Plitidepsin is derived from Aplidium albicans, a marine organism that typically attaches itself to hard surfaces, such as reefs.
The search for better medical treatments for COVID-19 has led a team of scientists from the Icahn School of Medicine at Mount Sinai, with colleagues in San Francisco, to plitidepsin—a promising small molecule drug derived from a sea organism. When tested in human lung cells, plitidepsin was particularly effective in stopping the replication of SARS-CoV-2, the virus that causes COVID-19. In fact, in pre-clinical trials, plitidepsin was 28-fold more effective than remdesivir—the only antiviral drug currently approved by the U.S. Food and Drug Association (FDA) to treat COVID-19.
Kris M. White, PhD
The research team from Mount Sinai and the University of California at San Francisco recently published their work in Science, revealing one of the most promising efforts to date in identifying an already approved drug that could be successfully repurposed to fight COVID-19. Plitidepsin is approved in Australia—under the name Aplidin—as a treatment for multiple myeloma, a cancer that forms in a group of white blood cells.
One of plitidepsin’s strengths is that it inhibits eEF1A, a host protein within human cells that every variant of SARS-CoV-2 needs to survive. Viruses hijack a human’s cellular machinery in order to thrive and create more copies of themselves, but plitidepsin works by blocking an important pathway that would be used by SARS-CoV-2, its variants, and potentially other respiratory diseases such as respiratory syncytial virus and influenza. In a separate preliminary study in bioRxiv, the research team, and a group of colleagues in England, showed that plitidepsin was effective against b.1.1.7, the newly identified British variant of SARS-CoV-2.
“Aplidin is quite unique in its potency,” says one of the study’s corresponding authors, Kris M. White, PhD, Assistant Professor of Microbiology, and a member of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine. “It is likely going to be able to work against any variant of SARS-CoV-2 and other coronaviruses, including new pandemics that might happen in the future. eEF1A appears to be a broadly used protein for viruses because it has an important role in protein production, making it important for the host cell and also extremely important for the virus. Now we’re looking to test plitidepsin against these other viruses as well.”
Corresponding study author Adolfo García-Sastre, PhD, Professor of Microbiology and Director of the Emerging Pathogens Institute at the Icahn School of Medicine, says, “The ongoing pandemic created the immediate need for us to find antiviral therapeutics that could be moved into the clinic. This led us to screen clinically approved drugs with established data and safety profiles. We found that plitidepsin was a very promising therapeutic candidate.”
Adolfo García-Sastre, PhD
The decision to pursue plitidepsin resulted from research the team conducted last spring, when they identified 332 different host proteins that SARS-CoV-2 interacted with. The scientists looked to see which ones had FDA-approved drugs that targeted the host protein for cancer or other diseases and began following a trail that ultimately led them to Aplidin. Within a week after publishing their work in Nature, the researchers were contacted by PharmaMar, the drug’s small Madrid-based manufacturer.
In October, PharmaMar released the results of a phase 1,2 clinical trial of Aplidin for use against COVID-19, which showed the drug was safe and effective in helping hospitalized patients recover from the disease. By day seven after taking Aplidin, the patients’ viral load was reduced by 50 percent, and by day 15, viral load was reduced by 70 percent. More than 80 percent of patients had been discharged from the hospital on or before day 15.
The results of the clinical trial also confirmed the tolerability of Aplidin for patients with COVID-19. Tolerability had already been observed in studies of approximately 1,300 cancer patients who actually received higher doses of Aplidin than the COVID-19 patients. PharmaMar is currently establishing phase 3 clinical trials.
“The data has shown that it’s worth trying the drug in a phase 3 clinical trial,” says Dr. White. “There’s a good chance we might see efficacy and that it will be well tolerated by the patients at certain doses.” Like remdesivir, plitidepsin would be given intravenously in a hospital setting.
The researchers have proposed that the drug be tested for use alongside remdesivir and also dexamethasone, an anti-inflammatory authorized for use in severely ill COVID-19 patients. As with other antiviral drugs, plitidepsin would work only if given early in the disease cycle, in the active viral replication stage of COVID-19.