An article on the preclinical potency of plitidepsin against SARS-CoV-2 was published this Tuesday in the journal Science . As a consequence, some media have highlighted the results very vehemently. For example, that “it reduces the viral load of SARS-CoV-2 by almost 100%” and even that “it is the most powerful antiviral that has ever been described.” The president of the production company has also stated that “with two or three injections at non-toxic doses we will cure the disease” caused by the coronavirus.
We understand that scientific communication should be much more prudent and cautious when reporting on the results of this type of preclinical trials with therapeutic agents aimed at such a relevant pathology, from a health and social impact point of view, such as covid-19. Creating an environment of maximum expectations among the population could be counterproductive, even in the short term.
Plitidepsin, developed by the Spanish pharmaceutical company PharmaMar, and whose trademark is Aplidin, is an active ingredient with antiviral and antitumor properties of marine origin. This agent causes the destruction of cancer cells through apoptosis, which is the process of programmed cell death used by the body to get rid of cells that have been irreversibly damaged.
Before the COVID-19 pandemic, this drug had been evaluated as an antitumor agent against different types of cancer, mainly multiple myeloma. At the moment, plitidepsin has only been approved in Australia as a first-line drug for the treatment of this disease, but it has not received authorization from the European Medicines Agency for any indication. The reasons are not only efficiency but, fundamentally, safety.
The biological target on which plitidepsin acts is the protein eEF1A2. When it binds to it, it blocks its pro-oncogenic property and prevents the transport of poorly sequenced proteins, which are toxic to the tumor, to the proteasome for destruction. It also prevents the activation of the aggresome by eEF1A2 and its destruction in cell lysosomes. These biological effects cause an excess of poorly sequenced proteins and cell death by apoptosis. Some studies have identified this protein in SARS-CoV viruses, which has led to the theoretical suggestion that it could be effective against the coronavirus.
What are the new contributions?
The new preclinical study has been carried out by researchers from PharmaMar Spain together with other North American and French centers. It has been carried out through in vitro cell culture assays and in vivo mice and provides new data in relation to this antitumor agent.
Plitidepsin has been found to have 27.5 times more potent in vitro antiviral activity against SARS-CoV-2 than another antiviral used in the early stages of the pandemic and now clinically questioned, remdesivir. For this, a line of human kidney embryonic cells has been used that express the ACE2 receptor that the coronavirus uses to enter the cells. Its toxicity is limited.
The study also confirmed, using a drug-resistant mutant, that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated by the inhibition of the biological target eEF1A.
Finally, the authors also indicate that the in vivo efficacy of plitidepsin treatment has been demonstrated in two mouse models. They achieved a reduction of viral replication in the lungs by two orders of magnitude, similar to that obtained with 50 mg / kg of remdesivir.
Additionally, in a press release also issued today by the company, it is stated that “the trial demonstrated a reduction in viral replication, with a 99% decrease in viral loads.” However, these data are difficult to extrapolate from the results of the published study, although the drug has been shown to reduce the expression of subgenomic RNA, a marker of viral replication used in the development of the vaccine against SARS-CoV-2. .
And this means?
The lowest plasma concentration of a drug over its dosage range is indicated by the “trough concentration.” The ease of determining this parameter is an advantage, since a single blood draw is sufficient just before the next drug intake.
To permanently inhibit the replication of a virus requires an “effective concentration” of the drug throughout the entire therapeutic range. This means that if the minimum concentration observed is higher than the effective concentration, the inhibition of the virus would be adequate.
This effective concentration is a theoretical parameter that can be found in the medical literature and that is calculated in vitro from a phenotypic study of sensitive strains of the virus, as is the case of the study published in Science . In this way, the drug concentration necessary to inhibit 50%, 90%, and 95% of viral replication can be determined.
This “inhibitory concentration” is corrected by binding in humans to plasma proteins of the drug. Thus, a parameter is obtained that would correspond to the effective concentration necessary to reduce, in the real conditions of a human body, viral replication in those percentages of 50, 90 and 95%.
This correction for plasma protein binding can be done in different ways, with very different results. Since viral replication must be inhibited as much as possible, effective concentrations at 95% or 90% are more appropriate than 50%, but the latter is often used because its determination is much more accurate.
Thus, the results of the 50% inhibitory concentration provided by the study indicate that plitidepsin shows greater potency in vitro than remdesivir, but also similar efficacy in vivo, with greater toxicity. The 90% inhibitory concentration results are within this order of magnitude.
Thus, up to now, and in the absence of new studies, both preclinical and clinical, there is no scientific evidence to be able to extrapolate the data obtained in this study to humans for the proposed indication. Neither in terms of efficacy nor safety parameters, much less can we use these data to estimate the doses to be used in future clinical trials, also taking into account that, as indicated in this study, the dose of plitidepsin used in the trial clinical course is significantly less than that used in these experiments.
And the clinical evidence?
Last April, in the middle of a perfect storm to evaluate drugs in the treatment of covid-19, the AEMPS authorized a phase II study (mainly to search for doses and also to analyze the first efficacy data) to evaluate the profile safety of plitidepsin in patients with SARS-Cov-2 who require hospital admission.
However, the preliminary data of this study have not yet been published, so we cannot confirm the data obtained in the experimental models in the laboratory.
In conclusion
There is a growing body of data showing the possible antiviral activity of plitidepsin against SARS-CoV-2. However, it seems inappropriate, in light of all the above, to launch to public opinion statements that we are dealing with “the most powerful antiviral ever described”, especially when the European Medicines Agency itself questions the safety of this medicine , at least at the recommended doses for the treatment of multiple myeloma.
The obvious consequences of similar statements, in addition to creating uncertainties among patients and even clinicians, are shown in the results of the exchange, with a 20% increase in PharmaMar shares.
It would be advisable, at least in the health field, to separate the results obtained from biomedical research from the economic returns, which business leaders should just choose, and hope that the data provided can, in due course, translate into true clinical hope . This, without a doubt, would provide its developers with the expected and desired economic benefits.
Francisco López-Muñoz, Professor of Pharmacology and Vice-rector for Research and Science at the Camilo José Cela University, Camilo José Cela University and Jose Antonio Guerra Guirao, Professor of Pharmacology and Toxicology. Pharmacy faculty. Complutense University of Madrid., Complutense University of Madrid
This article was originally published on The Conversation. Read the original.
