Treatments against the coronavirus: the antiviral drug made in Spain is 100 times more potent than the current treatment against the coronavirus | Scientific technology

One of the most desperate battles in the fight against the coronavirus is to find effective treatment for patients who have contracted the virus and who are at high risk of serious illness or death from Covid-19. The search for cures so far has been disappointing. Only dexamethasone, a corticosteroid, has been shown to reduce mortality in patients with Covid-19. But this drug doesn’t actually fight the virus itself, but rather the uncontrolled inflammatory response it causes in patients with the worst prognosis.

On Monday, an international team of researchers released the first verified scientific data on the effectiveness of a new treatment that could become the most potent antiviral drug against the coronavirus: plitidepsin. Scientists led by Spanish virologist Adolfo García-Sastre from Mount Sinai Hospital in New York, explain that the drug is 100 times more potent than remdesivir, the first antiviral drug approved to treat Covid-19, which so far did not show that it is entirely effective, according to the study authors.

Treatments like plitidepsin that do not target the virus, but rather a specific protein, are more resistant to the new variants

Plitidepsin is a synthetic drug based on a substance produced in a species of sea squirt found in the Mediterranean Sea: invertebrate and hermaphrodite animals that live attached to rocks and docks, like sea jets. The company PharmaMar, based in Madrid, developed the drug, sold under the name Aplidina, to treat multiple myeloma of blood cancer. The drug, however, has only been approved in Australia.

When the coronavirus pandemic broke out, PharmaMar began a clinical trial to test whether plitidepsin could be used against Covid-19. According to the company, the drug lowers the viral load in hospitalized patients, but it still has not released its scientific data which needs to be verified.

The García-Sastre research team, in collaboration with experts from the University of California at San Francisco, the Institut Pasteur in Paris and PharmaMar, followed all the proteins of the new coronavirus that interact with human proteins . They then analyzed the already existing drugs that could interrupt these interactions. From this analysis, the team identified 47 promising drugs, of which plitidepsin appeared to be the most promising. According to a new study published in the journal Science On Monday, it is between nine and 85 times more effective at preventing the virus from multiplying than two other promising drugs in this group.

The researchers compared the effectiveness of plitidepsin and remdesivir in two mouse models infected with SARS-CoV-2. The results showed that plitidepsin reduced virus replication 100 times more than remdesivir. In addition, it also fights inflammation of the respiratory tract.

According to the study, the drug does this by not directly attacking the virus, but rather the human protein that the virus needs to take control of a cell’s biological machinery so that it can grow into the hundreds of thousands. copies of itself. Plitidepsin temporarily blocks the human protein known as eEF1A. Without the reproduction mechanism of this protein, the virus cannot function. “Our data and the first positive results from the PharmaMar clinical trial suggest that plitidepsin should be strongly considered for expanded clinical trials for the treatment of Covid-19,” the authors conclude.

Treatments that do not target the virus, but rather a patient-specific protein, are more resistant to newer variants of the virus. A patient’s genetics change much more slowly than that of a virus, which means that this type of drug will not be as affected by the arrival of new mutant strains of the coronavirus. The García-Sastre research team has just published a preliminary study which shows that plitidepsin and ralimetinib, another molecule used against cancer, are also effective against the more contagious strain of coronavirus B.1.1.7 identified for first time in UK. Remdesivir is also effective against this strain, but unlike plitidepsin, it attacks the virus directly.

This is a very promising study because it provides us with a possible new treatment for the infection.

Virologist Isabel Sola, from the Spanish National Research Council

The molecular mechanism targeted by plitidepsin is also important for the replication of many other viruses, such as the common cold and respiratory syncytial virus, García-Sastre explained in a press release. This suggests that it has the potential to create generic antiviral drugs against many other pathogens, he added.

Independent experts say there is still a long way to go. Marcos López, president of the Spanish Society of Immunology, says the new research is “a very good preclinical study by a very reliable group of researchers”. He adds: “What happens next is the clinical trial in patients and the clarification of when the infection is the most effective drug.”

Elena Muñez, the lead investigator of the Solidarity trial on the effectiveness of four untested treatments for Covid-19 at Puerta de Hierro hospital in Madrid, warns that the results of the study “are very preliminary”. “This kind of preclinical data is based on totally controlled experiments with mice, a very different situation from the reality we see with patients in hospitals,” she explains.

Virologist Isabel Sola of the Spanish National Research Council (CSIC) is more optimistic. “This is a very promising study because it offers us a possible new treatment for the infection,” she says. His team conducted an earlier study on plitidepsin and found it to be effective in stopping the replication of the coronavirus that causes the common cold, as well as another type of coronavirus that causes the deadly Severe Acute Respiratory Syndrome (SARS). “We saw that it had a lot more potency than remdesivir,” Sola explains. Plitidepsin works against the coronavirus N protein, which the virus needs to protect its genetic sequence and to reproduce in the early stages of infection. “Plitidepsin and remdesivir would only have an effect on the early stages of the infection when there is still viral replication, but not in the later and more severe phases when there is generalized inflammation,” explains- she does.

Another point in favor of plitidepsin is that numerous trials show that it is not toxic in moderate doses. This information comes in part from studies done to measure its effect against myeloma, but also from other trials which found that it did not have serious side effects. “The mechanism of action of this drug is new,” says Ana Fernández Cruz, specialist in infectious diseases at the Puerta de Hierro hospital in Madrid. “By targeting the cells of the infected person and not the virus, it could be used in combination with remdesivir, which is positive.”

PharmaMar is in the process of finalizing the official document to request authorization to start a phase 3 trial on the effectiveness of plitidepsin in patients at Covid-19 hospital. “This work confirms both the potent action of plitidepsin and its high therapeutic rate,” says José María Fernández, president of PharmaMar. He adds that thanks to the “special mechanism of action” of the drug, it can inhibit SARS-CoV-2, whether or not the virus has a mutation in its S protein, as is the case with the new strains detected in France. Great Britain, South Africa and Denmark. . “We are working with medical agencies to start a phase 3 trial which will take place in different countries,” he says.

English version by Melissa Kitson.