After a yearlong search for existing drugs that might help COVID-19 patients and point to a cure, a UCSF-led science team has identified what they say is an especially promising candidate: an anti-cancer drug that kills the coronavirus in lab studies and is almost 30 times more potent than remdesivir, one of the few antiviral drugs available to treat the disease.
The new peer-reviewed research, published Monday in the journal Science, highlights a drug called Aplidin, which was originally extracted from an exotic marine creature called Aplidium albicans — a type of “sea squirt” 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 isn’t commercially available in most parts of the world and isn’t yet approved to treat COVID-19, though it has been tested in a few dozen COVID-19 patients in Spain.
“We need some new weapons in the arsenal,” said Nevan Krogan, a UCSF molecular biologist who led the science team along 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 grew from a joint effort of multiple labs at UCSF’s Quantitative Biosciences Institute, within the School of Pharmacy. Dubbed 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 emerge at a moment of widespread frustration in the fight to stem the pandemic, with deaths topping 400,000 in the U.S. and more contagious strains of the virus emerging and circulating. Although COVID-19 vaccines are highly effective at preventing the disease, they remain scarce and can’t help patients who are already sick, fueling a need for better antiviral drugs.
Over the last year, the QCRG scientists have peered into the molecular world of the virus, making a detailed map of how it hijacks and rewires human cells at the microscopic level. Then the team studied that map to narrow the search for drugs that could plausibly stop infection, testing thousands of existing drugs and experimental compounds against the virus in the lab.
Aplidin rose above the pack. Extremely low concentrations of the drug killed the virus in infected human lung cells and similar cells from monkeys. Scientists also infected dozens of mice with the virus, giving them COVID-19, then injected them with Aplidin, which essentially eliminated the virus from their bodies, according to the paper. Meanwhile, using genetic techniques, the team discovered that the drug does its job in an unusual way: Instead of attacking the virus itself, as remdesivir does, Aplidin blocks activity of a specific protein inside human cells that the virus needs to replicate itself.
“I’m very excited about this data, because of the potency,” said García-Sastre.
Recently, the research team also collaborated with a lab in the United Kingdom to test Aplidin against the new variant of the coronavirus there, known as B-117. The drug killed the variant, too, and was more potent against the variant in lab tests than remdesivir, the scientists report in a separate paper posted Sunday on biorxiv.org, a website where biologists share new results before they’re peer-reviewed.
In Spain, 45 patients with COVID-19 have taken Aplidin as part of a Phase 2 clinical trial, and Pharma Mar has released data on the first 27 patients. The drug reduced the amount of time they spent in the hospital, with 81% of patients returning home within 15 days, as opposed to the typical rate of 47%, according to the company. More expansive Phase 3 trials of the drug in COVID-19 patients are being planned in Spain and the U.S., said Pascal Besman, the company’s chief operating officer.
One downside of Aplidin is that it’s an intravenous drug. That means it’s difficult to administer outside of a hospital, limiting its potential reach, said Dr. Peter Chin-Hong, a UCSF infectious disease expert and physician who was not involved in the Aplidin research.
Chin-Hong also pointed out that earlier attempts to deploy existing drugs against COVID-19 have fizzled, failing to cure patients in trials; Aplidin must prove its mettle against COVID-19 in rigorous human studies. But if it does, he said, it might be useful as one piece of a multi-drug “cocktail” therapy.
“We have to keep on trying,” Chin-Hong said. “Teaching the old drugs new tricks should always be on our mind.”
Krogan and García-Sastre said Aplidin could be especially relevant in a world where dangerous new strains of the coronavirus are popping up. 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, slashing the virus’ ability to replicate and spread.
“If you get a drug that targets a human protein, it would be incredibly hard for the virus to mutate away from being reliant on it,” said Krogan, who is also an investigator with the Gladstone Institutes, a Bay Area biomedical research organization.
Pharma Mar says its mission is to find medicines in the oceans, where the water teems with viruses and some aquatic creatures have evolved virus-killing weapons that are “much, much stronger” than anything humans have designed, said José Maria Fernández Sousa-Faro, Pharma Mar’s founder and CEO. “I think it’s because nature, that is very wise, has been able to do fine-tuning.”
Pharma Mar originally developed Aplidin as a cancer drug, studying its effects in trials with multiple myeloma patients. In 2017, the European Medicines Agency, which regulates drugs in the European Union, refused to approve Aplidin, pointing to side effects experienced by some cancer patients who took it and saying the benefits of the drug did not outweigh the risks. But Pharma Mar successfully challenged the ruling in EU court, vacating the decision, and Australian regulators approved Aplidin for treating multiple myeloma in 2018.
Pharma Mar scientists say that virus patients require substantially lower doses of the drug than cancer patients do, needing to take it for three days instead of months. In tests with COVID-19 patients so far, side effects of Aplidin have been minimal.
Source: San Francisco Chronicle