Plitidepsin
A sea-squirt-derived cancer drug that blocks the protein-making factor eEF1A, tried in myeloma and in COVID-19
Plitidepsin was first found in a Mediterranean sea squirt and is now made in the laboratory. It jams eEF1A, a factor cells need to build proteins, which slows cancer cells and also stops viruses from using the cell's machinery. Australia registered it in December 2018, as Aplidin with dexamethasone, for multiple myeloma that has come back after several treatments; Europe's medicines committee recommended refusal in 2017-2018 and again in 2025, when the company withdrew its application; FDA has not approved it. A phase 3 COVID-19 trial stopped early. It is an intravenous hospital cancer drug.
Manufacturer's recommended dosing (Australian label, TGA): 5 mg/m² (with dexamethasone), 3-hour infusion on days 1 and 15 of each 4-week cycle, Intravenous Details ↓
Recommended Dosing
Manufacturer's recommended dosing (Australian label, TGA)
From the prescribing information. Other doses studied, if any, are in the full dosing data below.
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Plitidepsin was isolated from Aplidium albicans, a small sea squirt from the Mediterranean, and is now manufactured by total synthesis under the name Aplidin. Chemically it is a cyclic depsipeptide: a ring of amino acid-derived units in which some links are ester bonds rather than the usual peptide bonds. It is given by intravenous infusion and spreads widely through the body, with red blood cells acting as a major reservoir.
Its target is eEF1A, the elongation factor that brings each new amino acid to the ribosome while a protein is being built. A 2016 study found it binds the eEF1A2 form, which many tumours overproduce, and that cancer cells made resistant to it had lost eEF1A2; putting the protein back restored sensitivity. Because viruses depend on the same machinery to make their proteins, a 2021 Science paper tested it against SARS-CoV-2 and found it about 27 times more potent than remdesivir in cell culture, acting through eEF1A, and it cut virus levels in mouse lungs a hundredfold when given beforehand.
As a cancer drug it had a long and uneven path. Single-agent trials from the 2000s found muscle toxicity was the dose-limiting effect and that activity was limited: modest responses in multiple myeloma, about one in five responses in peripheral T-cell lymphoma, and failure in dedifferentiated liposarcoma and other solid tumours. Adding dexamethasone in myeloma raised the response rate, which led to the phase 3 ADMYRE trial in 255 patients with myeloma that had returned after three to six earlier treatments. Plitidepsin plus dexamethasone delayed progression compared with dexamethasone alone (median 2.6 against 1.7 months, a 35% lower risk), but overall survival (11.6 against 8.9 months) was not significantly different, partly because many control patients crossed over.
Regulators read those results differently. Australia's Therapeutic Goods Administration registered Aplidin on December 10, 2018 (ARTG 291661), with dexamethasone, for relapsed and refractory myeloma after at least three earlier regimens including a proteasome inhibitor and an immunomodulatory drug, at 5 mg/m² on days 1 and 15 of each 4-week cycle. Its assessment noted raised liver enzymes in most treated patients and an unconvincing survival result. In Europe the medicines committee gave negative opinions in late 2017 and early 2018. PharmaMar challenged the refusal over a conflict of interest on the expert panel, the EU General Court ruled in its favour in October 2020, and in 2024 the application went back to the European Medicines Agency for reassessment; refusal was recommended again in 2025, and PharmaMar withdrew the application on July 23, 2025, citing a change in marketing strategy. FDA has never received an application. Whether the Australian registration is still active today could not be confirmed: the ARTG record (291661) could not be read on October 29, 2026, so treat it as registered in 2018 rather than as currently marketed.
The COVID-19 programme followed the Science paper. A Spanish phase 1 trial gave 1.5 to 2.5 mg a day for three days to 46 hospitalised adults, with nausea the main side effect and falling viral loads, and patients followed for 16 months later had no long-term complications attributed to it. The phase 3 NEPTUNO trial, planned for 609 patients, stopped after 205 because COVID-19 admissions fell; the time to coming off oxygen was two days shorter on plitidepsin, which did not reach statistical significance. Spanish doctors have since used it on compassionate grounds in immunocompromised patients who cannot clear the virus.
It is a cytotoxic drug given by intravenous infusion in hospital under specialist supervision. It is not sold as a research peptide and has no use outside cancer and antiviral trials.
Mechanism of Action
Plitidepsin binds the elongation factor eEF1A, which cells use to build proteins; that drives both its anticancer and its antiviral effects.
eEF1A2 binding
It binds eEF1A2 between its first two domains (KD about 80 nM); resistant cancer cells had less eEF1A2, and restoring it restored sensitivity (2016 study).
Host-directed antiviral action
By blocking eEF1A it stops SARS-CoV-2 from translating its proteins; a drug-resistant eEF1A mutant confirmed the target (2021 Science study).
Distribution and elimination
It concentrates in red blood cells and is cleared mainly through bile into the faeces, with little in urine (radiolabelled study).
Published Research
Studies of plitidepsin (Aplidin, aplidine) itself, read from their PubMed abstracts: the phase 3 myeloma trial and its analyses, earlier phase 1 and 2 trials, the COVID-19 trials, and the laboratory studies that identified its target.
ADMYRE phase 3 in myeloma
In 255 patients with relapsed or refractory myeloma after 3 to 6 regimens, plitidepsin 5 mg/m² on days 1 and 15 plus dexamethasone, against dexamethasone alone, gave median progression-free survival of 2.6 vs 1.7 months (HR 0.65). Overall survival was 11.6 vs 8.9 months, not significant (HR 0.80), with 37 control patients crossing over. Fatigue, myalgia and nausea were the commonest grade 3/4 effects.
ADMYRE, patients under 75
In the pre-planned subgroup under 75 (216 of 255 patients), plitidepsin plus dexamethasone cut the risk of progression or death by 48% and gave median survival of 13.0 vs 8.1 months (p = 0.035). Fatigue and nausea each affected 39% of treated patients.
Against pomalidomide, external control
Matched against individual patient data from pomalidomide-plus-dexamethasone trials, ADMYRE's plitidepsin arm had similar median survival (11.8 vs 13.9 months, HR 1.01), with fewer severe neutropenias (2.5% vs 37%) and infections but more gut side effects and raised creatine kinase. It is not a randomised comparison.
Phase 2 in myeloma
Fifty-one patients received 5 mg/m² every two weeks by 3-hour infusion. Response was 13% on plitidepsin alone and 22% after dexamethasone was added; anaemia, low platelets, fatigue and transient rises in liver enzymes and creatine kinase were the main toxicities.
With bortezomib and dexamethasone
In a phase 1 trial in 36 patients, the full doses (plitidepsin 5 mg/m², bortezomib 1.3 mg/m², dexamethasone 40 mg) were tolerated; at that dose 22% responded and 78% had clinical benefit, with low platelets in 46% and grade 3 ALT rises in 26%.
First phase 1 and pharmacokinetics
Sixty-seven patients with advanced cancers received 0.2 to 8 mg/m² as a 24-hour infusion every two weeks. Muscle toxicity with raised creatine kinase limited the dose; carnitine allowed an increase from 5 to 7 mg/m². The plasma half-life was 21 to 44 hours with a very large volume of distribution.
Where the drug goes
Six patients received radiolabelled plitidepsin. Over 20 days, 77% of the radioactivity was recovered, 71% in faeces and 6% in urine; blood held 3.7 times more than plasma, showing red cells as a main reservoir and bile as the main exit route.
Phase 2 in lymphoma
In 67 patients with relapsed aggressive non-Hodgkin lymphoma given 3.2 mg/m² weekly for three weeks of four, 21% of 29 with peripheral T-cell lymphoma responded (two complete responses), while none of 30 with other lymphomas did.
Phase 2 in liposarcoma
Twenty-four patients with dedifferentiated liposarcoma received 5 mg/m² on days 1 and 15. Only 9% were free of progression at three months against a 40% target, so the trial was negative.
Phase 1 in COVID-19
Forty-six adults hospitalised with COVID-19 received 1.5, 2.0 or 2.5 mg daily for three days. Two grade 3 related events occurred (hypersensitivity and diarrhoea); nausea affected 42%. Viral load fell by 1.35 log at day 4 and 3.85 log by day 31, and the drug reached higher levels in lung than plasma in preclinical work.
NEPTUNO phase 3 in COVID-19
In hospitalised adults needing oxygen, randomised to 1.5 or 2.5 mg a day for three days with dexamethasone or to standard care, the trial stopped at 205 of 609 planned patients as admissions fell. Time off oxygen was about two days shorter on plitidepsin (5 vs 7 days), not statistically significant (HR 1.37, p = 0.08, for 1.5 mg).
Long-term COVID-19 follow-up
Thirty-four patients from the phase 1 trial were reviewed about 17 months later: none had grade 3/4 late complications or heart rhythm changes, and most had normal lung function tests.
Compassionate use in immunocompromised patients
Fifty-four people with cancer and COVID-19 received plitidepsin outside trials. Those previously given anti-CD20 antibodies took longer to clear the virus (33 vs 15 days); no serious adverse events were recorded.
SARS-CoV-2 activity
In cell culture plitidepsin blocked SARS-CoV-2 at a 90% inhibitory concentration of 0.88 nM, 27.5 times more potent than remdesivir; a resistant eEF1A mutant confirmed the target, and preventive dosing cut lung virus a hundredfold in two mouse models.
eEF1A2 as the target
Plitidepsin bound eEF1A2 with a KD of 80 nM; tumour cells selected for 100-fold resistance had less eEF1A2, and restoring the protein restored sensitivity, pointing to eEF1A2 as its main anticancer target.
Development review
Single-agent plitidepsin had limited but tolerable activity in T-cell lymphoma, melanoma and myeloma; adding dexamethasone helped in myeloma, while results in other blood cancers and solid tumours were disappointing.
COVID-19 review
This review summarises its eEF1A mechanism and early COVID-19 data and concludes that clinical evidence was not yet enough for registration in COVID-19; it notes intravenous use limits it to hospitals.
Dosing Data
The first row is the dose in the Australian registration of Aplidin (TGA, AusPAR 2019), an Australian label rather than an FDA one; it follows the ADMYRE trial schedule. The other rows are doses given in the published human trials carded above.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no regulator's label that says in what form Plitidepsin is supplied. It is prepared and given by clinical staff, not bought and mixed at home: the next part says where.
Mixing a vial: a worked example
Nothing to mix at home, and no syringe units to work out: Plitidepsin is prepared and given by clinical staff, by a cancer team in hospital.
In the carded studies it was given as a 3-hour or 24-hour infusion into a vein every two weeks.
Source: PMID 20530693 and PMID 16172454 (studies carded under Research below).
Storage before and after mixing
Unknown: no label on file says how Plitidepsin is stored. It is kept and prepared by the hospital or clinic that gives it (see the part above); the home rules for a mixed vial in the mixing guide do not apply to it.
How it is taken
As the approved label gives it: Intravenous (3-hour infusion on days 1 and 15 of each 4-week cycle; Aplidin, relapsed/refractory myeloma after 3 or more regimens (Australian label)).
Source: Manufacturer's recommended dosing (Australian label, TGA): the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Aplidin, relapsed/refractory myeloma after 3 or more regimens (Australian label): Ongoing cycles.
When effects appear: unknown; no source on this page gives a time to effect for Plitidepsin. Results reported in the studies are under Published Research.
Source: Manufacturer's recommended dosing (Australian label, TGA), the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: Fatigue, nausea, vomiting and diarrhoea, the commonest effects across trials; Muscle pain and weakness with raised creatine kinase; muscle toxicity limited the dose in phase 1; Raised liver enzymes: ALT rose in about 85% of treated patients in ADMYRE (AusPAR); Low platelets and anaemia, more marked when combined with bortezomib; Hypersensitivity reactions (one patient in the COVID-19 phase 1 trial). Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Plitidepsin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the trials above and the Australian assessment report”).
Interactions
Unknown: a PubMed search for human interaction studies of Plitidepsin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Plitidepsin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Plitidepsin's expected mass, 1,110.3 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Not FDA Approved (Not approved in the US: no Drugs@FDA application (openFDA, searched October 29, 2026)). Elsewhere: approved in Australia (registered December 2018, ARTG 291661, relapsed/refractory multiple myeloma with dexamethasone; current status not confirmed October 29, 2026). Sport: Not on the 2026 List.
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the trials above and the Australian assessment report.
Contraindications & Cautions
From the Australian assessment report (2019) and the studies above:
Legal Status
Plitidepsin was registered once, in Australia; it is not approved in the US or the EU.
Frequently Asked Questions
?What is plitidepsin?
A cancer drug first found in a Mediterranean sea squirt and now made synthetically, sold in Australia as Aplidin. It blocks eEF1A, a factor cells use to make proteins.
?Where is it approved?
Australia registered it in 2018 for multiple myeloma that has returned after several treatments, given with dexamethasone. Europe refused it and the application was withdrawn in 2025; it has never been approved in the US.
?Did it work for COVID-19?
It was very potent against the virus in the laboratory, and a phase 1 trial was encouraging, but the phase 3 NEPTUNO trial stopped early when hospital admissions fell and its small advantage in time off oxygen was not statistically significant.
?How well does it work in myeloma?
Modestly. In the phase 3 trial, adding it to dexamethasone delayed progression by about a month on average, and the survival difference was not statistically significant in the whole group.
?Can I buy it?
No. It is an intravenous cytotoxic drug given in hospital under specialist care. It is not a research peptide and is not available for personal use.
References
- [other] PubChem CID 9812534, Plitidepsin: formula C57H87N7O15, molecular weight 1110.3. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/9812534
- [registry] ClinicalTrials.gov API v2, read October 28, 2026: NCT04784559 (phase 3, moderate COVID-19, terminated); NCT03117361 (phase 2, multiple myeloma with bortezomib and dexamethasone, terminated).
- [other] Therapeutic Goods Administration, Australian Public Assessment Report for Plitidepsin (Aplidin), 2019: decision December 10, 2018; ARTG 291661 entered December 12, 2018; 5 mg/m² on days 1 and 15 of a 4-week cycle with dexamethasone; ADMYRE results and liver enzyme findings. Read October 29, 2026.
- [other] Synapse (Patsnap), 'PharmaMar's MM drug gains another shot at EU approval', July 15, 2024: CHMP negative opinions in late 2017 and early 2018; the General Court annulled the decision in October 2020 over a conflict of interest; EMA to reassess the application. Read October 29, 2026.
- [other] US FDA, Drugs@FDA (openFDA): no application for plitidepsin. Searched October 29, 2026.
- [other] European Medicines Agency, Aplidin: withdrawal of application (re-examination), withdrawn by PharmaMar on July 23, 2025, citing a change in marketing strategy; page last updated October 6, 2025. Read October 29, 2026.
- [clinical-trial] Spicka I, et al. "Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma." Ann Hematol, 2019;98(9):2139-2150. PMID: 31240472.
- [pubmed] Mateos MV, et al. "Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Relapsed/Refractory Multiple Myeloma: Results for Patients Aged <75 Years." Cancers (Basel), 2025;17(21). PMID: 41228275.
- [pubmed] Ludwig H, et al. "Plitidepsin in combination with dexamethasone (ADMYRE trial) versus an external control arm of pomalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma." Ann Hematol, 2026;105(1):26. PMID: 41545603.
- [clinical-trial] Mateos MV, et al. "Phase II clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two weeks alone or with dexamethasone in relapsed and refractory multiple myeloma." Clin Cancer Res, 2010;16(12):3260-9. PMID: 20530693.
- [clinical-trial] Mateos MV, et al. "Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma." Cancer Med, 2023;12(4):3999-4009. PMID: 36127823.
- [clinical-trial] Faivre S, et al. "Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies." J Clin Oncol, 2005;23(31):7871-80. PMID: 16172454.
- [clinical-trial] van Andel L, et al. "Pharmacokinetics and excretion of (14)C-Plitidepsin in patients with advanced cancer." Invest New Drugs, 2017;35(5):589-598. PMID: 28111728.
- [clinical-trial] Ribrag V, et al. "Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma." Haematologica, 2013;98(3):357-63. PMID: 23065525.
- [clinical-trial] Toulmonde M, et al. "Aplidin in patients with advanced dedifferentiated liposarcomas: a French Sarcoma Group Single-Arm Phase II study." Ann Oncol, 2015;26(7):1465-70. PMID: 26041763.
- [clinical-trial] Varona JF, et al. "Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19." Life Sci Alliance, 2022;5(4). PMID: 35012962.
- [clinical-trial] Landete P, et al. "A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19." Clin Infect Dis, 2024;79(4):910-919. PMID: 39182994.
- [pubmed] Varona JF, et al. "Plitidepsin in adult patients with COVID-19 requiring hospital admission: A long-term follow-up analysis." Front Cell Infect Microbiol, 2023;13:1097809. PMID: 36909731.
- [pubmed] Aguareles J, et al. "Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment." Infect Dis (Lond), 2024;56(7):575-580. PMID: 38743059.
- [pubmed] White KM, et al. "Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A." Science, 2021;371(6532):926-931. PMID: 33495306.
- [pubmed] Losada A, et al. "Translation Elongation Factor eEF1A2 is a Novel Anticancer Target for the Marine Natural Product Plitidepsin." Sci Rep, 2016;6:35100. PMID: 27713531.
- [review] Alonso-Álvarez S, et al. "Plitidepsin: design, development, and potential place in therapy." Drug Des Devel Ther, 2017;11:253-264. PMID: 28176904.
- [review] Papapanou M, et al. "Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19." J Pers Med, 2021;11(7). PMID: 34357135.
Sources & Citations
Studies were read from their PubMed abstracts on October 29, 2026; regulatory status from the TGA's AusPAR for plitidepsin (2019), the EMA Aplidin page (last updated October 6, 2025), Drugs@FDA (openFDA) and ClinicalTrials.gov, read October 28-29, 2026. The formula is PubChem's.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.