Plitidepsin (also known as dehydrodidemnin B, marketed by

PharmaMar PharmaMar is a Spanish pharmaceutical company headquartered in Colmenar Viejo, Madrid, Spain. Founded in 1986 as a subsidiary of Zeltia, it absorbed its parent company and all its subsidiaries in a reverse merger takeover in 2015. The company ...

, S.A. under the trade name Aplidin) is a

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one ele ...

extracted from the

ascidian Ascidiacea, commonly known as the ascidians, tunicates (in part), and sea squirts (in part), is a polyphyletic class in the subphylum Tunicata of sac-like marine invertebrate filter feeders. Ascidians are characterized by a tough outer "tunic ...

''Aplidium albicans''. It is currently undergoing clinical trial testing. It is a member of the class of compounds known as

didemnin Didemnins are cyclic depsipeptide compounds isolated from a tunicate (ascidian, or sea-squirt) of the genus '' Trididemnum'' (family of Didemnidæ) that were collected in the Caribbean Sea. They were first isolated in 1978 at the University of ...

Chemical structure

Plitidepsin is a cyclic

depsipeptide A depsipeptide is a peptide in which one or more of its amide, -C(O)NHR-, groups are replaced by the corresponding ester, -C(O)OR, Many depsipeptides have both peptide and ester linkages. Elimination of the N–H group in a peptide structure results ...

, meaning it is a

cyclic Cycle, cycles, or cyclic may refer to: Anthropology and social sciences * Cyclic history, a theory of history * Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr. * Social cycle, various cycles in so ...

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

in which there is one or more

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

bond in place of one or more of a peptide bond. Its chemical structure is very close to that of didemnin B, the only difference being that the

lactate Lactate may refer to: * Lactation, the secretion of milk from the mammary glands * Lactate, the conjugate base of lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with ...

residue in didemnin B is present in the

oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a de ...

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...

version.

Pharmacological activity

Like all didemnin compounds, plitidepsin exhibits

antitumor Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. ...

antiviral Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do no ...

and

immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...

activities. It shows promise in shrinking tumors in pancreatic, stomach, bladder, and prostate cancers. Plitidepsin inhibits the human protein eEF1A which has potential interactions with multiple coronavirus proteins. Plitidepsin possesses

activity against

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a No ...

in vitro and in an in vivo mouse model.

Marketing authorisation status

European Union

In July 2003, plitidepsin was granted

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...

status by the European Medicines Agency for treating acute lymphoblastic leukemia. On 14 December 2017, EMA´s Committee for Medicinal Products for Human Use adopted a negative opinion, recommending the refusal of the marketing authorisation for the treatment of

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ane ...

. PharmaMar requested a re-examination of the initial opinion. After a re-examination of the opinion, the refusal of the marketing authorisation was confirmed on 22 March 2018. The CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks. Improvement in overall survival was not sufficiently demonstrated, and severe side effects were reported more frequently with the combination of Aplidin and dexamethasone than with dexamethasone alone. On 1 October 2018, PharmaMar appealed against this decision, alleging a lack of impartiality on the part of certain members of the Scientific Advisory Group that had advised the CHMP. On 28 October 2020, the General Court upheld PharmaMar's appeal and annulled the decision refusing marketing authorisation for Aplidin, and the European Commission then returned the application for Aplidin to the EMA.

Australia

In Australia plitidepsin was approved in December 2018, 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. It may be used after two prior lines of therapy if refractory and/or intolerant to both a proteasome inhibitor and an immunomodulator.

Clinical trials

As of 2007, it was undergoing multicenter

phase II clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

. In 2016, early results in a small phase I trial for

were announced.

References

{{Chemotherapeutic agents Depsipeptides Experimental cancer drugs