The Research Behind Remdesivir

The Research Behind Remdesivir
Molecular models of the nucleotide analogue drug remdesivir (right) and its target the enzyme RNA-dependent RNA (ribonucleic acid) polymerase (RdRp, centre) from the SARS-CoV-2 coronavirus. ( JUAN GAERTNER/SCIENCE PHOTO LIBRARY/Getty Images)
Marina Zhang
11/24/2022
Updated:
3/24/2023
0:00

Remdesivir was the first medication approved for use in treating COVID-19 and one of the most expensive.

The drug is priced at $3,120 for a five-day treatment under private health insurance plans, and for U.S. government health programs, the cost is $2,340 per regimen.
In treatment guidelines published by the National Institutes of Health (NIH), remdesivir is recommended: “for the treatment of COVID-19 in patients who do not require supplemental oxygen and who are at high risk of progressing to severe disease.”

However, remdesivir has a complex history.

A vial of the investigational drug remdesivir is visually inspected at a Gilead manufacturing site in March 2020. (Gilead Sciences via AP)
A vial of the investigational drug remdesivir is visually inspected at a Gilead manufacturing site in March 2020. (Gilead Sciences via AP)

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.

Roche advertised that the drug would reduce severe outcomes, hospitalization, and mortality from influenza. The United States and the United Kingdom spent $1.5 billion and £424 million ($672 million in 2012 USD), respectively, on the drug. However, Tamiflu proved marginally better than paracetamol (known as acetaminophen). Tamiflu came with significant risks, including behavioral changes, hallucinations, and suicide ideation.
In 2014, Roche was sued by whistleblower Dr. Thomas Jefferson, a physician and a researcher who studied neuraminidase inhibitors like Tamiflu for more than 20 years.
Jefferson alleged in the suit that “there was no evidence for clinicians or policymakers to use Tamiflu to prevent serious outcomes in pandemic influenza outbreaks and that the drug labeling should be changed to reflect these findings.”
According to Jefferson’s lawyer, the lawsuit seeks reimbursement of taxpayer funds, with Roche vulnerable to a judgment in excess of $4.5 billion. The suit is still ongoing.
Another controversial Gilead drug is Truvada. This HIV medication is deep in lawsuits due to its patented active ingredient—tenofovir disoproxil fumarate (TDF). Gilead uses TDF in many of its hepatitis and HIV drugs despite TDF having shown severe risks of causing bone loss, kidney injury, and kidney failure. People in their 30s and 40s have reported osteoporosis and other bone deficiencies after using Truvada for a few years, though the company has denied these accusations.
Patients suing Gilead allege that “Gilead withheld a safer alternative, tenofovir alafenamide, or TAF, in order to maximize profits from Truvada and other drugs containing TDF, including Viread, Atripla, Complera, and Stribild.”
Gilead Sciences Inc pharmaceutical company is seen after they announced a Phase 3 Trial of the investigational antiviral drug Remdesivir in patients with severe coronavirus disease (COVID-19), in Oceanside, California, U.S., April 29, 2020. (Mike Blake/Reuters)
Gilead Sciences Inc pharmaceutical company is seen after they announced a Phase 3 Trial of the investigational antiviral drug Remdesivir in patients with severe coronavirus disease (COVID-19), in Oceanside, California, U.S., April 29, 2020. (Mike Blake/Reuters)

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.
Then in 2018, remdesivir was trialed for Ebola. A study tested the drug with three other drugs to see if it would reduce mortality.
However, the safety monitoring board halted the study before it was completed, concluding that the two monoclonal antibody drugs “performed better” than remdesivir and a triple monoclonal antibody cocktail called ZMapp.
In a statement, the Data and Safety Monitoring Board, which oversaw the study, “recommended that the study be stopped and that all future patients be randomized to receive either REGN-EB3 or mAb114 in what is being considered an extension phase of the study.”
Members of the Ugandan Medical staff of the Ebola Treatment Unit stand inside the ward in Personal Protective Equipment (PPE) at Mubende Regional Referral Hospital in Uganda on Sept. 24, 2022.(Badru Katumba/AFP via Getty Images)
Members of the Ugandan Medical staff of the Ebola Treatment Unit stand inside the ward in Personal Protective Equipment (PPE) at Mubende Regional Referral Hospital in Uganda on Sept. 24, 2022.(Badru Katumba/AFP via Getty Images)

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.

Later, the NIH funded a study of rhesus monkeys and found that when used prophylactically or in early treatment, remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with Middle East respiratory syndrome coronavirus (MERS-CoV).
Since the MERS virus is within the coronavirus family, researchers presumed that the drug’s benefits would apply to COVID-19, and the drug was trialed for COVID-19 patients.

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.

A JAMA study published in January 2022 found that for people infected with the Wuhan strain, peak viral RNA levels would often coincide with when they first started showing symptoms. A review published in BMC Medicine found that the viral load in the upper respiratory tract declines after symptoms begin to appear; 17 studies and data from more than 2,000 COVID patients were evaluated for the review.
It appears, then, that remdesivir may have benefits if used in the early stages of the disease. Indeed, an Italian study found that, as an early treatment, it could reduce hospitalization and mortality.

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.

In January 2022, the Food and Drug Administration expanded remdesivir for non-hospitalized patients with mild to moderate COVID-19.

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.

The pivotal study used to propel the drug for emergency use authorization (EUA) is the Adaptive Covid-19 Treatment Trial (ACTT-1). It recruited 1,062 people and was sponsored by the NIH, with most of the authors receiving funding from Gilead.

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.

“They gave what’s called an active comparator,” said Dr. Richard Amerling, who has over 40 years of experience in nephrology. “It has the same treatment protocol agents, except for a based substitute, an agent called sulfobutyl for remdesivir.”

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.

The study’s supplementary appendix showed that compared to the placebo groups, remdesivir groups had more participants who were less sick and fewer patients who suffered from severe disease.

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.

In the middle of the study, the researchers changed the primary endpoint, which is uncommon and can compromise the validity of the study findings.
Nevertheless, the primary endpoint was changed to measure a decrease in the length of stay in the hospital.
“Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection,” the authors wrote in the study’s conclusion.

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.

Additionally, as with the studies on the COVID-19 vaccine, the placebo group at the end of the study was “unblinded.”
The placebo group was also given remdesivir at 10 days during the study because it was “an ethical obligation to immediately let the placebo group know so they can have access” to the drug.

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.

The first is a Chinese study of 233 patients, published in April 2020. It was a randomized, placebo-controlled, double-blind study, ticking all the boxes as an industry gold standard. Within the study, 155 were in the remdesivir group, and 78 were in the placebo group.

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.

The second was the SOLIDARITY study, funded by the World Health Organization (WHO).
The flag of the World Health Organization (WHO) at their headquarters in Geneva on March 5, 2021. (Fabrice Coffrini/AFP via Getty Images)
The flag of the World Health Organization (WHO) at their headquarters in Geneva on March 5, 2021. (Fabrice Coffrini/AFP via Getty Images)

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.

In an article in the journal Science, “The ‘very, very bad look' of remdesivir, the first FDA-approved COVID-19 drug,” the author wrote that the WHO SOLIDARITY study was considered by some scientists a “coup de grâce” since this study showed remdesivir does not reduce mortality or the time COVID-19 patients take to recover.

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.

Despite releasing a statement in November 2020 recommending against the use of remdesivir, in April 2022, the health agency updated its statement, recommending the drug’s use in early COVID-19 patients

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.

Kidney failure can lead to fluid accumulation in the lungs and across all the different organs, leading to organ collapse and death. Researchers have found kidney injuries and failures to be a “severe adverse effect” of remdesivir use.
A study evaluating the FDA adverse event reporting system (FAERS) found that in 12,869 acute kidney injury cases in COVID-19 patients, almost a third of the reports were suspected to be driven by remdesivir. The authors also found that 36.45 percent of patients who experienced acute kidney injuries after remdesivir died.

“Although causality was not confirmed, the association between remdesivir and acute kidney injury should not be ignored,” the authors concluded.

A Dutch study on 103 COVID-19 patients treated with remdesivir found that 15 days after treatment initiation, 11 percent of the patients had a decrease in their estimated filtration rate, and 25 to 35 percent had markers that may be linked with liver dysfunction.
The relatives of many COVID-19 patients who witnessed their family member’s rapid decline reported that the worsening happened soon after remdesivir was administered. This included kidney injury, multi-organ failure, and even death.
Some people claimed that hospitals administered remdesivir even after family members insisted against it.

However, not all seem negatively affected by remdesivir; some have made a complete recovery following its administration.

Amerling said it is likely that some people are more susceptible to the adverse effects of remdesivir than others, and people with pre-existing kidney or liver problems were likely to be at a higher risk.

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/

Marina Zhang is a health writer for The Epoch Times, based in New York. She mainly covers stories on COVID-19 and the healthcare system and has a bachelors in biomedicine from The University of Melbourne. Contact her at [email protected].
Related Topics