“New weapon” to kill COVID? UCSF-led team finds drug that could be much more effective than remdesivir

After a year-long search for existing drugs that could help patients with COVID-19 and indicate a cure, a scientific team led by UCSF has identified what it says is a particularly promising candidate: an anticancer drug that kills the coronavirus in laboratory studies and is nearly 30 times more potent than remdesivir, one of the few antivirals available to treat the disease.

New peer-reviewed research, published Monday in the journal Science, highlights a drug called Aplidin, which was originally extracted from an exotic sea creature called Aplidium albicans – a type of ‘sea spray’ found off the coast of Ibiza that looks a bit like a disembodied brain.

Aplidin, also known as plitidepsin, is owned by Pharma Mar, a Spanish company founded by a scuba diving scientist. Approved in Australia to treat multiple myeloma, a type of blood cancer, the drug is not commercially available in most parts of the world and is not yet approved to treat COVID-19, although it has been tested in a few dozen COVID- 19 patients in Spain.

“We need new weapons in the arsenal,” said Nevan Krogan, a UCSF molecular biologist who led the science team with Adolfo García-Sastre, a virus expert at the Icahn School of Medicine at Mount. Sinai Hospital in New York. “This is by far the best thing we’ve seen.”

The research was born from a joint effort of several laboratories of the Institute of Quantitative Biosciences of UCSF, within the School of Pharmacy. Dubbed the QBI COVID-19 research group, or QCRG, the team works closely with scientists from Mount Sinai, the Institut Pasteur in Paris and other institutions.

The group’s findings emerge at a time of widespread frustration in the fight to stem the pandemic, with deaths exceeding 400,000 in the United States and more contagious strains of the virus emerging and circulating. While COVID-19 vaccines are very effective in preventing disease, they remain rare and cannot help patients who are already sick, fueling the need for better antiviral drugs.

Over the past year, QCRG scientists have scrutinized the molecular world of the virus, drawing a detailed map of how it hijacks and rewires human cells at the microscopic level. Next, the team studied this map to narrow the search for drugs that could likely stop the infection, testing thousands of existing drugs and experimental compounds against the virus in the lab.

Aplidin rose above the peloton. Extremely low concentrations of the drug killed the virus in infected human lung cells and similar monkey cells. Scientists also infected dozens of mice with the virus, giving them COVID-19, and then injected them with aplidine, which essentially cleared the virus from their bodies, according to the article. Meanwhile, using genetic techniques, the team found that the drug was doing its job in unusual ways: instead of attacking the virus itself, like remdesivir does, Aplidin blocks the activity of ‘a specific protein inside human cells that the virus needs to replicate.

“I am very excited about this data, because of its power,” said García-Sastre.

Recently, the research team also collaborated with a lab in the UK to test Aplidin against the new variant of the coronavirus, known as B-117. The drug also killed the variant and was more effective against the variant in lab tests than remdesivir, scientists report in another article posted Sunday on biorxiv.org, a website where biologists are sharing new results before it quits. ‘they are not peer reviewed.

In Spain, 45 patients with COVID-19 took Aplidin in a phase 2 clinical trial, and Pharma Mar has published data on the first 27 patients. The drug reduced time spent in the hospital, with 81% of patients going home within 15 days, compared to a typical rate of 47%, according to the company. More expansive Phase 3 trials of the drug in patients with COVID-19 are planned in Spain and the United States, said Pascal Besman, chief operating officer of the company.

A downside of Aplidin is that it is an intravenous medicine. This means it is difficult to administer outside of a hospital, which limits its potential reach, said Dr Peter Chin-Hong, UCSF infectious disease specialist and physician who was not involved in research on Aplidin.

Chin-Hong also pointed out that previous attempts to deploy existing drugs against COVID-19 have failed, failing to cure patients in trials; Aplidin must prove itself against COVID-19 in rigorous human studies. But if it does, he said, it could be useful as part of a multi-drug “cocktail” therapy.

“We have to keep trying,” Chin-Hong said. “Teaching old drugs new tricks should always be on our minds.”

Krogan and García-Sastre said that Aplidin could be particularly relevant in a world where dangerous new strains of the coronavirus are emerging. This is because the drug blocks the activity of a human protein, eEF1A, which the virus needs to reproduce and infect other cells, thereby reducing the ability of the virus to replicate and spread.

“If you get a drug that targets a human protein, it would be extremely difficult for the virus to mutate out of dependence on it,” said Krogan, who is also a researcher at the Gladstone Institutes, a biomedical research organization in the region. bay.

Pharma Mar says its mission is to find drugs in the oceans, where the water is teeming with viruses and some aquatic creatures have developed anti-virus weapons that are “much, much more powerful” than anything humans have designed. said José Maria Fernández Sousa-Faro, Founder and CEO of Pharma Mar. “I think it’s because nature, it’s very wise, has been able to make adjustments.”

Pharma Mar initially developed Aplidin as an anticancer drug, studying its effects in trials with patients with multiple myeloma. In 2017, the European Medicines Agency, which regulates medicines in the European Union, refused to approve Aplidin, highlighting the side effects experienced by some cancer patients who took it and claiming that the benefits of the medicine did not outweigh not about the risks. But Pharma Mar successfully challenged the ruling in an EU court, overturning the ruling, and Australian regulators approved Aplidin for the treatment of multiple myeloma in 2018.

Scientists at Pharma Mar say patients infected with the virus need much lower doses of the drug than cancer patients, and must take it for three days instead of months. In tests with patients with COVID-19 so far, side effects of Aplidin have been minimal.