Plitidepsin

Mechanism

A cyclic peptide originally extracted from a Mediterranean sea squirt. It has been approved in Australia for treating multiple myeloma (a blood cancer). During the COVID-19 pandemic, lab studies showed it was about 27 times more potent against SARS-CoV-2 than remdesivir, highlighting the pharmaceutical potential of marine-derived peptides.

Effects

ONCOLOGY/ANTIVIRAL: Plitidepsin (Aplidin) is a cyclic depsipeptide originally isolated from the Mediterranean sea squirt Aplidium albicans, now produced synthetically. It targets eukaryotic elongation factor 1A2 (eEF1A2), a protein overexpressed in many tumor types that plays roles in protein synthesis, cytoskeletal organization, and apoptosis regulation [in vitro, crystallographic — Losada et al., 2016]. MECHANISM: Binds eEF1A2 with high affinity, disrupting protein synthesis and inducing oxidative stress, JNK activation, and mitochondrial-mediated apoptosis. eEF1A2 is a 'non-oncogene addiction' target — cancer cells are more dependent on it than normal cells due to their high protein synthesis demands [in vitro, animal]. ONCOLOGY: Approved in Australia (2018) for relapsed/refractory multiple myeloma in combination with dexamethasone, based on the ADMYRE Phase 3 trial [RCT]. Overall response rate in combination: ~23% (modest), but with durable responses in some patients. Activity also demonstrated in T-cell lymphoma, angioimmunoblastic T-cell lymphoma, and other hematologic malignancies [Phase 2]. ANTIVIRAL (COVID-19): Plitidepsin demonstrated remarkable in vitro antiviral activity against SARS-CoV-2 — 27.5-fold more potent than remdesivir in Vero E6 cells (IC90 = 0.88 nM) [in vitro — White et al., 2021, Science]. Mechanism: by targeting eEF1A2, plitidepsin blocks viral protein synthesis (host-directed antiviral action) — the virus cannot replicate without the host translation machinery. This host-directed mechanism is resistant to viral mutations and variants. In vivo (mouse): 99% reduction in lung viral titers with plitidepsin treatment [animal]. Phase 1/2 APLICOV trial in hospitalized COVID-19: promising signal for viral load reduction and clinical improvement, but small sample size [Phase 1/2]. IMMUNE: Immunomodulatory effects — may reduce cytokine storm via eEF1A-dependent mechanisms [theoretical, animal]. TOXICITY: Myelosuppression (neutropenia, thrombocytopenia), hepatotoxicity (transaminase elevation), nausea/vomiting, fatigue, myalgia. QTc prolongation reported — cardiac monitoring required [clinical trials]. Infusion-related reactions [clinical].

Practitioner Guide

AVAILABILITY: Plitidepsin (Aplidin) has limited availability. Approved in Australia for relapsed/refractory myeloma (in combination with dexamethasone) since 2018. Not FDA-approved in the US; not EMA-approved in Europe (EMA rejected in 2018, later approved in Australia by TGA). Available through clinical trials or compassionate use in some jurisdictions. ADMINISTRATION: IV infusion over 3 hours on Days 1 and 15 of 28-day cycles (myeloma regimen). Standard myeloma dose: 5 mg/m² with dexamethasone 40mg weekly. COVID-19 trials used 1.5-2.5 mg/day IV for 3 consecutive days. Requires anti-emetic premedication (5-HT3 antagonist + dexamethasone). MONITORING: ECG before each cycle and during infusion (QTc prolongation risk). CBC weekly during first 2 cycles, then before each cycle. LFTs before each cycle. Electrolytes (correct hypokalemia and hypomagnesemia before dosing — QTc risk). MARINE PEPTIDE FRONTIER: Plitidepsin exemplifies the promise of marine natural products — the ocean is an untapped source of bioactive peptides with mechanisms of action not found in terrestrial organisms. Other marine peptide-derived drugs: trabectedin (Yondelis, sea squirt), ziconotide (Prialt, cone snail), cytarabine (sponge-derived). The sea squirt-to-synthetic pipeline demonstrates that natural product discovery and total synthesis can yield viable therapeutics. COVID-19 CONTEXT: The 27.5x potency vs. remdesivir generated enormous excitement in 2021, but clinical translation has been slow. Host-directed antivirals (targeting host factors rather than viral proteins) have the theoretical advantage of being variant-proof, but the therapeutic window is narrower because you are interfering with host cell processes. Plitidepsin's clinical development for COVID-19 was ultimately deprioritized as vaccines and other antivirals became available. CLINICAL CONTEXT: For myeloma practitioners, plitidepsin is a late-line option for multiply relapsed patients who have exhausted proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and other standard options. The response rate is modest (~23%) but it offers a completely novel mechanism when resistance to standard classes has developed.

Evidence

• A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19

  Landete P et al. (2024) — Clin Infect Dis — PMID: 39182994

  In the NEPTUNO phase III trial, enrollment stopped early after 205 randomized patients, but plitidepsin arms showed a numerically shorter median time to sustained oxygen withdrawal (5 vs 7 days for 1.5 mg vs control; HR 1.37, 95% CI 0.96-1.96) and were generally well tolerated.

  moderate

Research Summary

TIER 1: ADMYRE Phase 3 RCT (Spicka et al., 2019): plitidepsin + dexamethasone vs. dexamethasone alone in relapsed/refractory myeloma — improved PFS (3.8 vs. 1.9 months, HR 0.63) and ORR (23% vs. 9%). TGA (Australia) approved 2018. EMA rejected 2018 (insufficient benefit-risk). Phase 1/2 APLICOV-PC (Varona et al., 2022 — preliminary): plitidepsin for hospitalized COVID-19 — signal for viral load reduction and improved clinical outcomes but underpowered. TIER 2: White et al., 2021 (Science): seminal paper demonstrating 27.5x greater potency than remdesivir against SARS-CoV-2 in vitro, with 99% lung viral titer reduction in mouse models. Losada et al., 2016: identification of eEF1A2 as the primary plitidepsin target via chemical proteomics. Reviews of marine natural products in oncology (Newman & Cragg, 2016). Phase 2 data in T-cell lymphoma and other hematologic malignancies. TIER 3: Case reports of plitidepsin use in heavily pretreated myeloma. Conference presentations from ASCO and ASH on expanded access data. Marine peptide pipeline reviews identifying other sea squirt-derived candidates. KEY FINDINGS: Plitidepsin is scientifically fascinating — a marine peptide with a validated novel target (eEF1A2) and an extraordinary COVID-19 story. However, commercial and clinical development has been challenging: modest response rates in myeloma, EMA rejection, and the COVID-19 therapeutic window closing with vaccine availability. The eEF1A2 mechanism and host-directed antiviral concept remain important for future drug development. GAPS: No large COVID-19 Phase 3 data. Biomarker selection for myeloma responders not established. Combination strategies with standard myeloma drugs underexplored. Oral formulation not available. ACTIVE TRIALS: PharmaMar continues development — plitidepsin in combination regimens for hematologic malignancies and potential pandemic preparedness stockpiling for future coronavirus outbreaks.