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Other cytotoxics, enzymes and natural productsUsed in a few countriesNatural productNeeds review

Plitidepsin

Also known as Aplidin, Aplidine, dehydrodidemnin B

A cyclic depsipeptide first isolated from a Mediterranean tunicate and now made by total synthesis. Registered in Australia in 2018 with dexamethasone for relapsed or refractory multiple myeloma; the EU application was withdrawn in 2025.

From discovery to approval

  1. 1988 · First described

    A 2000 review by Rinehart says dehydrodidemnin B (Aplidine) was isolated in 1988 from the tunicate Aplidium albicans and differs from didemnin B in having a pyruvyl group in place of a lactyl group. A 2024 paper gives plitidepsin as another name for dehydrodidemnin B, and a 2017 review says plitidepsin was first isolated from Aplidium albicans.[2][3][4][5][6]

  2. 1998 · First use in people · 10 years after first description

    A 2017 review states that phase I trials with plitidepsin started in 1998; Rinehart's 2000 review says PharmaMar introduced Aplidine into phase I trials in January 1999.[3]

  3. 2018-12-10 · other regular · 30 years after first description

    Australian Therapeutic Goods Administration (TGA) decision of 10 December 2018 (entry on the ARTG 12 December 2018, ARTG 291661; AusPAR): in combination with dexamethasone for relapsed and refractory multiple myeloma after at least three prior regimens including a proteasome inhibitor and an immunomodulator, and after two prior lines if refractory or intolerant to both. A new chemical entity; the AusPAR extract read gives no provisional or conditional wording, so 'regular' is an inference.[5]

How it works

The EMA says plitidepsin blocks the protein eEF1A2, which is involved in breaking down wrongly folded proteins. Blocking it makes these toxic proteins accumulate in myeloma cells, damaging them and leading to their death.[1]

Where it came from and why

Rinehart's review says didemnin B was the first marine-derived compound to enter phase I and II trials, with responses in non-Hodgkin lymphoma but dropped for cardiotoxicity, and that Aplidine was more active and lacked that cardiotoxicity. A 1996 comparison of 42 didemnin congeners found gains in activity for dehydrodidemnin B.

Cancers

  • Multiple myeloma

    The Australian registration of Aplidin with dexamethasone covers relapsed and refractory multiple myeloma after at least three prior regimens including a proteasome inhibitor and an immunomodulator, and after two prior lines if refractory or intolerant to both.[5]

Worth knowing

  • In ADMYRE, median progression-free survival (independent review committee) was 2.6 months with plitidepsin plus dexamethasone versus 1.7 months with dexamethasone alone (hazard ratio 0.650, p = 0.0054); median overall survival was 11.6 versus 8.9 months (hazard ratio 0.797, p = 0.1261).[7]
  • On 23 July 2025 PharmaMar withdrew its EU application for Aplidin during a re-examination, after the EMA had recommended refusal because of a modest gain of about one month in progression-free survival and insufficiently shown overall survival benefit; the company's letter gave a change in its marketing strategy as the reason.[1]
  • A 2017 review states that single-agent plitidepsin showed limited antitumour activity in several malignancies, including peripheral T-cell lymphoma, melanoma and multiple myeloma.[3]

References

  1. European Medicines Agency. Withdrawal of application for the marketing authorisation of Aplidin (plitidepsin), EMA/243003/2025, 25 July 2025. Source
  2. Rinehart KL. Antitumor compounds from tunicates. Med Res Rev. 2000;20(1):1-27. PubMedDOI
  3. Alonso-Álvarez S, Pardal E, Sánchez-Nieto D, Navarro M, Caballero MD, Mateos MV, et al. Plitidepsin: design, development, and potential place in therapy. Drug Des Devel Ther. 2017;11:253-264. PubMedDOI
  4. Sakai R, Rinehart KL, Kishore V, Kundu B, Faircloth G, Gloer JB, et al. Structure--activity relationships of the didemnins. J Med Chem. 1996;39(14):2819-34. PubMedDOI
  5. Therapeutic Goods Administration (Australia). Australian Public Assessment Report for plitidepsin, proprietary product name Aplidin, sponsor Specialised Therapeutics Pharma Australia Pty Ltd, PM-2017-02669-1-4, final, 13 May 2019. Source
  6. Zhang H, Li X, Hui Z, Huang S, Cai M, Shi W, et al. A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs. Angew Chem Int Ed Engl. 2024;63(12):e202318784. PubMedDOI
  7. Spicka I, Ocio EM, Oakervee HE, Greil R, Banh RH, Huang SY, 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. PubMedDOI
  8. Gomes NGM, Valentão P, Andrade PB, Pereira RB. Plitidepsin to treat multiple myeloma. Drugs Today (Barc). 2020;56(5):337-347. PubMedDOI