most critical is the routine use of premedication to prevent infusion-related hypersensitivity reactions. This protocol requires the intravenous administration of an antiemetic (ondansetron), an H2 antagonist (ranitidine), and an antihistamine prior to each Plitidepsin infusion.[8] This measure is a direct consequence of the formulation's use of polyoxyl 35 castor oil, a known trigger for such reactions.

The Global Regulatory Landscape: A Case Study in Divergent Assessments

The regulatory history of Plitidepsin is highly unusual and serves as a compelling case study in how different national agencies can arrive at starkly different conclusions when evaluating the same clinical data, particularly when the data presents a nuanced risk-benefit profile.

Approval in Australia (TGA): World-First Registration

In a landmark decision, Australia's Therapeutic Goods Administration (TGA) granted marketing authorization for Aplidin® (Plitidepsin) in December 2018, making it the first and only major regulatory body to do so.[6] The approved indication is for use in combination with dexamethasone for the treatment of patients with relapsed and refractory multiple myeloma who have received at least three prior treatment regimens, including both a proteasome inhibitor and an immunomodulator. The indication also allows for its use in the third-line setting (after two prior lines of therapy) if a patient is refractory and/or intolerant to both of these key drug classes.[7] The TGA's approval suggests a regulatory philosophy that placed significant weight on the trial meeting its statistically significant primary endpoint of PFS, acknowledging the high unmet medical need in this heavily pretreated patient population and likely accepting the statistically modeled overall survival data as sufficient supportive evidence for a positive risk-benefit assessment.

The European Medicines Agency (EMA) Saga: Rejection, Annulment, and Withdrawal

Plitidepsin's journey with the European Medicines Agency was protracted, contentious, and ultimately unsuccessful.

• Initial Negative Opinion (2017-2018): In December 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of marketing authorization. This refusal was confirmed after a re-examination in March 2018.[1] The CHMP's core reasoning was that the drug's benefits did not outweigh its risks. Specifically, the committee highlighted the very modest PFS benefit of approximately one month, the lack of a demonstrated improvement in overall survival in the primary analysis, and the significant increase in severe side effects with the addition of Plitidepsin.[1]
• Legal Challenge and Annulment (2018-2024): In response, the developer PharmaMar took the highly unusual step of filing a lawsuit against the European Commission (EC), which formalizes the CHMP's recommendations. In October 2020, the General Court of the European Union ruled in favor of PharmaMar, annulling the EC's decision.[1] The court's ruling was not based on a re-evaluation of the scientific data, but on procedural grounds. It found that there was a conflict of interest involving an expert who participated in the EMA's Scientific Advisory Group for Plitidepsin while also being involved in the development of a competing product.[11]
• Re-evaluation and Withdrawal (2024-2025): After a series of appeals and further legal proceedings, the EC formally revoked its 2018 rejection decision in July 2024 and instructed the EMA to re-evaluate the marketing application from the point where the procedural irregularity occurred.[11] However, in a surprising turn, PharmaMar voluntarily withdrew its application for Aplidin® on July 23, 2025, during the re-examination process, officially citing a "change in their marketing strategy".[1] This strategic withdrawal, coming after a long and successful legal fight, strongly suggests a pragmatic corporate decision. While the company won the legal argument on procedure, the underlying clinical data from the ADMYRE trial remained unchanged. It is likely that the company concluded that a new scientific review by the CHMP would lead to the same negative conclusion on the risk-benefit balance. Withdrawing the application pre-emptively avoids a second formal rejection, allowing the company to pivot resources and preserve the drug's standing for other potential indications or regions.

Status in the United States (FDA) and Other Regions

In the United States, Plitidepsin has not been approved by the Food and Drug Administration (FDA) for any indication. It was granted Orphan Drug Designation for the treatment of acute lymphoblastic leukemia in 2004 (a designation that was later withdrawn or revoked) and for the treatment of multiple myeloma in 2004, a status it still holds.[12] This designation provides development incentives but does not confer marketing approval. Following the TGA's lead, approvals have reportedly been secured in some other markets in regions such as South America, Mexico, and Asia-Pacific, though it does not have widespread global registration.[26]

Emerging Potential as a Broad-Spectrum Antiviral Agent

In recent years, a new and potentially transformative therapeutic avenue has opened for Plitidepsin, leveraging its unique mechanism of action for antiviral purposes. This has shifted a significant portion of the research focus from oncology to infectious diseases.

Antiviral Mechanism of Action: Targeting a Host Factor

The antiviral activity of Plitidepsin is a direct extension of its anticancer mechanism: the inhibition of the host protein eEF1A.[1] Viruses are obligate intracellular parasites that lack their own machinery for protein synthesis and are therefore entirely dependent on co-opting the host cell's translational apparatus—including ribosomes and elongation factors like eEF1A—to replicate their proteins and build new virions.[23]

By binding to and inhibiting eEF1A, Plitidepsin disrupts a host factor that is critical for the lifecycle of numerous viruses. For coronaviruses like SARS-CoV-2, this inhibition has been shown to have a profound effect, specifically by blocking the biogenesis of double-membrane vesicles (DMVs). These DMVs are specialized organelles that the virus induces within the host cell to serve as protected sites for the replication of its RNA genome. By preventing the formation of these viral replication factories, Plitidepsin effectively halts the viral lifecycle at an early, post-entry step.[24]

This host-directed antiviral strategy carries a significant theoretical advantage over traditional antivirals that target specific viral proteins (e.g., proteases or polymerases). Viruses, particularly RNA viruses, have high mutation rates, which can lead to the rapid emergence of drug-resistant strains that render virus-targeted drugs ineffective. Because Plitidepsin targets a stable, conserved host protein, it is far less susceptible to being evaded by viral mutations. This makes it a promising candidate as a broad-spectrum antiviral, potentially effective against a wide range of viruses that depend on eEF1A for replication and resilient against newly emerging viral variants.[13]

Preclinical and Clinical Evidence in COVID-19

The potential of Plitidepsin as a treatment for COVID-19 was supported by exceptionally strong preclinical data.

• In vitro Potency: Multiple cell-based studies demonstrated that Plitidepsin is a highly potent inhibitor of SARS-CoV-2 replication. In one key study, its antiviral activity was found to be 27.5-fold more potent than that of remdesivir, which was a standard-of-care antiviral at the time.[14]
• In vivo Efficacy: This potent activity translated to animal models. In mouse models of SARS-CoV-2 infection, treatment with Plitidepsin resulted in a significant, multi-log reduction in viral loads in the lungs and a marked decrease in associated lung inflammation and pathology.[1]

These compelling preclinical results prompted rapid clinical investigation.

• APLICOV-PC Phase I/II Trial: An initial exploratory study in hospitalized patients with COVID-19 found that Plitidepsin was generally well-tolerated and was associated with a substantial reduction in patient viral load between days 4 and 7 of treatment, providing the first human signal of its antiviral effect.[14]
• NEPTUNO Phase III Trial (NCT04784559): This was designed as a large, multicenter, randomized, controlled trial to definitively evaluate the efficacy and safety of Plitidepsin in hospitalized adults with moderate COVID-19 requiring oxygen supplementation.[15] Unfortunately, the trial was discontinued prematurely after enrolling 205 of the planned 609 patients. The decision was made due to a significant global decline in COVID-19-related hospitalizations, which made further recruitment infeasible.[15] Because it was underpowered, the trial could not provide a definitive conclusion. However, the available data showed a positive trend favoring Plitidepsin. There was a 2-day improvement in the median time to sustained discontinuation of oxygen therapy in the Plitidepsin arms (5 days) compared to the standard of care control arm (7 days).[16]

While the NEPTUNO trial was inconclusive, the strong mechanistic rationale and positive signals have sustained interest in Plitidepsin as an antiviral. Research is ongoing, including a Phase II trial (NCT05705167) specifically evaluating its use as an antiviral therapy in high-risk, immunocompromised patients with hematological malignancies, a population that often struggles to clear viral infections.[16]

Synthesis and Forward-Looking Perspective

Plitidepsin stands as a unique therapeutic entity, defined by its marine origins, a first-in-class mechanism targeting the host protein eEF1A2, and a multifaceted pharmacology encompassing direct cytotoxicity, anti-angiogenic, and bone anti-resorptive properties. Its journey through clinical development and regulatory review has been a complex narrative of promise and challenge, culminating in a precarious clinical position and an intriguing, yet unproven, future potential.

In the treatment of relapsed/refractory multiple myeloma, Plitidepsin occupies a narrow and contested niche. The pivotal ADMYRE trial, while technically successful in meeting its primary endpoint of Progression-Free Survival, delivered a benefit that was statistically significant but of a magnitude that major regulators like the EMA deemed clinically marginal. This led to the highly divergent regulatory outcomes of a world-first approval in Australia versus a rejection in Europe. The subsequent withdrawal of the European application, even after a successful legal challenge, underscores the difficulty of gaining broad acceptance for a therapy with a modest efficacy signal and an added toxicity burden in a competitive therapeutic landscape. Its approval in Australia does, however, provide a valuable therapeutic alternative with a novel mechanism of action for a patient population with limited options.

The future of Plitidepsin in oncology is therefore uncertain. Its most viable path forward likely involves its use in combination with other anticancer agents, where its unique mechanism and favorable hematological safety profile could create synergistic effects.[32] Furthermore, the identification of predictive biomarkers related to eEF1A2 expression or function could help select patient populations most likely to derive a substantial benefit, enabling a more targeted and effective clinical application.

The most compelling and dynamic area for Plitidepsin's future development, however, has shifted decisively to virology. Its mechanism as a host-directed antiviral is scientifically elegant and addresses the critical challenge of viral resistance. The potent preclinical data against SARS-CoV-2 was among the strongest for any repurposed compound. Although the definitive Phase III NEPTUNO trial was cut short by the waning pandemic, rendering its results inconclusive, the positive trends observed, combined with the powerful mechanistic rationale, strongly support continued investigation. The true potential of Plitidepsin may lie not in its original indication, but as a broad-spectrum antiviral agent against other eEF1A-dependent viruses or as a critical tool in the arsenal against future pandemic threats.

Ultimately, the story of Plitidepsin is a powerful illustration of the complexities and uncertainties inherent in drug development. It demonstrates that a novel mechanism and a strong preclinical rationale are not, in themselves, guarantees of widespread clinical and regulatory success. The final chapter for this unique marine-derived compound has yet to be written, but its legacy may ultimately be defined by its ability to pivot from a challenging journey in oncology to a new and promising horizon in the global fight against viral diseases.

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