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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

Coronavirus: Facts vs. Panic

Separating facts from irrational fear in the global virus pandemic.

Coronavirus Facts vs Panic
A hospital sign in Switzerland urges patients to consider working from home. FABRICE COFFRINI/AFP via Getty Images

Coronavirus is nothing to sneeze at. But so far, widespread panic may not be justified.

You should know:

  • Almost all of the reported coronavirus deaths in the U.S. happened in long-term care facilities in Washington State. And almost all of those occurred at the same facility.
  • Most people who get coronavirus have mild or no symptoms.
  • No young or middle-age people have died of coronavirus in the U.S. 
  • Most around the world diagnosed from January-March 1 have already recovered.

Obviously, this is a fast-moving news target. For the latest information from the government, you can visit the Centers for Disease Control (CDC) coronavirus page at CDC.gov. The following information is accurate as of Thursday.

Q: What is the average American’s risk of getting coronavirus?

A: Low. CDC reports: “For the majority of people, the immediate risk of being exposed to the virus that causes COVID-19 is thought to be low.”

Q: What’s the likelihood that coronavirus is in my community?

A: Low. CDC reports: “There is not widespread circulation in most communities in the United States.”

Q: How many coronavirus deaths have there been in the U.S.?

A: So far, not many. CDC reports 36 deaths. Adding various news reports, the number could be about 40 and growing. Although one death is too many, the reported deaths are among 43 states (including the District of Columbia) reporting outbreaks since January in a population of more than 327 million people.

Q: How many young people have died of coronavirus in the U.S.?

A: So far, there are no reports of deaths among young people in the U.S. The U.S. Surgeon General reports the average age of people who have died from coronavirus in the U.S. is 80. Additionally, he says those who are most impacted have chronic, serious health problems such as heart disease, diabetes, and lung disease.

Q: Who has died so far?

A. These were compiled using CDC reports plus news and local health department reports: 

  • 31 Washington State elderly. That includes 27 in King County, (22 at the same elderly nursing facility in Kirkland), three in Snohomish county, and one in Grant County, a patient in their 80s.
  • Four California elderly: A woman in assisted living in her 90s, a hospitalized woman Santa Clara in her 60s, an “elderly man” in assisted living, and a 71-year-old man with underlying health conditions who’d been on a Grand Princess cruise ship. 
  • Two Florida residents in their 70s who had traveled overseas. 
  • One New Jersey diabetic man, 69, who suffered two cardiac arrests. 
  • One South Dakota man aged 60-69, with “underlying medical conditions”
  • One Georgia man, 67, with “underlying medical conditions”

Q: How many people have recovered?

A: News reports say that in China alone, out of 80,000 diagnosed, nearly 60,000 have already recovered. However, the true number of recovered is likely far higher since most of those who get the virus have mild or no symptoms, and so are not diagnosed at all.

Q: Why have there been so many coronavirus deaths in Italy?

A: Italy has reported 827 coronavirus deaths. Experts say the high number is partly because Italy has more residents in the vulnerable age category. Italy has the oldest population in Europe and more elderly per capita than the U.S. Most of the Italian deaths are in patients in their 80s and 90s. In addition, Italy has a great number of direct China contacts. Italy was the first to join China’s “silk road” economic partnership project. The coronavirus is believed to have originated in China. Italy’s 827 deaths are out of a population of 60 million people. Even though one death is too many, it is still a small relative number.

Q: Why am I hearing so many different fatality rates?

A: Experts say all coronavirus death rates are nothing more than estimates at the moment. That’s because it is impossible to know how many people have or had the virus. And that total number is needed to calculate an accurate rate. What makes it more difficult is the fact that most people have few or no symptoms, and so it is impossible to count them.

Some current death rates that sound high are being calculated in a particular age group. The rate will be highest among the elderly and, in the U.S., there have been zero deaths among people age 50 and under. Some death rates are being calculated as deaths among the sickest patients, those are diagnosed and treated, which will produce a much higher number than a more accurate death rate that takes into consideration those patients who are infected but do not become ill at all.

via – Just The News | SourceJust The News | Search  》coronavirus facts symptoms

How long can the new coronavirus last on surfaces?

A new study suggests the virus can live on surfaces for up to 3 days.

How long can the new coronavirus last on surfaces
The new SARS-CoV-2 remains a mystery. (Image: © NIAID-RML)

As the coronavirus outbreak continues to accelerate in the U.S., cleaning supplies are disappearing off the shelves and people are worried about every subway rail, deli counter and toilet seat they touch. 

But how long can the new coronavirus linger on surfaces, anyway? The short answer is, we don’t know. A new analysis found that the virus can remain viable in the air for up to 3 hours, on copper for up to 4 hours, on cardboard up to 24 hours and on plastic and stainless steel up to 2 to 3 days. However, this study, which was published in the preprint database medRxiv on Wednesday (March 11),  has not yet yet been peer-reviewed.

Another study published in February in The Journal of Hospital Infection analyzed several dozen previously published papers on human coronaviruses (other than the new coronavirus) to get a better idea of how long they can survive outside of the body. 

They concluded that if this new coronavirus resembles other human coronaviruses, such as its “cousins” that cause SARS and MERS, it can stay on surfaces —  such as metal, glass or plastic — for as long as nine days (In comparison, flu viruses can last on surfaces for only about 48 hours.)

But some of them don’t remain active for as long at temperatures higher than 86 degrees Fahrenheit (30 degrees Celsius). The authors also found that these coronaviruses can be effectively wiped away by household disinfectants. 

For example, disinfectants with 62-71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite (bleach) can “efficiently” inactivate coronaviruses within a minute, according to the study. “We expect a similar effect against the 2019-nCoV,” the researchers wrote, referring to the new coronavirus. But even though the new coronavirus is a similar strain to the SARS coronavirus, it’s not clear if it will behave the same.

It’s also not clear how frequently hands become contaminated with coronaviruses after touching a sick patient or contaminated surface, according to the study. The World Health Organization recommends washing hands or using alcohol-based hand rubs for decontamination of the hands, the authors wrote.

It’s possible that a person can be infected with the virus by touching a contaminated surface or object, “then touching their own mouth, nose, or possibly their eyes,” according to the Centers for Disease Control and Prevention (CDC). “But this is not thought to be the main way the virus spreads.” Though the virus remains viable in the air, the new study can’t say whether people can become infected by breathing it in from the air,  according to the Associated Press

The virus is most likely to spread from person to person through close contact and respiratory droplets from coughs and sneezes that can land on a nearby person’s mouth or nose, according to the CDC.

via – Livescience | SourceLivescience | Search  》coronavirus

Stanford Medical Expert Examines Social Distancing, Bell Curve Of Coronavirus Epidemic

Dr. Bonnie Maldonado
Dr. Bonnie Maldonado

STANFORD (KPIX 5) — Past the point of containment, the best hope is to slow a virus down, or “flatten the curve.” The idea is to keep the virus from spreading so quickly that it overwhelms our health care system’s ability to treat the very sick.

That is what social distancing is designed to do, but where on that curve is the United States now, and where might the country be heading?

“Of course, hindsight is 2020,” says Dr. Bonnie Maldonado, a pediatrician and infectious disease expert at the Stanford School of Medicine. “We never know where we are on the curve, until after the curve has been drawn.”

Maldonado says making any prediction about how the virus will spread in the United States is difficult, because the country is actually watching several different outbreaks at once.

“For example, in new Rochelle, New York, we know that that is a very specific kind of outbreak, and we could maybe pattern that one,” Maldonado explains. “But that has nothing to do with what is happening in Seattle, or in Santa Clara, or any other place. So it’s really hard to scale up a model that would take into account all of the different scenarios across the country.”

In that respect, Maldonado says Italy makes for a problematic comparison with the United States. And while the country has lagged in testing for the virus, there is some encouraging evidence at our hospitals.

“Even with lack of testing, we would probably be noticing a lot more people that are sick,” Maldonado says.

In other words, there has not yet been a dramatic or overwhelming surge in very sick patients. That means social distancing, and the other steps we are taking, could be putting the brakes on the virus, at least enough to keep that curve down.

“We know that from looking at epidemic curves going forward, 3 to 4 days of intervention can make a big difference between a flat epidemic and a peaked one,” Maldonado says of mitigation strategies like social distancing. “I do think we will be able to limit the spread, I just don’t know where it will stop.”