Plitidepsin – sea creature extract being tested for COVID-19
Scientists have been trying to repurpose drugs that have already been approved for one purpose for a new use—as treatment or prevention for SARS-CoV-2 infection.
For instance, the steroid dexamethasone, detailed later in this issue of TreatmentUpdate, has been found to improve the chances of survival of hospitalized people with COVID-19 who are receiving supplementary oxygen or invasive mechanical ventilation. Dexamethasone probably had this effect because it reduced the severe inflammation that is associated with serious symptoms of COVID-19. Dexamethasone may also have other effects on this new disease that are as yet little understood.
Dexamethasone is also used as part of a treatment against a cancer of B-cells called multiple myeloma. Due to this connection, some scientists in Spain and the U.S. think that another drug used for multiple myeloma—plitidepsin—could be repurposed as a potential treatment for COVID-19.
A biological mini-factory
Like many viruses, when SARS-CoV-2 infects a cell, it attempts to hijack the cell’s processes—its biological machinery—for its own purpose. That is, the virus (or nearly all viruses) attempts to turn an infected cell into a mini-virus factory, churning out copies of the infecting virus. SARS-CoV-2 does this by taking over the cellular machinery, particularly the parts of the cell that are used to make proteins. One cellular factor involved in the production of proteins has been labelled by scientists as eEF1A (eukaryotic translation elongation factor 1A).
Several viruses interfere with or attempt to take over eEF1A, including the flu virus, HIV and now SARS-CoV-2.
Plitidepsin in the lab
A Spanish company, PharmaMar, has extracted a compound found in ocean-dwelling creatures called sea squirts and made it into a drug called plitidepsin, which is used to treat multiple myeloma. In lab experiments with cells infected with SARS-CoV-2, very small concentrations of plitidepsin can significantly reduce production of this virus. Plitidepsin is also active against a common variant of SARS-CoV-2 called B117.
In experiments with mice infected with SARS-CoV-2, plitidepsin reduced levels of this virus by almost 100-fold and significantly reduced inflammation in the lungs caused by the virus.
Plitidepsin in people
PharmaMar has conducted a phase I/II study of plitidepsin, in which three groups of participants were given one of the following doses of the drug intravenously over three consecutive days:
- 1.5 mg
- 2.0 mg
- 2.5 mg
According to PharmaMar, plitidepsin reduced the amount of SARs-CoV-2 in people by 50% on day seven and 70% on day 15. The company has stated that 81% of participants were able to leave the hospital on or before their fifteenth day of hospitalization.
PharmaMar has expanded its study by enrolling more participants. It is also in discussion with regulatory authorities about a phase III clinical trial.
The doses of plitidepsin used in this study are relatively low and the company stated that they are “well tolerated in patients with minimal side effects.”
This is an important consideration because drugs that affect cellular processes (rather than having direct antiviral effects) carry the possibility of injuring cells, and this manifests as side effects. However, like most drugs that are being tested for potential in COVID-19, plitidepsin would only be used for a short period, which would reduce its potential for side effects.
For the future
The combination of plitidepsin and dexamethasone has been used safely in clinical trials with people who have multiple myeloma. This raises the possibility that both drugs could also be tested in people with severe symptoms of COVID-19.
Plitidepsin has to be given intravenously, which is not ideal in a pandemic where hospitals, clinics and their staff are busy or overwhelmed. If plitidepsin is successful in further clinical trials, it is possible that PharmaMar can invest in the science underpinning the development of an oral formulation of plitidepsin or an analogue.
As plitidepsin acts on cellular processes rather than directly on the virus, it is likely that the drug will retain its antiviral activity against variants of SARS-CoV-2 as well as other coronaviruses. This latter property may make it useful should a future coronavirus pandemic arise.
—Sean R. Hosein
- Martinez MA. Plitidepsin: a repurposed drug for the treatment of COVID-19. Antimicrobial Agents and Chemotherapy. 2021; in press.
- White KM, Rosales R, Yildiz S, et al. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 2021 Feb 26;371(6532):926-931.
- Wong JP, Damania B. SARS-CoV-2 dependence on host pathways. Science. 2021 Feb 26;371(6532):884-885.
- Reuschl AK, Thorne L, Zuliani Alvarez L, et al. Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B117 variant. BioRxiv [Preprint]. 2021 Jan 24:2021.01.24.427991.