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Tag: remdesivir antiviral

As the coronavirus spreads, a drug that once raised the world’s hopes is given a second shot

remdesivir-coronavirus
Gilead Science's Remdesivir is now being investigated for it's potential as Covid-19 treatment. (iStock/Getty Images)

A decade ago, a group of chemists cooked up a compound they simply called 3a and that, in lab experiments, fought off a number of different viruses. One was a type of coronavirus.

Now, the descendant of that molecule — Gilead Sciences’ remdesivir — is being rushed to patients with infections from the novel coronavirus in hopes that it can reduce the intensity and duration of Covid-19 and ease the burden of the pandemic on health systems.

Remdesivir, in the spotlight as scientists and governments scramble to find a treatment for the disease, took a circuitous route to center stage. Born as a general antiviral candidate, researchers threw it at an array of viruses and saw where it stuck. It bounced along from Gilead’s labs to academic centers, nudged by both federal taxpayer dollars and support from the company. It kept turning up whiffs of potential in cells and animals infected by other coronaviruses like SARS and MERS, but these bugs weren’t causing sustained global crises. For years, Gilead was primarily focused on ushering remdesivir into trials and toward approval for a different kind of infection: Ebola.

But there’s nothing like a pandemic to break the emergency glass on all possible options.

Remdesivir is now being tested in five Covid-19 clinical trials that have been set up at breakneck speed. It’s been delivered through a compassionate use program to some patients, including the first case in the United States. The first trial results are expected next month, though some analysts have already raised concerns about the prospects based on the drips of data emerging from a small number of patients.

Others’ hopes are high for the drug. As of now, there are no approved therapies for any coronavirus infection, and remdesivir is the farthest along in the development process of any candidate.

“There’s only one drug right now that we think may have real efficacy,” Bruce Aylward of the World Health Organization said last month. “And that’s remdesivir.”

Remdesivir’s odyssey illuminates the complicated trajectory drugs can take as they are forged, refined, scrutinized, and moved into human studies. But its long, meandering path also underscores why drugs need to demonstrate their efficacy in these studies. The drug similarly had lofty expectations as an Ebola treatment, and strong data from animal studies to boot. But in a landmark trial that compared four experimental therapies and was published last year, two other treatments were shown to dramatically reduce deaths from the infection, while remdesivir faltered, producing less impressive survival benefits.

“Drug discovery and development is usually a very long and tedious process and you could have many failures on the path to an approved product,” Tomas Cihlar, Gilead’s vice president of virology, said in an interview with STAT.

As for remdesivir’s chances in Covid-19, Cihlar said:  “It would be wonderful if it works. But it needs to be proven.”

When the patient with the first known U.S. case of Covid-19 was admitted to Providence Regional Medical Center in Everett, Wash., on Jan. 20, he wasn’t all that sick.

The 35-year-old man had the respiratory infection’s most common symptoms of fever and cough, but had no trouble breathing and no evidence of pneumonia — inflammation of the lungs’ air sacs. But around that time, his doctors saw a report from China that detailed that some patients there developed more severe symptoms several days into their illnesses.

“That perked our ears to the worsening of this disease,” said George Diaz, the infectious disease section chief at the hospital.

Within a few days, the man — who had visited family in Wuhan, China, where the outbreak is believed to have started, and returned home to Washington Jan. 15 — started experiencing shortness of breath and requiring oxygen. An X-ray revealed pneumonia.

Diaz informed officials at the Centers for Disease Control and Prevention, with whom he had been conferring daily, that the patient was taking a turn for the worse. The CDC suggested trying an experimental drug, and mentioned Gilead’s remdesivir.

Hospital officials got in touch with Gilead about providing the drug, and then got the approval from the Food and Drug Administration to treat the patient through a compassionate use program, which allows unapproved drugs to be given under select circumstances outside of clinical trials. Gilead overnighted the drug to the hospital.

“Treatment with intravenous remdesivir was initiated on the evening of day 7, and no adverse events were observed,” the medical team wrote in a case report in the New England Journal of Medicine. The man started feeling better the following day.

“We were aware that he was the first patient on the planet getting the drug for this infection, so we were super interested to see, hopefully, if he would improve,” Diaz recalled.

The apparent success in one patient does not prove the drug is effective. That is where the large trials that will compare remdesivir to placebos come in.

Remdesivir has been able to advance into clinical studies so quickly for two key reasons. For one, thanks to its use in Ebola, it was known to be generally safe in humans. And two, it had a large body of preclinical evidence — that is, data from studies in cells in lab experiments and in infected animals — that indicated it could temper coronavirus infections. One study published just last month by researchers from Gilead and the National Institute of Allergy and Infectious Diseases showed remdesivir inhibited the replication of MERS, a related coronavirus, in infected monkeys.

Much of this preclinical research has been conducted through collaboration among the National Institutes of Health, academic labs, and Gilead, steered by the Antiviral Drug Discovery and Development Center, or AD3C. The center is an NIH-funded program run out of the University of Alabama at Birmingham that, since 2014, has been on the hunt for new treatments for emerging viruses.

Since drug screens revealed that remdesivir had potential as a coronavirus fighter, it was routed into the arm of AD3C focused on this family, a project led by Mark Denison at Vanderbilt University and Ralph Baric at University of North Carolina. Starting in about 2015 and with the backing of Gilead, they and scientists in their labs have pulled back the curtain on how exactly remdesivir curtails coronaviruses and demonstrated that it can block the viruses from multiplying in infected animals.


With the coronavirus, drug that once raised global hopes gets another shot
Bottles of remdesivir in a hospital for Covid-19 patients in Wuhan, China. FeatureChina via AP

The researchers got an additional NIH grant to ready remdesivir for clinical trials, and thought the target could be MERS, which has caused 858 deaths and nearly 2,500 cases, mostly in Saudi Arabia, since it started infecting people in 2012. But even with that focus, they were also thinking about how the drugs they were studying could be used for the next spillover — when a virus jumps from animals to people.

“We’ve always thought that coronaviruses were a family on the move,” said Tim Sheahan, a UNC coronavirus expert.

Even with that expectation, though, the researchers who have toiled away for years on these projects without much fanfare find themselves caught off guard now.

“People like me, people doing basic science, oftentimes the work that we’re doing has no obvious direct translation to improving human health,” Sheahan said. “It’s hard to imagine that the work we’ve done in a lab in North Carolina could be saving people’s lives around the world. It’s incredibly gratifying, but it’s surprising and unusual for someone like me to experience this.”

But if remdesivir had hopes as an Ebola treatment, how can it also work against coronaviruses? Their viral families are so different, “it’s like saying a giraffe versus an elephant,” said Gene Olinger, a former U.S. Army Ebola researcher, who is now the scientific advisor at MRI Global, a nonprofit research organization.

The trick is that remdesivir does not go after the virus directly. Instead, it targets the system the virus uses to replicate itself, hijacking it like you would your office’s copy machine as part of a company-wide prank.

These viruses have a genome that consists of a strand of RNA. To make copies of themselves, they rely on a molecule called a polymerase to string together the individual building blocks of the viral genome. These are like the “letters” that we think of composing DNA.

Remdesivir is an “analog,” designed to mimic the appearance of one of the RNA letters, adenosine. It looks so similar that the polymerase can unknowingly pick it up instead of the real adenosine and insert it into the strand of viral genome that’s being constructed, like bringing home the wrong twin from summer camp. Once in place, the analog acts as a cap, preventing any additional pieces from being strung on. This leaves the strand short of the full genome. The virus can’t go on to replicate or infect other cells.

“The polymerase grabs it almost accidentally and uses it in place of adenosine,” said Maria Agostini, a postdoctoral researcher in Denison’s Vanderbilt lab. “The polymerase can kind of get it mixed up sometimes.”

The drug can inhibit coronaviruses as well as Ebola because their polymerases are similar enough that its cloak-and-dagger operation fools them all. (Remdesivir does not appear to work on other viruses with more unrelated forms of polymerase.)

Like a bad song clears out a dance floor, remdesivir can clear the viral levels in a person, as long as it can interrupt enough replication. The key, researchers say, is that it has to be delivered somewhat early in an infection, as the virus is still proliferating. In patients who develop severe disease, it’s not the virus that’s always the main problem. The body’s own immune system can react by heading into overdrive and causing secondary complications like organ damage. An antiviral can’t head that off once it’s begun.

“If you wait to treat someone until they’re in the ICU on a ventilator, it’s too late, you’re not going to do a darn thing,” said Richard Whitley, an infectious disease expert at UAB who coordinates the antiviral consortium.

When remdesivir stumbled in the Ebola trials last year, it was a disappointment, Gilead’s Cihlar acknowledged. But he argued it refocused the company’s attention to other targets for the drug.

They didn’t have to wait long.

In December, reports popped up from Wuhan of mysterious pneumonia cases. In early January, word came of a new coronavirus. “At that point, we started getting ready,” Cihlar said.

And when Chinese scientists published the virus’ genome, Gilead zeroed in on the portion that contained the recipe for the replication machinery — the polymerase. They saw it was nearly identical to the version in SARS — evidence that remdesivir might work against this virus as well. “That was a really strong signal for us,” he said.

There are now five clinical trials of remdesivir in Covid-19: two run by Chinese scientists, one looking at severe infections, and one at mild and moderate infections; one sponsored by NIAID; and two sponsored by Gilead in countries around the world with a large number of cases, looking at different disease severities and dosing regimens.

If the drug is successful in trials, most antiviral experts think the drug should primarily be used for patients with more severe symptoms and those who are hospitalized — some 15% to 20% of cases. But observers have also raised a number of points that could potentially trip up the trials. For one, the process moved so quickly that analysts have wondered if the best doses were chosen. They have also pointed to the fact that one of the Chinese trials includes patients whose symptoms started up to 12 days prior. There are concerns that might be too late.

“The overall trial might not be as spectacular as people think,” Umer Raffat, an analyst at Evercore ISI, said in a presentation last week. But, Raffat added, results from patients who start treatment early might show the drug has efficacy if given soon after symptoms arise.

Another detail that will be scrutinized: Can the drug, which is given intravenously into the bloodstream, reach the cells it needs to clear the respiratory infection?

“We don’t know if the amount of remdesivir that’s going to get into the lungs is enough to get the virus down,” said Andre Kalil, an infectious disease specialist at University of Nebraska Medical Center and an investigator in the NIAID-sponsored trial. “This is part of the reason we’re doing the study.”

Remdesivir may have had a head start, but other efforts are underway to come up with Covid-19 treatments. (These are separate from vaccine projects.) Virologists said they were keeping an eye on a candidate pursued by researchers at Vanderbilt, UNC, and Emory University that, in its various forms, has been identified as NHC, EIDD-2801, and EIDD-1931. The drug company Regeneron, which steered its Ebola antiviral to success in the same trial in which remdesivir stumbled, is working on a treatment, as are other biopharma companies. Some experts have proposed using antibody-containing blood from survivors of Covid-19 as a therapy.

If remdesivir does succeed in clinical trials, Gilead will only face a new round of questions.

The company has run into a buzzsaw of public and governmental criticism in the past over the cost of its HIV and hepatitis C antivirals, and any drug approved to treat Covid-19 will certainly face pricing scrutiny. A Gilead spokesperson said the company was not discussing pricing yet.

Health authorities are already stressing the importance of access to therapeutics that do make it to market.

“We cannot have a situation where people who need the drug don’t get it and people who don’t need the drug do,” Mike Ryan, who leads the WHO’s emergency program, said at a briefing this month when asked about the ongoing clinical trials. “We must find ways to ensure we can scale up production of any drugs that prove effective and we can ensure that those drugs are distributed on the basis of need and the basis of benefit.”

 

That points to another challenge Gilead could face with an approval for remdesivir: supply. Even if it was recommended only for people with severe infections who are hospitalized, that could still amount to thousands of patients needing doses, and needing them soon.

On a call with analysts this month, Gilead CEO Daniel O’Day said the company was “engaging our manufacturing and supply chain in the event of success” and said that it was already talking with partners about increasing production of remdesivir. But given that the drug is still in trials, he said, “right now the demand is really unknown.”

That same day, O’Day appeared at the White House with other drug and vaccine makers.

“We’re moving as fast as we can,” O’Day told President Trump as he described remdesivir. “I think everybody around the table is moving as fast as we can.”

Trump had a simple message for O’Day: “Get it done, Daniel. Don’t disappoint us, Daniel.”

via – Statnews | SourceStatnews | Search  》covid-19 vaccine

Remdesivir antiviral – potential treatment for COVID-19

The discovery that the antiviral drug remdesivir prevented MERS-CoV disease in monkeys supports the clinical trial testing of remdesivir as a treatment for COVID-19.

Remdesivir-antiviral
remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. This colorized scanning electron micrograph shows MERS virus particles (blue) both budding and attached to the surface of infected VERO E6 cells (yellow). Image credit: NIAID.

Three different coronavirus outbreaks (SARS, MERS, COVID-19) have emerged from animal reservoirs in the past two decades that have caused severe disease and concerns over global spread.

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) first appeared in 2012, eight years after the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) first emerged from China in late 2002/2003.  Although no cases of SARS-CoV have been detected since 2004, MERS-CoV continues to circulate with 2,499 reported cases and 861 deaths as of December 2019. The case fatality rate of MERS-CoV is 35% as compared to SARS-CoV which was around 10%.

Since the emergence of MERS-CoV, scientists have focused on developing animal models in which to test new treatments. Currently, there are no FDA-approved antivirals or vaccines for the treatment and prevention of MERS-CoV.

However, a new report from NIH’s National Institute of Allergy and Infectious Diseases (NIAID), published in the Proceedings of the National Academy of Sciences describes a step forward for remdesivir in the approval process for coronavirus treatment.

Remdesivir is an experimental antiviral drug with broad activity

Remdesivir (GS-5734) created in 2014 by the biotechnology company Gilead in Foster City, California was initially developed to fight infectious viral diseases such as Ebola.  As a nucleotide analogue prodrug, it is not active outside the cell. Studies indicate that in the cell, it is metabolized into more active metabolites that inhibit coronavirus replication through interference with viral enzymes (RNA polymerases) that are necessary for replication. Host RNA or DNA polymerases are not affected.

Studies have demonstrated that MERS-CoV enters cells with the help of an S protein or spike to help attach to host cells. The virus then hijacks or delays the normal immune system response as the infection steadily progresses.

Already, remdesivir has proven effective in treating monkeys infected with Ebola and Nipah viruses and human clinical trials are currently underway. Thus far, studies suggest that two other drugs are more effective than remdesivir in treating Ebola.

Multiple in vitro (test tube) studies have demonstrated that remdesivir has broad antiviral activity against viruses from different families (including filo-, pneumo-, and paramyxoviruses) without any noted adverse toxic effects.  For example, replication of a wide range of coronaviruses including SARS-CoV and MERS-CoV was inhibited in human airway (lung) epithelial cells.

In vivo studies with mice also demonstrated that remdesivir was effective against SARS-CoV.

Remdesivir prevented MERS-CoV in monkeys when administered before infection and improved disease symptoms when administered after the animals were infected.

Researchers randomly assigned 18 male rhesus macaques to three groups of six at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana.

One group of monkeys was treated prophylactically (24 h before MERS-CoV infection) with 5 mg/kg remdesivir. Another group was similarly given 5 mg/kg remdesivir but therapeutically (12 h after MERS-CoV infection which is close to the peak time for MERS-CoV replication).  A control group did not receive any remdesivir. The treatment was continued once daily for six days. On the sixth day, researchers assessed viral RNA levels and lesions (damage) present in lung tissues.

The researchers observed signs of respiratory disease in the control group, which included increased respiration rates and lung lesions that consisted of minimal to marked interstitial pneumonia.

Animals treated prophylactically exhibited normal lung tissue with significantly lower levels of MERS-CoV replication compared to the control group. No lesions were present in the lung tissues.

Since one-third of MERS-CoV cases are acquired in the hospital (through nosocomial transmission), prophylactic remdesivir treatment could prevent disease in healthcare personnel or individuals who are in close contact with already diagnosed MERS-CoV patients.

For patients already diagnosed with MERS-CoV, remdesivir may reduce virus replication and decrease the severity of lung lesions.

Five out of six animals treated with remdesivir after infection had increased respiration rates that were still significantly lower than the control group at days three and six. This group also demonstrated lower levels of MERS-CoV replication in the lungs than the control group but levels were higher than the prophylactically treated group.

Moreover, the total area of lungs affected by lesions was significantly smaller than the control group and the lung damage was less severe.

Researchers observed various levels of pneumonia severity when treated therapeutically. Two out of six animals did not show any evidence of pneumonia.

Clinical trials of remdesivir for COVID-19 are currently underway and needed for MERS-CoV

Now that remdesivir has demonstrated in vitro and in vivo activity in animal models against SARS-CoV and MERS-CoV, which are coronaviruses that are structurally similar to COVID-19, there is potential for it to be also effective as a treatment for COVID-19.

The drug is being advanced into human clinical trials for COVID-19 treatment in China, given the current necessity for treatment.  Results from these studies are expected to be available this spring.

Even though remdesivir is not yet licensed or approved by any drug regulators globally and there is no data available on its effectiveness as a treatment for COVID-19, it has been administered for emergency treatment in a small number of patients with in the absence of other approved treatment options. No adverse effects have been seen in these cases.

References:

  • Wit, E. de, Feldmann, F., Cronin, J., Jordan, R., Okumura, A., Thomas, T., … Feldmann, H. (2020, February 13). Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Retrieved from https://www.pnas.org/content/early/2020/02/12/1922083117#F3
  • (n.d.). Remdesivir prevents MERS coronavirus disease in monkeys. Retrieved from https://www.eurekalert.org/pub_releases/2020-02/nioa-rpm021320.php
  • Characterizing MERS-CoV Disease. (n.d.). Retrieved from https://www.niaid.nih.gov/diseases-conditions/characterizing-mers-cov-disease
  • (n.d.). Retrieved from https://www.gilead.com/science-and-medicine/pipeline
  • Severe 2019-nCoV Remdesivir RCT – Tabular View. (n.d.). Retrieved from https://clinicaltrials.gov/ct2/show/record/NCT04257656
  • Company Statements. (n.d.). Retrieved from https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-company-ongoing-response-to-the-2019-new-coronavirus
  • Gilead Assesses Ebola Drug as Possible Coronavirus Treatment (1). (n.d.). Retrieved from https://news.bloomberglaw.com/pharma-and-life-sciences/gilead-assesses-ebola-drug-as-possible-coronavirus-treatment
  • https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?ua=1
  • https://www.nature.com/articles/srep43395