After a year-long search for existing drugs that could help COVID-19 patients and point to a cure, a scientific team led by UCSF has identified what they say is an especially promising candidate: an anticancer drug that kills the coronavirus in studies and is almost 30 times more potent than remdesivir, one of the few antivirals available to treat the disease.
The new peer-reviewed research, published Monday in Science magazine, highlights a drug called Aplidin, which was originally extracted from an exotic sea creature called Aplidium albicans – a type of “sea squirt” found on the Ibiza coast that looks like a little like a disembodied brain.
Aplidin, also known as plitidepsin, is owned by Pharma Mar, a Spanish company founded by a 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 has not yet been approved to treat COVID-19, although it has been tested on a few dozen COVID- 19 patients in Spain.
“We need some new weapons in the arsenal,” said Nevan Krogan, a molecular biologist at UCSF who led the scientific team along with Adolfo García-Sastre, a virus specialist 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 grew out of a joint effort by several laboratories at UCSF’s Quantitative Biosciences Institute, within the School of Pharmacy. Called the QBI COVID-19 Research Group, or QCRG, the team works closely with scientists at Mount Sinai, the Institut Pasteur in Paris and other institutions.
The group’s findings come at a time of widespread frustration in the struggle to contain the pandemic, with deaths reaching 400,000 in the United States and more contagious strains of the virus emerging and circulating. Although COVID-19 vaccines are highly effective in preventing disease, they remain scarce and cannot help patients who are already sick, increasing the need for better antiviral drugs.
Last year, QCRG scientists investigated the molecular world of the virus, making a detailed map of how it hijacks and reconnects human cells at a microscopic level. The team then studied this map to narrow the search for drugs that could plausibly stop the infection, testing thousands of existing drugs and experimental compounds against the virus in the laboratory.
Aplidine has outgrown packaging. Extremely low concentrations of the drug killed the virus in infected human lung cells and monkey-like cells. Scientists also infected dozens of mice with the virus, giving them COVID-19 and then injected aplidine, which basically eliminated the virus from their bodies, according to the newspaper. Meanwhile, using genetic techniques, the team found that the drug does its job in an unusual way: instead of attacking the virus itself, as remdesivir does, aplidine blocks the activity of a specific protein within human cells from which virus needs to replicate itself.
“I’m very excited about this data, because of the power,” said García-Sastre.
Recently, the research team also collaborated with a laboratory in the United Kingdom to test Aplidin against the new variant of the local coronavirus, known as B-117. The drug also killed the variant and was more potent against the variant in laboratory tests than remdesivir, the scientists reported in a separate article published on Sunday at biorxiv.org, a website where biologists share new results before being reviewed.
In Spain, 45 patients with COVID-19 took Aplidin as part of a Phase 2 clinical trial, and Pharma Mar released data on the first 27 patients. The drug reduced the length of hospital stay, with 81% of patients returning home within 15 days, against the typical rate of 47%, according to the company. More extensive Phase 3 trials of the drug in patients with COVID-19 are being planned in Spain and the United States, said Pascal Besman, the company’s director of operations.
A disadvantage of Aplidin is that it is an intravenous drug. This means that it is difficult to administer outside a hospital, limiting its potential reach, said Dr. Peter Chin-Hong, an infectious disease specialist at UCSF and a doctor who was not involved in the Aplidin research.
Chin-Hong also pointed out that previous attempts to implant existing drugs against COVID-19 had failed, failing to cure patients in tests; Aplidin must prove its worth against COVID-19 in rigorous human studies. But if that happens, he said, it could be useful as part of a multi-drug “cocktail” therapy.
“We have to keep trying,” said Chin-Hong. “Teaching old drugs new tricks should always be on our mind.”
Krogan and García-Sastre said Aplidin may be especially relevant in a world where new dangerous strains of the coronavirus are emerging. That’s because the drug blocks the activity of a human protein, eEF1A, that the virus needs to make copies of itself and infect other cells, reducing the virus’s ability to replicate and spread.
“If you get a drug that targets a human protein, it would be incredibly difficult for the virus to mutate and not depend on it,” said Krogan, who is also a researcher at Gladstone Institutes, a biomedical research organization in the Bay Area.
Pharma Mar says its mission is to find drugs in the oceans, where the water is full of viruses and some aquatic creatures have developed anti-virus weapons that are “much, much stronger” than anything humans have conceived of, said José Maria Fernández Sousa-Faro, Founder and CEO of Pharma Mar. “I think it’s because nature, which is very wise, was able to fine-tune it.”
Pharma Mar originally developed Aplidin as a cancer drug, studying its effects in tests with patients with multiple myeloma. In 2017, the European Medicines Agency, which regulates medicines in the European Union, refused to approve Aplidin, pointing out the side effects experienced by some cancer patients who took it and saying that the benefits of the medicine do not outweigh the risks. But Pharma Mar successfully challenged the decision in the EU court, overturning the decision, and Australian regulators approved Aplidin for the treatment of multiple myeloma in 2018.
Pharma Mar scientists say that patients with viruses require substantially lower doses of the drug than cancer patients, needing to take it for three days instead of months. In tests with COVID-19 patients so far, the side effects of Aplidine were minimal.
Jason Fagone is a writer for the San Francisco Chronicle. Email: [email protected] Twitter: @jfagone