Cancer drug derived from sea squirts outperforms remdesivir in COVID-19 preclinical models

Scientists found PharmaMar’s myeloma drug plitidepsin, derived from sea squirts, might be a more potent anti-COVID-19 drug than Gilead's remdesivir. (Quantitative Biosciences Institute)

The search among existing drugs for potential COVID-19 treatments has pointed to another promising candidate—a cancer drug that appears to perform better than Gilead Sciences’ FDA-approved remdesivir against the SARS-CoV-2 virus behind the disease.

In a new study published in Science, researchers from the Icahn School of Medicine at Mount Sinai and the University of California, San Francisco found in preclinical experiments that Spanish drugmaker PharmaMar’s plitidepsin, approved under the brand name Aplidin in some countries for multiple myeloma, was almost 30 times more potent than remdesivir.

What’s more, in a separate paper posted on the journal preprint site bioRxiv, the researchers showed the drug had comparable antiviral activity against the original SARS-CoV-2 strain and the new, more contagious B117 variant, which was first discovered in the U.K.

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Based on the positive results, PharmaMar said it’s in talks with regulatory agencies on initiating phase 3 clinical trials of plitidepsin in COVID.

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Plitidepsin was derived from Aplidium albicans, a sea squirt found off the coast of Spain. It was originally meant to target the human protein eEF1A, the expression of which can lead to cellular signaling that gives rise to cancer.

The Icahn-led team previously found that targeting some host proteins involved in gene-to-protein translation machinery—which is critical for the replication of many viral pathogens—could block SARS-CoV-2. That finding led them to test plitidepsin.

In the new study, the scientists confirmed that plitidepsin indeed worked against SARS-CoV-2 through inhibition of eEF1A, which interacts with the coronavirus’s nucleocapsid (N) protein during an infection.

In studies in human cells, plitidepsin demonstrated anti-SARS-CoV-2 activity that was 27.5-fold more potent than that of remdesivir. As remdesivir has been cleared by the FDA to treat COVID-19, the researchers tested plitidepsin alongside the Gilead drug. Their analysis suggested that plitidepsin has an “additive effect” to remdesivir.

The researchers also tested the drug in two different mouse models. In mice that got plitidepsin shortly before being infected with SARS-CoV-2, the drug significantly reduced viral load and lung inflammation compared with controls. Plitidepsin prompted a reduction in viral load that was on par with remdesivir’s, but the cancer drug was better at relieving lung inflammation, the team reported.

Plitidepsin holds one potential advantage over traditional antivirals like remdesivir, the team argued. By targeting the host protein rather than viral proteins, plitidepsin could potentially avoid the drug resistance that can result from mutations.

In the second study, the team tested plitidepsin against the more highly transmissible B117 variant of SARS-CoV-2. The drug showed similar antiviral activity against both the early-lineage virus and the mutated version in both human gastrointestinal and lung epithelial cell lines, and it was significantly more potent than remdesivir against both viruses, the team found.

Repurposing existing drugs has been a popular strategy among scientists searching for possible COVID-19 treatments. Several other cancer drugs have been proposed to either directly inhibit the virus or attenuate the rogue inflammatory response resulting from the SARS-CoV-2 infection.

PTC Therapeutics is testing its investigational DHODH inhibitor PTC299 in a phase 2/3 trial based on the belief that the drug can both inhibit viral replication and suppress the production of inflammatory molecules. AstraZeneca previously evaluated its BTK blood cancer therapy Calquence in COVID-19, but the drug failed to reduce death rates or respiratory failure.

PharmaMar already has positive phase 1/2 data for plitidepsin in COVID-19. In October, the company said the APLICOV-PC trial (PDF) showed that plitidepsin achieved significant reduction in viral load in hospitalized patients, and a remarkable correlation has been observed between the decrease in viral load and clinical improvement, among other metrics.

“We believe that 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 Mount Sinai-UCSF team wrote in the Science study.