One of the most desperate battles in the fight against the new coronavirus is finding effective treatments against the infection to help those already infected people who are at high risk of suffering a serious illness or dying from covid.
So far the search for treatments has been disappointing.
Only dexamethasone has been shown to reduce mortality from covid and it does not actually fight the virus, but the outrageous inflammatory reaction suffered by those infected with the worst prognosis.
This Monday an international team of researchers published the first proven scientific data on the effectiveness of a new treatment that could become the most powerful antiviral against the new coronavirus: plitidepsin.
The scientists, led by the Spanish virologist Adolfo García-Sastre, from the Monte Sinaí Hospital in New York, explain that this drug is about 100 times more potent than remdesivir, the first antiviral approved to treat covid that until now has not demonstrated a overwhelming efficacy, as they recall in the study.
Plitidepsin is a synthetic drug based on a substance produced by an invertebrate from the Mediterranean Sea
Plitidepsin is a synthetic drug based on a substance produced by a species of sea squirts in the Mediterranean Sea: invertebrate and hermaphrodite animals that live anchored to stones or piers.
The Pharmamar company has developed the drug under the brand name Aplidine to treat multiple myeloma - a blood cancer - although for now it has only been approved in Australia.
After the start of the pandemic, the company began clinical trials using this drug against covid.
The compound reduces viral load in hospitalized patients, according to the company, although properly reviewed scientific data to confirm this has not yet been published.
García-Sastre's team, together with experts from the University of California in San Francisco, the Pasteur Institute in Paris and the Pharmamar company, have tracked all the proteins of the new coronavirus that interact with human proteins.
They have then analyzed known drugs that can interfere with these interactions and have identified 47 promising drugs.
Among all of them, plitidepsin seems one of the most promising.
It is between nine and 85 times more effective in preventing the virus from multiplying than two other promising drugs in the same group, according to their study, published today in
Science
.
Researchers have compared the effects of this drug with those of remdesivir in two mouse models infected with SARS-CoV-2.
The results show that plitidepsin reduces the replication of the virus about 100 times more and that it also fights inflammation in the respiratory tract.
Therapies directed not against the virus, but against a specific protein of the patient are more resistant to the appearance of new variants of the virus
The work details how the drug works.
The molecule does not attack the virus directly, but rather a human protein that it needs to hijack the biological machinery of cells and use it to make hundreds of thousands of copies of itself.
Plitidepsin blocks a human protein known as eEF1A without which the virus replication machinery is unable to function.
"Our results and the positive data from Pharmamar's clinical trials suggest that further clinical trials with plitidepsin should be prioritized for the treatment of covid," the authors conclude.
Therapies directed not against the virus, but against a specific protein of the patient are more resistant to the appearance of new variants of the virus.
The patient's genetics change much less quickly than that of the virus, so this type of treatment would not be as affected by the arrival of new mutated variants of the coronavirus.
García-Sastre's team has just published another study, in this case still preliminary, in which it shows that two of these treatments - plitidepsin and ralimetinib, another molecule used against cancer - have similar effectiveness against the British variant of the coronavirus.
So does remdesivir, which is directly directed against the virus, but plitidepsin is 10 times more potent against SARS-CoV-2 than remdesivir.
The molecular mechanism to which this drug is directed is also important for the replication of many other viruses, including influenza and respiratory syncytial virus, ”García-Sastre explained in a statement.
This suggests that it has the potential to create generic antivirals against many other pathogens, he adds.
Independent experts warn that there is still a long way to go.
"We are facing a very good preclinical study carried out by a very reliable group of researchers," says Marcos López, president of the Spanish Society of Immunology.
"The part of clinical trials in patients and clarifying at what time of the infection this drug could be more effective", he highlights.
Elena Muñez, principal investigator of the Solidarity trial at the Puerta de Hierro hospital in Madrid, warns that these results "are very preliminary."
"This type of preclinical data is based on experiments with fully controlled mice, a situation very different from the reality we see with patients in a hospital," he highlights.
"It is a very promising study because it provides us with a new possible treatment against infection, something that unfortunately still happens to many people", highlights the CSIC virologist Isabel Sola.
His team did a previous study with this drug and found that it was effective in preventing the replication of a coronavirus that causes a cold and also another that can cause a fatal disease, SARS of 2002. “We saw that it had much more potency than remdesivir. ”Explains Sola.
Plitidepsin acts against the N protein of the coronavirus, which is essential to protect its genetic sequence and is essential to assemble new copies of it in the early stages of infection.
This drug temporarily blocks a key human protein so that the virus can carry out these functions.
"Both plitidepsin and remdesivir would have an effect only in the early stages of infection during which there is still viral replication, but not in the later and more severe stages when there is already widespread inflammation," he adds.
One of the strengths in favor of this new drug is that there is abundant evidence that it is not toxic at moderate doses.
In part, the information comes from studies that were conducted to measure its effect against myeloma, but also from other trials in which a dose of this drug was being tested very similar to that used against COVID in combination with dexamethasone. , the corticosteroid that today is the only treatment against covid that has been shown to save lives.
In those studies, plitidepsin had no serious side effects.
"The mechanism of action of this drug is novel," says Ana Fernández Cruz, infectious diseases assistant at Hospital Puerta de Hierro in Madrid.
"As it is directed at the cells of the infected and not the virus, it could be used in combination with remdesivir, which is positive," he highlights.
Pharmamar is finalizing the official document to request the start of a phase III trial in which the effectiveness of this drug in patients hospitalized for covid will be studied.
"This work confirms both the powerful activity and the high therapeutic index of plitidepsin and that, due to its special mechanism of action, it inhibits SARS-CoV-2 regardless of its mutation in its protein S, like those of the British strains , South African, Brazilian or the new variants that have recently come out in Denmark ”, explains José María Fernández, President of Pharmamar.
"We are working with drug agencies to begin the phase III trial that is going to be done in several countries," he adds.
