Some Information About Remdesivir

Short summary

Remdesivir is a moderately potent anti-viral drug. In clinical trials to test safety, the drug appears to be reasonably safe and well-tolerated. The data on whether it can decrease the death rate shows it does not do that. But what the data does appear to show, and this needs to be confirmed, is that the drug significantly shortens the time it takes a person to recover from the infection.

What remains unclear to me are (i) what "recovery" from the infection means, or how it is defined, and (ii) how early in the infection the drug needs to be started for it to have enough time to have a significant beneficial clinical effect. If the drug is started too late in a person's infection, it cannot save them if they are going to die with or without the drug.

Short technical summary

The FDA gave emergency authorization to use Remdesivir to treat the Covid-19 infection. Stories in the news yesterday indicated that some strange things had been going on in the process of authorizing use of the drug. One strange thing was a change in the 'clinical endpoint' for the drug from a reduced death rate to a reduced time to recovery, which went from 15 days to 11 days. That reduction in time to recover was called 'significant'. In drug development, 'significant' almost always means statistical significance of p < 0.05 (p means probability).

The p < 0.05 statistic means that there is a 5% chance the observed efficacy of the drug is a fluke or a false positive. A p < 0.05 value is only a modest showing that the drug is active in whatever clinical test it is analyzed in. It is preferable to hit a p-value of  0.01 or lower to have greater confidence that a drug's observed clinical activity is real.

In vivo: an assay or test in an animal or human

In vitro: an assay or test not in an animal or human, typically in cells growing in tissue culture or in cell extracts or artificial assays for individual enzymes

A February 2020 paper in the journal Cell Research reported basic antiviral activity and in vitro toxicity data for remdesivir. The drug returned values of EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87. That indicated a moderately potent drug with a relatively low toxicity profile in vitro.

The EC50 = 0.77 μM value means that at a concentration of 0.77 micromolar (μM), the drug inhibited viral replication by 50%. The EC50 is the half maximal effective concentration the drug shows in an assay. EC50 = 0.77 μM means that remdesivir is moderately potent in this particular assay. Drugs with an EC50 of 0.1 μM or lower are usually preferred.

The CC50 > 100 μM value refers to the concentration of the drug needed to kill half of the cells used in the assay. It is a general indicator of how toxic the drug is. In this case, the cells used were epithelial cells from monkey kidney. The cell line is called Vero E6 and it was developed in the 1960s. Thus, a drug that is not very toxic will have a high CC50. The lower the CC50, the more toxic the drug is. A CC50 of > 100 μM indicates that remdesivir is moderately toxic for Vero E6. It does not provide detailed information about how toxic remdesivir would be in humans.

Clinical trial experience with remdesivir in humans indicated a fairly low toxicity:

"Intravenous infusions in previously phase I clinical trials have good safety and pharmacokinetic properties. Also, no cytotoxicity, hepatorenal toxicity, or no serious adverse reactions related to metering have been observed in climbing experiments. Subjects were tolerant in studies that repeated 150 mg intravenously daily for 7–14 days. Remdesivir did not show any renal injuries in a multi-dose study."

The selectivity index value, SI > 129.87, is just EC50 ÷ CC50 (0.77 μM ÷ 100 μM). The higher the SI, the better the efficacy vs safety profile for the drug is in the assay used. Since remdesivir is not very water soluble, the CC50 is expressed as > 100 μM instead of = 100 μM. The real selectivity index cannot be evaluated due to the low water solubility for remdesivir, but it is likely to be higher than 130. However, since the SI is for an in vitro assay, it is not nearly as important as the reported toxicity and efficacy data obtained from controlled human clinical trials.

Remdesivir is a ribonucleotide analog that the virus uses to replicate itself and by incorporating the molecule into viral RNA and stopping complete duplication of the viral genome. The similarity of the remdesivir structure to natural ribonucleotides in essence "tricks" the virus polymerase into using it in place of real ribonucleotides that are always present in human, animal and cells of other kinds of self-replicating life, e.g., plants. This is a chemical strategy that has been used against RNA viruses for decades, including the first analog used to treat HIV, AZT (azidothymidine), back in the 1980s.

Remdesivir