One of the most desperate battles in the fight against the coronavirus is to find an effective treatment for patients who have contracted the virus and are at a high risk of serious illness or death from Covid-19. Up until now, the search for treatments has been disappointing. Only dexamethasone, a corticosteroid medication, has shown that it can reduce mortality in Covid-19 patients. But this medication does not actually fight the virus itself, but rather the uncontrolled inflammatory reaction it causes in patients with the worst prognosis.
On Monday an international team of researchers published 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 the Spanish virologist Adolfo García-Sastre from Mount Sinai hospital in New York, explain that this drug is 100 times more potent than remdesivir, the first antiviral drug approved to treat Covid-19, which until now has not shown that it is entirely effective, according to the authors of the study.
Treatments like plitidepsin that do not target the virus, but rather a specific protein, are more resistant to new variants
Plitidepsin is a synthetic drug based on a substance produced in a species of ascidians found in the Mediterranean Sea: invertebrate and hermaphrodite animals that live attached to rocks and docks, such as sea squirts. The Madrid-based company PharmaMar developed the pharmaceutical, which is sold under the name Aplidina, to treat the blood cancer multiple myeloma. 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 reduces the viral charge in hospitalized patients, but it has still not published its scientific data which must be verified.
García-Sastre’s research team, together with experts from the University of California in San Francisco, the Pasteur Institute in Paris and PharmaMar, tracked all the proteins of the new coronavirus that interact with human proteins. They then analyzed 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 stopping the virus from multiplying than two other promising drugs from 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. What’s more, it also fought inflammation in respiratory tracts.
According to the study, the drug does this by not directly attacking the virus, but rather the human protein the virus needs to take control of a cell’s biological machinery so that it can make hundreds of thousands of copies of itself. Plitidepsin temporarily blocks the human protein known as eEF1A. Without this protein’s reproduction machinery, the virus cannot function. “Our data and the initial positive results from PharmaMar’s clinical trial suggests 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 specific protein of the patient, are more resistant to new variants of the virus. The genetics of a patient change much more slowly than that of a virus, meaning this type of drug will not be as affected by the arrival of new, mutant strains of the coronavirus. García-Sastre’s research team has just published a preliminary study which shows that plitidepsin and ralimetinib, another molecule used against cancer, are similarly effective against the more contagious B.1.1.7 coronavirus strain first identified in the United Kingdom. Remdesivir is also effective against this strain, but unlike plitidepsin, it directly attacks the virus.
It is a very promising study because it provides us with a new possible treatment against infectionVirologist Isabel Sola, from the Spanish National Research Council
The molecular mechanism targeted by plitidepsin is also important to the replication of many other viruses, such as the 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 Immunology Society, says the new research is “a very good pre-clinical study by a very reliable group of researchers.” He adds: “What lies next is the clinical trial in patients and clarifying at what moment of the infection is the drug most effective.”
Elena Muñez, the lead investigator in the Solidarity trial into the effectiveness of four untested treatments for Covid-19 at Puerta de Hierro hospital in Madrid, warns the results of the study “are very preliminary.” “This type of pre-clinical data is based on totally controlled experiments with mice, a situation that is very different to the reality we see with patients in hospitals,” she explains.
Virologist Isabel Sola, from the Spanish National Research Council (CSIC), is more optimistic. “It is a very promising study because it provides us with a new possible treatment against infection,” she says. Her team carried out an earlier study with plitidepsin and found that it was effective at 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,” says Sola. Plitidepsin acts against the N-protein of the coronavirus, which the virus needs to protect its genetic sequence and make copies of itself in the first phases of infection. “Both plitidepsin and remdesivir would only have an effect on the early stages of infection when there is still viral replication, but not in later and more serious phases when there is widespread inflammation,” she explains.
Another point in plitidepsin’s favor is that numerous trials show that it is not toxic in moderate doses. This information comes partly from studies done to measure its effect against myeloma, but also from other trials that found it had no serious side effects. “The action mechanism of this drug is novel,” says Ana Fernández Cruz, a specialist in infectious diseases at 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 finalizing the official document to request permission to start a Phase 3 trial into the effectiveness of plitidepsin in Covid-19 hospital patients. “This work confirms both plitidepsin’s potent action and its high therapeutic rate,” says José María Fernández, the president of PharmaMar. He adds that thanks to the drug’s “special action mechanism” it can inhibit SARS-CoV-2, independently of whether the virus has a mutation on its S protein, as is the case with the new strains detected in Britain, South Africa and Denmark. “We are working with medicine agencies to begin a Phase 3 trial that will take place in various countries,” he says.
English version by Melissa Kitson.