Remdesivir was the first medication approved for use in treating COVID-19 and one of the most expensive.
However, remdesivir has a complex history.
Who Made Remdesivir?
Gilead, a pharmaceutical giant, began researching the drug we now know as remdesivir in 2009, intending to make a drug that would treat hepatitis C or respiratory syncytial virus (RSV).However, the company soon shelved remdesivir, as the drug was shown to have little benefit for either of these diseases.
Gilead has also marketed several drugs that were later implicated in lawsuits.
A well-known example is Tamiflu, a patented antiviral drug for influenza; Gilead created the drug and licensed it to the drug company Roche.
Remdesivir: History of Controversy and Failure
In 2016, Gilead took remdesivir off the shelf. The drug was trialed for the Zika virus and showed moderate benefits. However, before the company could capitalize on it, concern about Zika waned.In the study, approximately 54 percent of the patients in the remdesivir treatment group died, while monoclonal antibodies against Ebola reported an overall mortality rate of 33.5 percent. One patient administered remdesivir experienced low blood pressure and subsequent cardiac arrest.
Remdesivir was shelved once again.
Would Remdesivir Work for COVID-19?
Mechanistically, remdesivir should have antiviral effects against COVID-19.The drug can block the action of RNA-dependent RNA polymerase (RdRp), an enzyme present in all RNA viruses, including SARS-CoV-2.
As with all viruses, when the COVID-19 virus enters the cell, it needs to use the cell’s mechanism to create more of the virus. The SARS-CoV-2 virus replicates using its viral RNA stored in the center of the virus.
In an infection, the viral RNA will enter the human (host) cells and instruct the cells to produce more of the COVID-19 virus.
However, cells have their own “malware” program to prevent a viral attack.
Because viral RNA molecules differ from human RNA, the cell’s defense program can recognize that the instructions came from a virus and that there has been a firewall breach. The cell will then launch an attack.
RdRp changes the format of the instructions to pass scrutiny under this malware system. It does so by rewriting the instructions using the cell’s human RNA molecules. This way, the instructions look like they came from the cell.
This is where remdesivir comes in.
Remdesivir mimics human RNA molecules; it has been modified so that once it is added to the sequence, no additional human RNA molecules can be added.
Since no human RNA molecules can be added after remdesivir, the presence of remdesivir in any COVID-19 instruction creates an incomplete sequence and prevents the complete synthesis of the COVID-19 virus.
Most viral replication happens during the first week of infection when a person is asymptomatic or experiencing very mild flu-like symptoms.
However, remdesivir is administered mainly in hospitalized patients past the early stages of virus replication. Rather than the virus causing damage at this point, the body’s immune system is likely driving the damage and organ failure. This is why medical professionals question the use of remdesivir for hospitalized patients.
By the time patients are admitted to the hospital, they are likely suffering from the inflammatory symptoms caused by their immune systems against the virus and its particles; viral replication, judging by the declining viral load, would seem to be decreasing.
What Does the Data Show?
There is no shortage of research into the efficacy of remdesivir.The US Government Accountability Office reported that “[a]s of December 2020, federal funding for preclinical studies and clinical trials involving remdesivir totaled about $162 million.” That figure does not take into account studies conducted outside of the US.
In the study, half of the participants were given remdesivir for 10 days, and the other half were given a placebo.
At the outset, the study had a few questionable details, as the “placebo” given was not exactly a placebo.
A placebo is not supposed to bring about any change, harm, or benefit to the people taking it, as it is used as a baseline for safety.
Giving pharmaceutical agents would put the people taking the so-called placebo at risk of drug benefits and harm. If adverse events are reported in the placebo group, it may mask the harm of remdesivir, especially if the numbers between the two groups are similar.
In this study, 24.6 percent of the remdesivir group reported adverse events, which is lower than the 31.6 percent reported in the placebo group.
To demonstrate the drug’s benefits, before the study, the researchers set the primary endpoint as the drug’s ability to reduce mortality.
However, while there was less mortality experienced in the remdesivir group than in the control group, the participants in the remdesivir group were also less sick at the time of enrollment.
For participants who did not need oxygen or needed only supplemental oxygen, the group that received remdesivir had a higher enrollment of 307 compared to 266 in the placebo group.
In severe patients who needed ventilation or high-flow oxygen, the group that received remdesivir had a lower enrollment of 226 compared to 252 in the placebo group.
However, the remdesivir group also had a higher readmission rate of 5 percent compared to 3 percent in the placebo group.
Other scientists have also picked up on the changed endpoint, finding the support for the use of remdesivir to be very weak, which is a significant concern.
This meant that researchers would no longer have a group they could follow to observe the long-term trends between the two groups because they eventually took the same drug.
These concerns raised regarding remdesivir’s pivotal trial cast doubt on the drug’s effectiveness.
“It’s just a fact that the best a drug is ever going to look is in the initial trial,” said Amerling, “and this was a trial done entirely by Gilead and [the NIH] and manipulated to the hilt to produce a fig leaf of a benefit.”
Before the publication of ACTT-1, two notable studies had found remdesivir to have no significant benefit in treating COVID-19 and advised against its use.
Patients were put on a 10-day treatment with remdesivir. The study had to be stopped early, as 12 percent of the remdesivir group reported adverse effects compared to five percent of the placebo patients.
There were 11,330 people recruited for the study, with other drugs also tested. There were 2,750 subjects assigned to receive remdesivir, and the rest received other drugs, with no placebo for the study.
As with the Chinese study, the SOLIDARITY study found no reduction in mortality, ventilation, or hospital stay for any of the drugs investigated.
Including Gilead’s pivotal trial and the two other studies mentioned above, at the time this article is published, at least 67 clinical or randomized controlled trials have been published on Pubmed on remdesivir use in COVID-19.
After excluding articles where the author’s opinion on remdesivir use or the significance of the remdesivir effect was unclear, only 24 articles remained for final evaluation.
Of the 24 articles, 13 were funded by Gilead or had authors who had financial ties with the company. The Epoch Times found that 11 of these articles reported clinical benefits of remdesivir or implied recommendation of remdesivir as a COVID-19 treatment, while two found no significant benefits in using remdesivir.
Of the other 11 articles that reported no financial ties with Gilead, five reported no significant benefit of remdesivir in clinical use. The remaining six recommended or found a clinical benefit of remdesivir use.
Side Effects and Safety Concerns
The FDA’s product label for remdesivir (pdf) states that users should inform their health providers of underlying kidney and liver diseases.The label also refers to kidney injuries observed in animal studies and reported in humans during studies.
Kidneys filter fluids to maintain the balance between water and salt concentrations. Kidneys also help to clear out toxins through the urine and are critical for the overall balance of the body.
“Although causality was not confirmed, the association between remdesivir and acute kidney injury should not be ignored,” the authors concluded.
However, not all seem negatively affected by remdesivir; some have made a complete recovery following its administration.
References
Gilead-funded or conducted by researchers with financial affiliation to Gilead:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262788/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757570/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863204/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454434/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212963/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334931/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499739/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477473/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270059/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523116/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490137/#CR17 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439621/ https://jamanetwork.com/journals/jama/fullarticle/2769871
Studies reporting no financial affiliation with Gilead:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279143/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190303/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865433/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636497/ https://academic.oup.com/cid/article/75/1/e403/6515763 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426890/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9383489/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562044/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384598/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010446/