Gilead’s Remdesivir Delivered Orally in Capsule Could Reduce COVID Hospitalizations

Researchers at University of California San Diego School of Medicine (San Diego, CA, USA) have modified Gilead Sciences’ (Foster City, CA, USA) remdesivir, an antiviral drug originally discovered as part of a program to develop antiviral agents with activity against novel emerging viruses. In the first months of the COVID-19 pandemic, it was tested as a potential therapeutic and found to measurably reduce recovery time for hospitalized COVID-19 patients. The Food and Drug Administration approved its use in October 2020 and it remains the only FDA-approved antiviral for treatment of SARS-CoV-2 infection.

Currently, remdesivir must be administered intravenously, a process that restricts its use to patients hospitalized with relatively severe or advanced cases of COVID-19. The FDA has approved the use of remdesivir only for adults and children age 12 and older. The researchers have described cell and animal studies that demonstrate how lipid modifications of remdesivir nucleoside can improve drug delivery, effectiveness and toxicity compared to remdesivir. The researchers synthesized three new lipid prodrugs, which combine a therapeutic agent (in this case, remdesivir nucleoside) with one of several types of lipid-phosphates. The resulting conjugated molecule uses new pathways to enter cells: the lipid phosphate portion carrying along the drug. The lipid phosphate prodrugs of the remdesivir nucleoside can be taken orally, remaining intact and bioactive in the body following absorption from the digestive system.

To become active, remdesivir requires modification by multiple enzymes. This complicated metabolism likely contributes to variable antiviral activity and toxicity in different cell types. For example, remdesivir works well in lung cells, but is less effective in other organs and is relatively more toxic in hepatocytes (liver cells), which limits the amount of drug that can be administered to patients. In comparison, the lipid prodrugs are activated by a simple single enzymatic reaction and show a consistently potent antiviral activity and minimal toxicity across many cell types. The researchers assessed the lipid prodrugs in a variety of animal and human cell types and found that the lipid prodrugs uniformly inhibited SARS-CoV-2 RNA replication across cell types. They were well tolerated by hamsters, with levels of the drug remaining stable and persistent - a problem with current remdesivir treatments.

“COVID-19 is a two-stage disease,” said Robert T. Schooley, MD, professor of medicine at UC San Diego School of Medicine. “Rapid viral growth occurs shortly after infection and can trigger a misdirected immune response that results in an ‘inflammatory’ pneumonia in those who don’t do well. In order to be maximally effective, antiviral therapy must be given early in the illness before the inflammatory phase of the illness results in hospitalization. These compounds are designed to be taken orally, rapidly absorbed from the gastrointestinal tract and to largely bypass the liver where most of remdesivir’s toxicity is seen.”

Related Links:
University of California San Diego School of Medicine
Gilead Sciences