Remdesivir

GOVT. MADHAV SCIENCE P.G.COLLEGE UJJAIN M.P.

A GRADE ACCREDITED THROUGH NAAC

EVERYTHING YOU NEED TO KNOW ABOUT REMDESIVIR…

FROM CHEMICAL FORMULA TO STRUCTURE
FROM DRUG TRIAL TO SUCCESS STORY
FROM MEDIA REPORTS TO SERIOUS RESEARCH PAPERS.

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REMDESIVIR

Remdesivir is a broad-spectrum antiviral medication developed by
the biopharmaceutical company Gilead Sciences. As of 2020, remdesivir is being tested
as a specific treatment for COVID-19, and has been issued an Emergency Use
Authorization (EUA) in the U.S. for those hospitalized with severe disease. It may
shorten the time it takes to recover from the infection. Treatment is given by injection
into a vein.

Remdesivir explained – what makes this drug
work against viruses?

May 6, 2020 10.20pm AEST
Author

1. Katherine Seley-Radtke
2.

Professor of Chemistry and Biochemistry and President-Elect of the
International Society for Antiviral Research, University of Maryland, Baltimore
County

Disclosure statement

Dr. Katherine Seley-Radtke has previously consulted for Gilead Sciences and owns
Gilead Sciences stock. She currently receives funding from the National Institutes of
Health (NIH), the National Institute of General Medicine (NIGMS), the National Institute
of Allergies and Infectious Diseases (NIAID). She is the President-elect of the
International Society for Antiviral Research (ISAR) and is the Secretary and former
President of the International Society of Nucleosides, Nucleotides & Nucleic Acids
(IS3NA), both non-profit scientific professional societies

University of Maryland, Baltimore County provides funding as a member of The
Conversation US.



With the FDA approving Gilead’s Remdesivir as an emergency use treatment for the
most acute cases of COVID-19, many people are wondering what type of a drug it is.

Remdesivir is a member of one of the oldest and most important classes of drugs –
known as nucleoside analogue. Currently there are more than 30 of these types of drugs
that have been approved for use in treating viruses, cancers, parasites, as well as
bacterial and fungal infections, with many more currently in clinical and preclinical
trials.

Fake genetic building blocks
The reason nucleoside analogues and a similar group called nucleotide analogues are so
effective is that they resemble the naturally occurring molecules known as nucleosides

– cytidine, thymidine, uridine, guanosine and adenosine. These are the essential
building blocks for the DNA and RNA that carry our genetic information and play critical
roles in our body’s biological processes.
Slight differences in the chemical structure of these analogues from naturally occurring
compounds make them effective as drugs. If an organism like a virus incorporates a
nucleoside analogue into its genetic material, rather than the real thing, even small
changes to the structure of these building blocks prevent the regular chemistry from
happening and ultimately foils the ability of the virus to replicate.
The basic structure of a nucleoside includes a sugar group and a base (A, C, G, T or U),
and in the case of a nucleotide, a group containing a phosphate which is a collection of
oxygen and phosphorus atoms.

Every building block of DNA is made from three parts: a sugar, a base (A, C, G, or T) and
a phosphate group. Every building block of RNA is made from (A, C, G, or U).
The first nucleoside analogues were approved for medicinal use in the 1950s. The early
nucleosides had only simple modifications, typically either to the sugar or the base,
while today’s nucleosides, such as Remdesivir, typically have several modifications to
their structure. These modifications are essential to their therapeutic activity.

How does Remdesivir work as antiviral therapeutic?
This activity occurs because nucleoside/tide analogues mimic the structure of a natural
nucleoside or nucleotide such that they are recognized by, for example, viruses. Due to
those structural modifications, however, they stop or interrupt viral replication, which
stops the virus from multiplying and infecting more cells in the body.
As a result, they are known as direct-acting antivirals, and this is the case for
Remdesivir, which works by blocking the coronavirus’s RNA polymerase – one of
the key enzymes that this virus needs to replicate its genetic material (RNA) and
proliferate in our bodies. Remdesivir works when the enzyme replicating the
genetic material for a new generation of viruses accidentally grabs this nucleoside
analogue rather than the natural molecule and incorporates it into the growing
RNA strand. Doing this essentially blocks the rest of the RNA from being replicated;
this in turn prevents the virus from multiplying.
The drug Remdesivir is basically an altered version of the natural building block
adenosine – which is essential for DNA and RNA. Comparing the structure of Remdesivir
with adenosine, one can see there are three key modifications that make it effective.
The first is that Remdesivir, as it is administered, is not the actual active drug; it is
actually a “prodrug,” meaning it must be modified once in the body before it becomes an
active drug. Prodrugs are used for many reasons, including protecting a drug until it
reaches its site of action. The active form of Remdesivir contains three phosphate
groups; it is this form that is recognized by the virus’s RNA polymerase enzyme.

A naturally occurring nucleotide (left) which is a building block of RNA and DNA and
Remdesivir (right) which is a variation on its natural counterpart.
The second important modification on Remdesivir is the carbon-nitrogen (CN) group
attached to the sugar. Once Remdesivir is incorporated into the RNA growing chain, the
presence of this CN group causes the shape of the sugar to pucker, which, in turn,
distorts the shape of the RNA strand such that only three more nucleotides can be
added. This terminates the production of the RNA strand and is what ultimately
sabotages the replication of the virus.

The third important structural feature which makes Remdesivir differ from adenosine is
the change of one particular chemical bond on the molecule. Rather than a bond linking
a carbon and nitrogen atoms, chemists replaced the nitrogen with another carbon,
creating a carbon-carbon bond. This is critical to the success of this drug because
coronaviruses have a special enzyme that recognizes unnatural nucleosides and clips
them out. But by changing this chemical bond, Remdesivir cannot be removed by the
enzyme, allowing it to stay in the growing chain and block replication.

Remdesivir trials

Remdesivir originally was found during a drug discovery program at Gilead to search
for inhibitors of the hepatitis C virus, which is another RNA virus. Although Gilead
ultimately selected a different nucleoside analogue for treatment of hepatitis the
company tested the drug to see if it was effective against other RNA viruses.
Remdesivir exhibited potent activity against Ebola and Middle Eastern respiratory
virus, among others.

Now the drug is being tested against the SAR-CoV-2 virus in the first clinical trial
launched in the United States.

According to the NIH, patients who received Remdesivir had a faster recovery
compared to those who received placebo; 11 days compared with 15 days for those who
received the placebo. “Results also suggested a survival benefit, with a mortality rate of
8.0% for the group receiving Remdesivir versus 11.6% for the placebo group,”
according to the NIH press release.

While these results are preliminary, there are a plethora of clinical trials underway
across the world. Regardless, a certain amount of caution is still needed. As noted by Dr.
Anthony Fauci on NBC’s “Today” show, “the antiviral drug Remdesivir is the first step in
what we project will be better and better drugs coming along” to treat COVID-19, but
cautioned, “This is not the total answer.”

I share this view with many other scientists in the field. No matter what those results
ultimately show, Remdesivir will mostly certainly be part of a cocktail of drugs, just as is
standard for treating other viruses such as HIV and hepatitis C.

A combination, or cocktail, of drugs will provide a more effective and more complete
therapy that blocks the virus from replicating. The other benefit of such a drug cocktail
is that it lowers the chance the virus will develop resistance to the therapy. In the
meantime, these early results for Remdesivir are proving to be an important source of
hope for many of us across the world as we wait for this pandemic to subside.

US OKs Remdesivir; India
plans trials

TNN | May 3, 2020, 02.34 AM IST

The US Food and Drug Administration has allowed emergency use of the experimental
anti-viral drug Remdesivir, previously used for Ebola, to treat Covid-19 patients even as
India is looking to import the drug to kick-start local trials.
The drug has delivered encouraging results on Covid patients in need of advanced care
and helped quicken recovery. India, which is part of WHO’s solidarity trial on the drug,
is exploring options to source it, official sources said. “Around four hospitals have been
identified as trial sites and are waiting for ethics committee approval. We are also in the
process of enrolling patients for the trial. Trials in India can start as soon as the drug
arrives,” a senior official said.
Currently there are limited stocks of the drug which is under different trials in various
countries. However, with the US FDA authorisation, its demand is likely to go up
substantially.
“We are working to access the drug for our people and all efforts will be made to make
the drug available in India if it proves to be beneficial,” Niti Aayog member Dr V K Paul,
who also heads the government-formed Empowered Group on Emergency Response to
Covid-19, told TOI.
Experts said though the trial is significant as it is suggestive of reduction in symptomatic
time, it cannot be used as a standard treatment because of limited evidence. The need
for larger controlled clinical trials, which can demonstrate clear impact on hard clinical
end-points, including mortality reduction, remains as search for an effective life-saving
cure continues, said Dr K Srinath Reddy of Public Health Foundation of India.
On Friday, the US FDA authorised the emergency use of Remdesivir for treatment of
Covid-19 after preliminary results from a government-sponsored study in US showed
that Gilead Science’s drug shortened the time to recovery by four days— from 15 days
to 11 days —in hospitalised Covid-19 patients.

Emergency-use authorisation allows products to be used for treatment without full data
on their safety and efficacy, which has to be still submitted as trials continue.
Remdesivir is the world’s first drug that has offered some evidence of being effective for
Covid-19, which has killed more than 2,30,000 people worldwide and infected over
three million.

“Based on the totality of scientific evidence available to FDA, it is reasonable to believe
that Remdesivir may be effective in treating Covid-19, and that, when used under the
conditions described in this authorisation, the known and potential benefits of
Remdesivir when used to treat Covid-19 outweigh the known and potential risks of
such products; and there is no adequate, approved, and available alternative,” said the
FDA in the letter.

“One trial compared 5-day regimen with 10-day regimen and noted equal clinical
recovery time. There was no control group and effect on deaths was not studied.
Another trial was randomised, had a control group of standard care, and observed a
benefit in reduction of recovery time from severe illness. Impact on death was, however,
statistically not significant and hence unproven,” said Dr Reddy.

Researchers say other trials like the WHO multi-country solidarity trial will be helpful in
establishing the efficacy of the drug. While there are also ‘compassionate use
programme’ for Remdesivir, India is not part of it. Compassionate use programme is
employing a new, unapproved drug to treat a severely ill patient in a scenario where
there is no other treatment available.

An official in the drug regulator’s office said for such use there is no drug approval
required. However, a clinical management protocol has to be prepared and needs to be
approved by ICMR.

Press Trust of India

Washington
May 2, 2020
UPDATED: May 2, 2020 11:16 IST

(Representational Image)
The US food and drug regulatory body has allowed emergency use of an investigational
anti-viral vaccine to treat Covid-19 patients after some researches, including one led by
an Indian-American physician, found that the drug helped recover some of the infected
cases faster.
The Food and Drug Administration (FDA) gave emergency use authorization (EUA) for
the use of investigational anti-viral Remdesivir in the treatment of Covid-19 patients.
The FDA authorization came after researches, including one led by Indian-American
physician Aruna Subramanian, reported Remdesivir shortened the recovery times in
people who have fallen ill from the new coronavirus.
"I''m pleased to announce that Gilead now has an EUA (emergency use authorization)
from the FDA for Remdesivir," US President Donald Trump told reporters at the White
House on Friday.
Trump said that EUA is an important treatment for hospitalized coronavirus patients.
Health and Human Services Secretary Alex Azar said that this is a significant step
forward in battling COVID-19.
The EUA allows for Remdesivir to be distributed in the US and administered
intravenously by health care providers, as appropriate, to treat suspected or laboratory-
confirmed COVID-19 in adults and children hospitalized with severe condition.
By Friday, over 63,000 Americans have died of the coronavirus and over one million
have tested positive with COVID-19.

Trump said that his administration has been doing work with the teams at the FDA,
National Institute of Health and Gilead for spearheading this public-private partnership
to make this happen very quickly.

"I think this really illustrates what can happen in such a short time. For the first case,
that was diagnosed in the United States to now, our first step forward with a therapeutic
in less than 90 days," said Deborah Birx, a member of the White House Task Force on
Coronavirus.

In a statement, Gilead said that the EUA will facilitate broader use of Remdesivir to treat
hospitalised patients with severe Covid-19 disease, enabling access to the vaccine at
additional hospitals across the country.

Remdesivir is authorized for the treatment of hospitalised patients with severe Covid-
19 disease, it said, adding that the optimal duration of treatment is still being studied in
ongoing clinical trials.

Under the EUA, both five-day and 10-day treatment durations are suggested, based on
the severity of disease. The authorisation is temporary and does not take the place of
the formal new drug application submission, review and approval process, Gilead noted.

"This EUA opens the way for us to provide emergency use of Remdesivir to more
patients with severe symptoms of COVID-19," said Daniel O'Day, Chairman and Chief
Executive Officer of Gilead Sciences.

"We will continue to work with partners across the globe to increase our supply of
Remdesivir while advancing our ongoing clinical trials to supplement our
understanding of the drug''s profile. We are working to meet the needs of patients, their
families and healthcare workers around the world with the greatest sense of urgency
and responsibility," he said.

According to Gilead, the EUA is based on available data from two global clinical trials -
the National Institute for Allergy and Infectious Diseases' placebo-controlled Phase 3
study in patients with moderate to severe symptoms of Covid-19, including those who
were critically ill, and Gilead''s global Phase 3 study evaluating 5-day and 10-day dosing
durations of Remdesivir in patients with severe disease.

Multiple additional clinical trials are ongoing to generate more data on the safety and
efficacy of the vaccine as a treatment for Covid-19, it said.

Indian-American Subramanian, MD, Clinical Professor of Medicine, Chief,
Immunocompromised Host Infectious Diseases, Stanford University School of Medicine,
is one of the lead investigators of the study.

Earlier in an interview to Fox news, Subramanian said that "there''s a lot more work to
be done in terms of exactly who should get this drug, what is the best timing, who is at
highest risk for having complications And what can we add to this or what can we
improve upon this to make outcomes even better."

"This (remdesivir) is a direct-acting antiviral. It has been shown to have great promise
in the lab and in animal models and for the first time now in human clinical trials,"
Subramanian told Fox News.

"We know that so far, it''s been very safe and tolerable. We''ve had good clinical
outcomes and yesterday we found that compared to placebo, that is people who are
given no medication, people do much better," she said.

FDA Commissioner Stephen M. Hahn said, "today''s action is an important step in our
efforts to collaborate with innovators and researchers to provide sick patients timely
access to new therapies where appropriate, while at the same time supporting research
to further evaluate whether they are safe and effective."

Last Updated : May 03, 2020 09:11 PM IST | Source: Moneycontrol.com

Remdesivir will be available to
coronavirus patients this week:
Gilead CEO

"We intend to get that to patients in the early part of this next week, beginning to work
with the government which will determine which cities are most vulnerable and where
the patients are that need this medicine," O'Day said.
Moneycontrol News @moneycontrolcom

Gilead Sciences has said that its antiviral drug, Remdesivir, will be available to patients
as early as this week, Gilead Science CEO Daniel O’Day told American television channel
CBS. "We intend to get that to patients in the early part of this next week, beginning to
work with the government which will determine which cities are most vulnerable and
where the patients are that need this medicine," O'Day said on CBS’ "Face of the Nation".
"We’ve donated the entire supply that we have within our supply chain and we did that
because we acknowledge and recognize the human suffering, the human need here, and
want to make sure nothing gets in the way of this getting to patients," O'Day said,
according to CNBC.

"What we will do is provide that donation to the US government and they will
determine — based upon things like ICU beds, where the course of the epidemic is in
the United States — they will begin shipping tens of thousands of treatment courses out
early this week and be adjusting that as the epidemic shifts and evolves," the Gilead CEO
said.

Earlier, in an exclusive interaction with Moneycontrol, a Gilead spokesperson had said
that the company is open to collaborate with governments, pharmaceutical companies,
including from India, and is even considering proposals of patent-pooling to expand
capacity and provide access to Remesdesivir for COVID-19 patients across the world.

"It will be essential for countries to work together to create enough supply for people all
over the world and we look forward to these collaborative efforts. In the event of
regulatory action, we are in discussions with various groups about how we might bring
remdesivir to the developing world," Gilead had said.

Earlier, on April 29, the company had said that Remdesivir helped improve symptoms in
COVID-19 patients who were given the drug early than among those who were treated
later.

In Pics | All you need to know

about Gilead's experimental

antiviral drug Remdesivir

The drug is not yet licensed or approved anywhere globally and has not yet been
demonstrated to be safe or effective for the treatment of COVID-19
Moneycontrol News @moneycontrolcom

Gilead Sciences said on April 29 that its experimental anti-viral drug Remdesivir helped
improve symptoms in novel coronavirus, or COVID-19, patients who were given the
drug early than among those who were treated later.

Remdesivir is not yet licenced or approved anywhere globally and has not yet
been demonstrated to be safe or effective for the treatment of COVID-19.

Interest in Gilead's drug has been high as there are currently no approved treatments or
preventive vaccines for COVID-19, and doctors are desperate for anything that might
alter the course of the disease that attacks the lungs and can shut down other organs in
extremely severe cases.

The closely-watched drug has moved markets in the past few weeks. On April 29,
broader markets once again rose on the data and Gilead shares also jumped 9 percent.

Gilead said in a statement that it will continue to discuss with regulatory authorities the
growing data set regarding Remdesivir as a potential treatment for COVID-19.

Last Updated : May 01, 2020 09:09 PM IST | Source: Moneycontrol.com

Exclusive: Gilead says open to
collaborate with govts, drug firms
to make Remdesivir globally
available

There is a possibility of Indian companies becoming part of the consortium, in the past
Gilead used voluntary licenses to rope in Indian cos to manufacture and launch HIV and
hepatitis-C medications in low-middle-income countries (LMICs).
Viswanath Pilla @viswanath_pilla

Gilead Sciences, the US-drug maker said it is open to collaborate with governments,
pharmaceutical companies, including from India, and is even considering proposals of
patent-pooling to expand capacity and provide access to its antiviral drug Remesdesivir
for COVID-19 patients across the world.
"On the supply side, we are working to build a global consortium of pharmaceutical and
chemical manufacturers to expand global capacity and production and have pledged to
donate all our existing supply for patients in need," Gilead spokesperson told
Moneycontrol in an email interview.
"It will be essential for countries to work together to create enough supply for people
all over the world and we look forward to these collaborative efforts. In the event of

regulatory action, we are in discussions with various groups about how we might bring
remdesivir to the developing world," Gilead said.

Gilead didn't provide any timeframe about its launch in India.
The company didn't specify if there are any Indian generic drug companies in the
consortium. However, there is a possibility of Indian companies becoming part of the
consortium, in the past Gilead used voluntary licenses to rope in Indian companies to
manufacture and launch HIV and hepatitis-C medications in low-middle-income
countries (LMICs).

Remdesivir has shown positive results in two clinical trials, one conducted by the
company and another by US government in treating patients with severe COVID-19
disease. The results were announced on April 29. The drug maker said the latest data
allows a shorter treatment time which allows more patients to get access to the
potential treatment. Remdesivir is yet to be approved by USFDA. But the regulatory
agency is reviewing clinical trial data and is expected to issue an emergency use
authorisation anytime soon.

Globally there are about 3.24 million confirmed cases of COVID-19, around 230,615
people have died due to pandemic, according to Johns Hopkins Coronavirus Resource
Center. India reported about 34,780 cases and 1151 deaths so far.

Exploring potential new formulations & combinations

Gilead said the newly released trial results will open up many opportunities to explore
the utility and potential of remdesivir.

"Our teams will look at ways to potentially bring the treatment to a broader patient
population by investigating other formulations and means of delivery. We will also
engage with partners to explore how remdesivir might work with other therapies," the
company said.

Patent pooling

Gilead said it is aware of proposals for manufacturers to license their intellectual

property under various pooled arrangements.

"We will carefully consider whether these proposals would benefit the amount of
supply or the speed at which it is made available once we understand the details of such
proposals," the company said.

A patent pooling allows for voluntary licenses on medicines patents that enable generic
competition and facilitate the development of new formulations. Gilead in the past used
patent pool to provide access to its life saving patented anti-HIV and hepatitis-C
medicines to patients living in low-and-middle-income countries at affordable prices.

Compulsory licensing

Gilead expressed concern over compulsory licensing, and said it is open to have
dialogue with countries.

"Compulsory licensing is a concern – not because of intellectual property rights but
because there is a real risk that it could create chaos in the supply chain for scarce raw
materials and other manufacturing inputs that could reduce the amount of remdesivir
that could be produced and increase the time it takes to do so," Gilead said.

"We would hope that before any country issues a compulsory license that they first
speak to us about how they can be a part of a coordinated supply solution," the company
added.

Gilead said Remdesivir is a result of a decade of research.

The company has patented the drug in US, China and other parts of the world. Gilead
filed additional patent applications for remdesivir for its uses against coronavirus
globally, including China, in 2016. The patent application for the uses against
coronavirus is still pending in China.

India access

Gilead said India is not on the Compassionate Use program for Remdesivir.

A compassionate use is the use of a new, unapproved drug to treat a seriously ill patient
when no other treatments are available. Currently Gilead is providing the drug on
compassionate use and expanded access criteria in US and certain other countries.

The company said for patients in India, they have enroll in the Solidarity trial of WHO.

"India is part of the large global study designed by the WHO - the Solidarity trial. This
trial is the best way for patients to access Remdesivir, enabling access to Remdesivir
and collecting data to inform the use of this investigational compound and support
potential regulatory approvals that can enable broader use of Remdesivir," the company
said.

NEWS NATURE
29 APRIL 2020 UPDATE 04 MAY 2020

Hopes rise for coronavirus drug remdesivir

Despite conflicting studies, results from largest trial yet show the antiviral speeds up
recovery, putting it on track to become a standard of care in the United States.

Heidi Ledford

Coronavirus causes severe respiratory illness in some people.Credit: Zhang
Yazi/China News Service via Getty
An experimental drug — and one of the world’s best hopes for treating COVID-19 —
could shorten the time to recovery from coronavirus infection, according to the largest
and most rigorous clinical trial of the compound yet. On 1 May, the US Food and Drug
Administration (FDA) granted an ‘emergency use authorization’ for clinicians to use the
drug, called remdesivir, which is administered intravenously, in hospitals for people
with severe COVID-19.
Remdesivir interferes with the replication of some viruses, including SARS-CoV-2,
which is responsible for the current pandemic. On 29 April, Anthony Fauci, director of
the US National Institute of Allergy and Infectious Diseases (NIAID), announced that a
clinical trial in more than 1,000 people had showed that those taking remdesivir
recovered in 11 days on average, compared with 15 days for those on a placebo.

“Although a 31% improvement doesn’t seem like a knockout 100%, it is a very
important proof of concept,” Fauci said. “What it has proven is that a drug can block this
virus.”

There were also fewer deaths among trial participants who received the drug, he said,
but that trend was not statistically significant. The shortened recovery time, however,
was significant, and was enough of a benefit that investigators decided to stop the trial
early, he said, to ensure that those participants who were receiving placebo could now
access the drug. Fauci added that remdesivir would become a standard treatment for
COVID-19. The FDA’s authorization is not a final drug approval, and can be revoked
when the conditions required for emergency use are no longer in effect. Distribution of
the drug in the United States will be under government control.

Rollercoaster ride
The news comes after weeks of data leaks and on a day of mixed results from clinical
trials of the drug. The drug’s maker, Gilead Sciences of Foster City, California,
announced on the same day that in its own trial, more than half of 400 participants with
severe COVID-19 had recovered from their illness within two weeks of receiving
treatment. But the study lacked a placebo-controlled arm, making the results difficult to
interpret. Also on 29 April, a smaller trial run in China announced that it had found1 no
benefits from remdesivir when compared with a placebo. But that trial was stopped
early owing to difficulty in enrolling participants as the outbreak subsided in China.
Nevertheless, onlookers are hopeful that the large NIAID trial provides the first glimmer
of promise in a race to find a drug that works against the coronavirus, which has
infected more than three million people worldwide.

“There is a lot of focus on remdesivir because it’s potentially the best shot we have,”
says virologist Stephen Griffin at the University of Leeds, UK.

Small trials
Fast-flowing, conflicting information on remdesivir in the past few weeks has left people
reeling. In the rush to find therapies to combat COVID-19, small clinical trials without
control groups have been common. “I’m just very annoyed by all of these non-controlled
studies,” says Geoffrey Porges, a biotechnology analyst for the investment bank SVB
Leerink in New York City. “It’s reassuring that 50–60% of patients are discharged from
the hospital, but this is a disease that mostly gets better anyway.”

With so much uncertainty, the remdesivir-watchers were waiting anxiously for final
results from the NIAID trial, which were not expected until the end of May. In lieu of a
vaccine ,which could still be more than a year away, effective therapies are crucial in
reducing deaths and limiting economic damage from the pandemic. Yet, despite the
flood of small clinical trials, no therapy has been convincingly shown to boost survival
in people with COVID-19.

The NIAID results put a new sheen on remdesivir.The NIAID did not release detailed
safety data. The study in China found no significant difference between remdesivir and
placebo in the frequency of adverse events, but 12% of people who received remdesivir
dropped out of the study due to side effects including nausea and cardiopulmonary
failure, compared to only 5% on placebo.

“It may not be the wonder drug that everyone’s looking for, but if you can stop some
patients from becoming critically ill, that’s good enough,” says Griffin.

Fauci said the finding reminded him of the discovery in the 1980s that the drug AZT
helped to combat HIV infection. The first randomized, controlled clinical trial showed
only a modest improvement, he said, but researchers continued to build on that success,
eventually developing highly effective therapies.

Remdesivir works by gumming up an enzyme that some viruses, including SARS-CoV-2,
use to replicate. In February, researchers showed2 that the drug reduces viral infection
in human cells grown in a laboratory.

Gilead began to ramp up production of remdesivir well before the NIAID results came
out. By the end of March, the company had produced enough to treat 30,000 patients.
And by streamlining its manufacturing process and finding new sources of raw
materials, Gilead announced, it hopes to produce enough remdesivir to treat more than
one million people by the end of the year.

That calculation was based on the assumption that people would take the drug for ten
days, but the results announced from Gilead’s trial on 29 April suggest that a five-day
course of treatment could work just as well. If so, that would effectively double the
number of people who could be treated, says Porges.

Many drugs needed
In the long term, clinicians will probably want a bevy of antiviral drugs — with different
ways of disabling the virus — in their arsenal, says Timothy Sheahan, a virologist at the
University of North Carolina in Chapel Hill, who has teamed up with Gilead researchers
to study remdesivir. “There is always the potential for antiviral resistance,” he says.
“And to hedge against that potential, it’s good to have not only a first-line, but also a
second-, third-, fourth-, fifth-line antiviral.”

Researchers are furiously testing a wide range of therapies, but early results, although
not yet definitive, have not been encouraging. The malaria drugs chloroquine and
hydroxychloroquine, both of which have anti-inflammatory effects, drew so much
attention from physicians and the public that some countries have depleted their
supplies of the drugs. Yet studies in humans have failed to show a consistent benefit,
and some have highlighted the risks posed by side effects of the drugs that affect the
heart.

Early interest in a mix of two HIV drugs called lopinavir and ritonavir flagged when a
clinical trial in nearly 200 people did not find any benefit of the mix for those with
severe COVID-193. Another promising therapeutic hypothesis — that inhibiting the
action of an immune-system regulator called IL-6 could reduce the serious
inflammation seen in some people with severe COVID 19— has met with mixed results
thus far.

Still, a host of other therapies are being tested in people, and many researchers are
hunting for new drugs at the bench. Sheahan and his colleagues have found4 a
compound that is active against SARS-CoV-2 and other coronaviruses, including a
remdesivir-resistant variant of a coronavirus, when tested in laboratory-grown human
cells.

But much more testing would be needed before the compound could be tried in people.
“What we’re doing now will hopefully have an impact on the current pandemic,” he says.
“But maybe more importantly, it could position us to better respond more quickly in the
future.”

doi: 10.1038/d41586-020-01295-8

Gilead may tie up with Indian firms to
produce Remdesivir

Coronavirus news: Indian Council of Medical Research (ICMR) had hinted that if the
medicine proves effective, and if cost effective versions of the medicine can be made
available through Indian generic companies, then it can be considered for treating
COVID-19 patients in India

Joe C Mathew New Delhi Last Updated: April 30, 2020 | 12:09 IST

Coronavirus news: Gilead likely to announce voluntary licence agreement

MORE FROM THE AUTHOR

US based Gilead Sciences is likely to announce voluntary licence agreements with Indian
medicine manufacturers to allow them to produce generic versions of Remdesivir, an
experimental drug that is looked at as a potential candidate for the treatment of novel
coronavirus (COVID-19) treatments. Mumbai based Cipla and Hyderabad based Dr Reddy's
Laboratories are among the companies that could sign partnership agreements with Gilead,
industry sources say.
The drug, undergoing clinical trials globally at the moment, is yet to be approved for
COVID-19 treatment. Indian Council of Medical Research (ICMR) had hinted that if the
medicine proves effective, and if cost effective versions of the medicine can be made
available through Indian generic companies, then it can be considered for treating COVID-19
patients in India too.
Recently, Mumbai-based civil society organisation Cancer Patent Aid Association (CPAA)
had written to the government demanding the revocation of one of the patents on Remdesivir,

citing India's strict innovative step and novelty requirements as eligibility criteria. The
experimental drug, however, has a couple of undisputed patents also in India.
On April 10, Daniel O' Day, chairman and CEO, Gilead had stated that seven clinical trials
are going on to determine whether Remdesivir is a safe and effective treatment for COVID-
19 at the moment. The company anticipates that by May, the initial data from the placebo-
controlled NIAID trial as well as data from the Gilead study of patients with moderate
symptoms of COVID-19 will be available.
While the company has not said anything about its voluntary licensing plans, it has stated that
it has supplemented its internal manufacturing with significant additional capacity from
multiple manufacturing partners in North America, Europe and Asia. "Looking ahead, we are
building a geographically diverse consortium of pharmaceutical and chemical manufacturing
companies to help us meet and exceed these production goals by expanding capacity for raw
materials and production beyond what any company could do individually," the company has
stated.
Gilead is also on record on its plans to implement 'expanded access programs as quickly as
possible to help the most critically ill patients around the world'.

The antiviral compound remdesivir potently
inhibits RNA-dependent RNA polymerase
from Middle East respiratory syndrome
coronavirus

1. Calvin J Gordon1,
2. Egor P Tchesnokov1,
3. Joy Y. Feng2,
4. Danielle P Porter3 and
5. Matthias Gotte4*

+Author Affiliations

1. 1University of Alberta, Canada
2. 2Biology, Gilead Sciences, United States
3. 3Gilead, United States
4. 4Medical Microbiology and Immunology, University of Alberta, Canada
1. ↵* Corresponding author; email: [email protected]

Abstract

Antiviral drugs for managing infections with human coronaviruses are not yet approved,
posing a serious challenge to current global efforts aimed at containing the outbreak of
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir (RDV) is an
investigational compound with a broad spectrum of antiviral activities against RNA
viruses, including SARS-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is
a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-
expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in
insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV
RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex.
The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart
ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach
suggests that it is more efficiently incorporated than ATP and two other nucleotide
analogues. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at
position i+3. Hence, the likely mechanism of action is delayed RNA chain termination. The
additional three nucleotides may protect the inhibitor from excision by the viral 3’–5’
exonuclease activity. Together, these results help to explain the high potency of RDV
against RNA viruses in cell-based assays.

Students Page…..

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7. Manisha Katariya M.Sc. IV Semester Chemistry
8. Rohit Yogi M.Sc. II Semester Chemistry
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emdesivir……………..

Remdesivir is a broad-spectrum antiviral medication developed by the American
biopharmaceutical company Gilead Sciences.It is a nucleotide analog, specifically an adenosine
analog, which inserts into viral RNA chains, interfering with viral replication by causing their
premature termination.

Remdesivir was created and developed by Gilead Sciences, under the direction of scientist
Tomáš Cihlář,as part of Gilead's research and development program on treatments for Ebola
virus disease and Marburg virus infections.[6] Gilead Sciences subsequently discovered that
remdesivir had antiviral activity in vitro against multiple filoviruses, pneumoviruses,
paramyxoviruses, and coronaviruses.

Molecular weight. :-602.6 g/mol

Molecular formula: - C27H35N6O8P

Structure:-

IUPAC Name :-2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-
5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

Machanism

Remdesivir is a prodrug that metabolizes into its active form GS-441524. An adenosine
nucleoside analog, GS-441524 interferes with the action of viral RNA-dependent RNA polymerase
and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA
production.In some viruses such as the respiratory syncytial virus it causes the RNA-dependent
RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible
chain termination. Unlike with many other chain terminators, this is not mediated by preventing
addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five
additional bases have been added to the growing RNA chain.

Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance to remdesivir
were identified in 2018. These mutations make the viruses less effective in nature, and the
researchers believe they will likely not persist where the drug is not being used.

Remdesivir was originally investigated as a treatment for ebola virus but has potential to treat a
variety of RNA viruses its activity against the coronavirus (cov) family of viruses such as SARS-cov
and MERS -cov was described on 2017 and it is also being investigated as a potential treatment for
a SARS cov2 infections

On 29 April 2020, the National Institute of Allergy and Infectious Diseases (NIAID)
announced that remdesivir was better than a placebo in reducing time to recovery for
people hospitalized with advanced COVID‑19 and lung involvement.Previously data
from one randomized controlled trial was released early in error and before peer
review; it did not show improvement. Gilead Sciences stated that due to low enrollment
the study was halted while a non-associated researcher stated it does mean if there is
any benefit, then that benefit will be small. Other clinical trials are underway or
planned.

In a clinical trial conducted in China over February-March 2020, remdesivir was not
effective in reducing the time for improvement from COVID-19 infections or deaths, and

caused various adverse effects in the remdesivir-treated participants, requiring the
investigators to terminate the trial.

In a clinical trial conducted in China over February-March 2020, remdesivir was not
effective in reducing the time for improvement from COVID-19 infections or deaths, and
caused various adverse effects in the remdesivir-treated participants, requiring the
investigators to terminate the trial.

In March 2020, a small trial of remdesivir in rhesus macaque monkeys with COVID‑19
infections found that it prevents disease progression. On 18 March 2020, the World
Health Organization (WHO) announced the launch of a trial that would include one
group treated with remdesivir.

In January 2020, Gilead began laboratory testing of remdesivir against SARS-CoV-2,
stating that remdesivir had been shown to be active against severe acute respiratory
syndrome (SARS) and Middle East respiratory syndrome (MERS) in animal models. On
21 January 2020, the Wuhan Institute of Virology applied for a Chinese "use patent", for
treating COVID-19

Pharmacodynamics: Dosing was predicted to be twice daily to maintain therapeutic
concentrations required for treatment of COVID infections.

References : Students Searched

PUBchem.

Drugbank.

Gilead sciences .

One Health 9 (2020) 100128
Contents lists available at ScienceDirect

One Health

journal homepage: www.elsevier.com/locate/onehlt

Current knowledge about the antivirals remdesivir (GS-5734) and GS- T
441524 as therapeutic options for coronaviruses

E. Susan Amiriana,⁎, Julie K. Levyb

a Public Health & Healthcare Program, Texas Policy Lab, School of Social Sciences, Rice University, Houston, TX, USA
b Maddie's Shelter Medicine Program, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA

ARTICLE INFO ABSTRACT

Keywords: Recent international epidemics of coronavirus-associated illnesses underscore the urgent medical and public
Remdesivir health need for vaccine development and regulatory body approved therapies. In particular, the current cor-
GS-5734 onavirus disease 2019 (COVID-19) pandemic has quickly intensified interest in developing treatment options to
Coronavirus mitigate impact on human life. Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being
COVID-19 tested as a potential treatment for COVID-19 in international, multi-site clinical trials. Currently available evi-
SARS-CoV-2 dence about the antiviral effects of remdesivir against coronaviruses is primarily based on in vitro and in vivo
Compassionate use studies (including some on a chemically related compound, GS-441524™), which have demonstrated largely
favorable findings. As the pandemic progresses, information from human compassionate use cases will continue
to accumulate before the clinical trials are concluded. It is imperative for public health practitioners and the One
Health community to stay up to date on the most promising potential therapeutic options that are under in-
vestigation. Thus, the purpose of this review is to synthesize the knowledge to date about remdesivir as a
therapeutic option for coronaviruses, with a special focus on information relevant to the One Health community.

1. Introduction options for coronavirus disease 2019 (COVID-19) [6,7].
Remdesivir (GS-5734, Fig. 1a) is an investigational broad-spectrum
The first human coronaviruses (HCoVs) were identified in the 1960s
[1], and for the majority of the past six decades, HCoVs have generally small-molecule antiviral drug that has demonstrated activity against
maintained a relatively innocuous reputation as a cause of the common RNA viruses in several families, including Coronaviridae (such as SARS-
cold [2]. However, public perception and awareness of HCoVs has CoV, MERS-CoV, and strains of bat coronaviruses capable of infecting
shifted considerably in the last twenty years, with the onset of three human respiratory epithelial cells), Paramyxoviridae (such as Nipah
high profile outbreaks that have garnered international attention and virus, respiratory syncytial virus, and Hendra virus), and Filoviridae
have subsequently led to renewed interest in potential therapeutic op- (such as Ebola virus) [8–12]. Originally developed to treat Ebola virus
tions for HCoV-related illnesses. In 2002–2003, severe acute respiratory infection [8], remdesivir is a prodrug of the parent adenosine analog,
syndrome coronavirus (SARS-CoV) infected more than 8000 people, GS-441524 (Fig. 1b), both of which are metabolized into an active
reaching 26 countries and resulting in a 10% case fatality rate [3]. In nucleoside triphosphate (NTP) by the host (Fig. 1c) [13]. The parent
the ~7 years between April 2012 and November 2019, there were 2494 nucleoside, GS-441524, has displayed antiviral activity against SARS-
laboratory-confirmed cases of infection with Middle East respiratory CoV, Marburg virus, and feline infectious peritonitis virus, among
syndrome coronavirus (MERS-CoV) that reached 27 countries and had a others [9,14–16]. A number of studies have examined the effects of
mortality rate of approximately 34% [4], though serologic studies have these two drugs on coronaviruses (CoVs) both in vitro and in vivo using
implied that the prevalence of MERS-CoV may have been under- mouse and non-human primate animal models [9–11,13,17,18].
estimated [5]. Most recently, the emergence of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) in December 2019 in Wuhan There are currently no antiviral drugs approved for the treatment of
and its subsequent spread to over 160 countries across the world has CoV-specific illnesses. Given the rapidly evolving pandemic of COVID-
generated intense interest in vaccine development and treatment 19, it is crucial for public health practitioners and the One Health
community to stay up to date on potential therapeutic options that are
under investigation [19]. Based on existing data, remdesivir is a

⁎ Corresponding author at: Public Health & Healthcare Program, Texas Policy Lab, School of Social Sciences, Rice University, 6100 Main St, Houston, TX 77005,
USA.

E-mail address: [email protected] (E.S. Amirian).

https://doi.org/10.1016/j.onehlt.2020.100128
Received 15 March 2020; Received in revised form 24 March 2020; Accepted 24 March 2020
Available online 27 March 2020
2352-7714/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).

E.S. Amirian and J.K. Levy

2

Fig. 1. Chemical structures of: a) Remdesivir⁎; b) GS-441524⁎⁎; c) triphosphate metabolite of both drugs†. One Health 9 (2020) 100128
* Original source of image: PubChem Database, National Center for Biotechnology Information. PubChem Database. Remdesivir, CID = 121304016, https://pubchem.ncbi.nlm.nih.gov/compound/cid-121304016
(accessed on Mar. 21, 2020).
** Original source of image: PubChem Database, National Center for Biotechnology Information. PubChem Database. GS-441524, CID = 44468216, https://pubchem.ncbi.nlm.nih.gov/compound/44468216 (accessed on
Mar. 21, 2020).
†Adapted from Reference [50].

E.S. Amirian and J.K. Levy One Health 9 (2020) 100128

promising candidate, and multi-site clinical trials of remdesivir are now fidelity of the base-pairing process may result in remdesivir resistance
underway among hospitalized adults with COVID-19 [20]. This review [33]. In fact, Agostini et al. also induced mutations in MHV (through
summarizes the knowledge to date on remdesivir as a therapeutic op- passage in remdesivir) that conferred strong resistance against the drug,
tion for CoVs. but these mutated strains were outcompeted by wild-type MHV in co-
infected cell cultures that were not exposed to remdesivir [13]. How
2. Overview of coronaviruses well this experiment would represent a situation in which a resistance
mutation developed naturally, though, is unclear. Nonetheless, some
Viruses classified under the Coronaviridae family are enveloped evidence suggests that remdesivir could have an additional mechanism
positive-sense, single-stranded RNA viruses that exhibit high genetic of action that has yet to be discovered, which, if true, may allow for
diversity [21]. Within the Orthocoronavirinae subfamily, there are four partial antiviral activity to continue despite viral mutations that en-
genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and hance replication fidelity [11–13].
deltacoronavirus. Viruses in this family can infect a wide variety of host
species, such as birds, humans, and non-human mammals, including 4. Summary of studies on remdesivir and coronaviruses
dromedary camels, alpacas, domestic pigs, dogs, cats, ferrets, minks,
and bats [5,11,12,16,22–24]. However, to our knowledge, only viruses The existing studies on the potential antiviral effects of remdesivir
of the alpha- and betacoronavirus genera infect humans [2], though that are of highest relevance to the virus underlying the current pan-
those in the gamma- and deltacoronavirus genera have indirect effects demic, SARS-CoV-2, are those that have been conducted on genetically
through economic impacts on the agricultural production of poultry similar coronaviruses. As discussed above, within the Coronaviridae
and pigs [12]. Host specificity is believed to be largely dependent upon family of viruses, there is a substantial amount of genetic heterogeneity,
variation in the CoV spike attachment glycoprotein [23]. Although the even among human strains [34]. This genetic diversity is posited to be
infectivity of most strains is host species-specific, host range is wide attributable to the large viral genome and the molecular nuances of the
across different CoVs, and some bat CoVs rely on the same host receptor viral RNA replication processes (e.g., RdRp infidelity) [21]. Although
(angiotensin-converting enzyme-2; ACE-2) as human CoVs to facilitate remdesivir is a broad-spectrum antiviral, its efficacy against other fa-
entry into cells [11,25,26]. It has been hypothesized that the CoV milies of viruses may not be generalizable to its effectiveness against
propensity for host-switching may partly be attributable to re- SARS-CoV-2, and attempts to predict the level of potential general-
combination events that alter the spike protein, which, in turn, affects izability are hampered by the possibility that the drug may have sec-
interactions with host receptors (e.g., ACE-2) [27,28]. ondary mechanisms of action that are yet to be elucidated. As a result,
this review focuses on studies of the effects of remdesivir on CoVs
Historically, HCoVs were largely considered to be relatively low specifically; however, some information about research on other lesser
virulence viruses that produced less severe, self-limiting disease, and related viruses (e.g., Ebola) is briefly mentioned for additional context
were predominantly known as the second most prevalent cause of colds on the drug.
and upper respiratory infections (URIs), after rhinoviruses [2,29]. The
endemic human CoVs that cumulatively account for about 10–30% of 4.1. In vitro studies
URIs are HCoV-229E and HCoV-NL63, which are both alphacor-
onaviruses, and HCoV-OC43 and HCoV-HKU1, which are both beta- The majority of in vitro efficacy studies conducted to date have re-
coronaviruses [2]. Among patients with URIs severe enough to warrant ported positive results on the anti-CoV activity of remdesivir and GS-
hospitalization, one study found that approximately 5% of cases were 441524 (Table 1). Commonly used metrics in these studies are the half
attributable to rhinoviruses or HCoVs, but a substantial proportion of maximal effective concentration (EC50), which is the drug concentra-
these hospitalized patients had underlying pulmonary or cardiac co- tion at which half of the maximum response is attained after exposure,
morbidities that may have exacerbated their conditions [29]. or the half maximal inhibitory concentration (IC50), which is the drug
concentration at which half of the peak inhibiting effect of the drug
The virus underlying COVID-19 (SARS-CoV-2) is a betacoronavirus against a specific viral function is achieved. Lower EC50 and IC50 values
that is closely related to SARS-CoV. These CoVs share ~80% RNA se- indicate higher potency. Typical outcomes measured in such studies
quence identity [30,31]. The similarity is even greater between the include the amount of viral RNA (e.g., copies of certain open reading
viruses when comparing the sequences specific to a key drug target, the frames) in the culture, the number of virus-infected cells in the culture,
RNA-dependent RNA polymerase (RdRP) (> 90% sequence identity) or changes in viral replication rates.
[30]. By contrast, MERS-CoV shares about 50% genomic sequence
identity with SARS-CoV-2 [31], and with the exception of some bat In studies of SARS-CoV and MERS-CoV in human respiratory epi-
strains, many animal CoVs are even less similar [12]. thelial cell cultures, remdesivir has demonstrated strong antiviral ac-
tivity (EC50 ≈ 0.07 μM for either virus) with relative consistency, and
3. Remdesivir mechanism of action has been shown to be capable of inhibiting MERS-CoV replication at
levels below those that would result in unacceptable cytotoxicity
As a nucleoside analog, remdesivir acts as an RdRp inhibitor, tar- [11,13]. Interestingly, a study published in February 2020 by Wang
geting the viral genome replication process. The RdRp is the protein et al. was the first, to our knowledge, to examine the effect of re-
complex CoVs use to replicate their RNA-based genomes. After the host mdesivir against SARS-CoV-2, the HCoV involved in the current pan-
metabolizes remdesivir into active NTP, the metabolite competes with demic [17]. This study investigated the impact of seven different drugs
adenosine triphosphate (ATP; the natural nucleotide normally used in on viral titers, cytotoxicity, and infection rates, using Vero E6 cells (a
this process) for incorporation into the nascent RNA strand [32]. The cell line originating from African green monkey kidney epithelial cells).
incorporation of this substitute into the new strand results in premature They found low potency of most of these drugs for inhibiting SARS-
termination of RNA synthesis, halting the growth of the RNA strand CoV-2. EC50 values ranged widely from 109.5 μM for ribavirin to
after a few more nucleotides are added. Although CoVs have a proof- 1.13 μM for choloquine and 0.77 μM for remdesivir, which were the
reading process that is able to detect and remove other nucleoside two drugs that required the lowest concentrations for blocking viral
analogs, rendering them resistant to many of these drugs, remdesivir infection.
seems to outpace this viral proofreading activity, thus maintaining
antiviral activity [30]. Unsurprisingly, Agostini et al. reported that a A few in vitro studies have also investigated the utility of remdesivir
mutant murine hepatitis virus (MHV) devoid of proofreading ability against non-human CoVs. For example, a study by Murphy et al. re-
was more sensitive to remdesivir [13]. The opposite is also possi- ported anti-CoV activity of remdesivir's parent nucleoside, GS-441524,
ble—that mutations that improve proofreading or otherwise increase against an alphacoronavirus that only infects wild and domestic cats,

3

E.S. Amirian and J.K. Levy One Health 9 (2020) 100128

Table 1 4.2. In vivo studies: animal models & veterinary studies
Summary of in vitro studies on remdesivir (GS-5734) efficacy against cor-
onaviruses. Animal studies on remdesivir efficacy against CoVs have utilized
transgenic mice and rhesus macaques [10,11,13,18]. For example,
Study Coronavirus Cell line⁎ EC50 or IC50⁎⁎ using a mouse model with a Ces1c-knockout (which better emulates
human metabolism of remdesivir compared to wild-type mice) and a
Remdesivir MERS-CoV Calu-3 2B4 IC50 = 0.025 μM humanized MERS-CoV receptor, Sheahan et al. found that both pro-
Sheahan et al. [11] HAE IC50 = 0.074 μM phylactic and therapeutic remdesivir had protective effects against
SARS-CoV HAE IC50 = 0.069 μM MERS-CoV replication and associated pathology, generally resulting in
Agostini et al. [13] SARS-CoV HAE EC50 = 0.07 μM less lung damage and better pulmonary function compared to controls
MERS-CoV HAE EC50 = 0.07 μM [10]. Interestingly, among mice that were infected with a higher virus
Brown et al. [12] MHV† DBT EC50 = 0.03 μM quantity (i.e., more plaque-forming units), those receiving prophylactic
HCoV-OC43 Huh7 EC50 = 0.15 μM remdesivir one day before infection had significantly better 6-day sur-
Sheahan et al. [10] HCoV-229E Huh7 EC50 = 0.024 μM vival than infected control mice that did not receive remdesivir. How-
Wang et al. [17] LLC-PK1 EC50 = 3.8 μM ever, the mice were sacrificed before longer follow-up data could be
GS-441524 PDCoV‡ LLC-PK1 Not reached obtained. Similarly, in a rhesus macaque model of MERS-CoV patho-
Murphy et al. [14] Huh7 EC50 = 0.02 μM genesis, prophylactic and therapeutic administration of remdesivir de-
Agostini et al. [13] MERS-CoV Calu-3 2B4 EC50 = 0.09 μM monstrated favorable results, reducing respiratory tract viral titers and
SARS-CoV-2 Vero E6 EC50 = 0.77 μM pulmonary pathology [18]. Prophylactic use was initiated 24 h prior to
viral challenge, whereas therapeutic use was initiated 12 h after chal-
FIPV¥ CRFK EC50 = 0.78 μM lenge. While respiratory rate was not substantially different between
SARS-CoV HAE EC50 = 0.18 μM the prophylactic, therapeutic, and control groups, x-ray scores, re-
MERS-CoV HAE EC50 = 0.86 μM presenting the severity of pulmonary infiltrates, were significantly
MHV† DBT EC50 = 1.1 μM better in the prophylactic and therapeutic groups, comparing each to
controls [18]. Incidentally, remdesivir has also been associated with
⁎ Calu-3: human bronchial epithelial cells; HAE: human airway epithelial beneficial effects, including reduced severity of respiratory signs and
improved survival, against challenge with Nipah virus, which is a non-
cells; DBT: mouse delayed brain tumor; Huh7: human liver cells; LLC-PK1: CoV virus in the Paramyxoviridae family, in African green monkeys
[21].
porcine kidney cells; Vero E6: African green monkey kidney epithelial cells;
In a Ces1c-knockout mouse model of SARS-CoV infection, prophy-
CRFK: feline kidney cells. lactic and therapeutic remdesivir treatment resulted in lower lung viral
⁎⁎ EC50 = Half maximal effective concentration; IC50 = half maximal in- titers, and if therapy was administered 1 day post-infection (which is
before peak viral replication), it was associated with greater pulmonary
hibitory concentration. EC50 or IC50 provided as reported by each respective function, compared to controls [11]. However, there were no differ-
study. ences in disease pathology or survival if treatment was administered
2 days post-infection.
† MHV = murine hepatitis virus.
‡ PDCoV = porcine deltacoronavirus. Some veterinary studies have also examined the effects of the parent
¥ FIPV = feline infectious peritonitis virus. nucleoside, GS-441524, in cats with FIP, a condition associated with
very high mortality in cats [14,16]. Gilead Sciences (Foster City, Cali-
the feline infectious peritonitis (FIP) virus (EC50 = 0.78 μM; Table 1) fornia) had provided this drug to researchers at the University of Ca-
[14]. In 2019, Brown et al. observed some antiviral effects of remdesivir lifornia, Davis to evaluate its potential utility in veterinary indications
against SARS-like bat CoVs (specifically, Bat-CoV HKU3, Bat-CoV [35]. Subsequently, GS-441524 became an intermediate in the pro-
SCH014, and Bat-CoV WIV1) and MERS-like bat CoVs (specifically, Bat- duction of the prodrug, remdesivir, which has superior ability to
CoV HKU5) [12]. transport the active compound into cells [9,18]. Because both drugs
yield the same active metabolite in host cells, some prior studies on the
Further, this study detected a weaker antiviral effect against porcine antiviral activity of remdesivir also investigate GS-441524 [15,18],
deltacoronavirus (PDCoV; Table 1), particularly when tested in porcine and/or discuss its relevance in the veterinary studies [9,12].
cell lines. Among currently known CoVs, PDCoV has the least similar
RdRp sequence compared to SARS-CoV and MERS-CoV (only 67–69% In 2018, Murphy et al. examined the efficacy of GS-441524 against
similarity in amino acid sequence) [12]. In fact, the RdRp of PDCoV has FIP in 12 experimentally infected cats [14]. Controls were not included,
a different amino acid at a specific site (phenylalanine to leucine at as historical data on untreated cats were available, demonstrating a
residue 483), a dissimilarity that has been previously associated with mortality rate close to 100% [14,36]. After experimental challenge with
increased resistance to remdesivir in other CoVs [12,13]. Therefore, it the FIP virus, 2 cats did not develop FIP-related signs and remained
was important to attempt to disentangle whether the lower antiviral untreated [14]. In the 10 infected cats, treatment was initiated upon
activity observed could be related to a viral characteristic of PDCoV or onset of FIP-associated clinical signs (~10–18 days post infection), and
if it could be attributable to differences in the cell lines used. While continued for 2 weeks. Of these cats, half (n = 5) were treated with a
diminished potency of remdesivir against PDCoV was noted in cultures 5 mg/kg dose of GS-441524 administered subcutaneously once per day,
of porcine kidney epithelial cells (LLC-PK1), in a human liver cell line and the other half (n = 5) were treated with 2 mg/kg daily. If disease
(Huh7), the EC50 was relatively low (EC50 not reached in LLC-PK1 vs. recurred after initial treatment, cats were re-treated using the same
EC50 = 0.02 μM in Huh7; Table 1). Similarly, the EC50 was sub- regimen for another 2 weeks. Follow-up continued for 8 months. All
stantially higher for antiviral activity against an endemic HCoV (229E) treated cats demonstrated favorable responses to GS-441524 treatment
in the porcine cell line (3.8 μM compared to 0.02 μM in Huh7), again within 24–48 h, regardless of dose, and were still alive and clinically
indicating the likely lower potency of the drug in this context. Thus, the unremarkable 8 months post infection. Two cats (one from each dose
observed variations in remdesivir potency against the same viruses in group) experienced disease recurrence at 4 weeks and 6 weeks after
the different cell lines may imply that there is some factor associated initial treatment and were re-treated. Adverse events related to treat-
with the cell line, rather than the virus, that may be affecting the drug's ment, other than temporary discomfort at the injection site, were not
antiviral activity. In fact, the authors state that these findings may observed. This study was based on a small number of animals, and it is
imply that LLC-PK1 cells lack a cellular process necessary for remdesivir
antiviral activity, which could also support the hypothesis that re-
mdesivir may have another mechanism of action that is not presently
understood.

4

E.S. Amirian and J.K. Levy One Health 9 (2020) 100128

unclear whether experimental infection is a relevant representation of that one of these three patients is the same patient described in the case
naturally-occurring FIPV infection in cats. Future studies with addi- report discussed above [37].
tional follow-up time would be helpful for assessing whether un-
expected long-term sequelae are observed in the cats, since such in- Some safety data were formally collected during a clinical trial
formation on surviving animals is sparse given the high fatality rate. conducted in the Democratic Republic of Congo that randomized 175
patients to be treated with remdesivir for Ebola [39]. Incidentally,
In a field trial of treatment with GS-441524 for naturally occurring randomization to remdesivir treatment was discontinued in this trial
FIP, Pedersen et al. treated 31 cats with an initial dose of 2 mg/kg daily after an interim analysis showed superior survival for two other trial
[16]. Within the first week of treatment, 4 cats (13%) with severe drugs, despite preclinical and compassionate use data having been fa-
disease died or were euthanized, a fifth cat died after 26 days, and vorable for remdesivir against the Ebola virus prior to the trial [9].
another was euthanized about 2-weeks post relapse due to the devel- Interestingly, patients who received remdesivir had slower rates of viral
opment of neurological signs and a lack of response to treatment. The clearance compared to patients who received single-dose antivirals
remaining cats completed at least 12 weeks of treatment, but 8 ex- (specifically, MAb114 and REGN-EB3), which the authors hypothesized
perienced relapses requiring re-treatment with GS-441524. Dose esca- may be related to the fact that the treatment plan for remdesivir in-
lation from 2 mg/kg to 4 mg/kg daily was required for 5 cats. A total of volved multiple intravenous infusions. However, for now, information
25 treated cats (81%) survived FIP for at least 44 weeks of follow up, on the potential efficacy of remdesivir specifically against CoVs is lar-
indicating that GS-441524 (and presumably, its prodrug remdesivir) is gely limited to in vitro and animal studies, though COVID-19 related
also a promising therapeutic candidate for treatment of alphacor- knowledge is evolving quickly.
onavirus-related disease in cats. Most cats in this study had “wet” or
effusive FIP, the hallmark of which is the accumulation of fluids in the Overall, past studies on other CoVs may have limited general-
abdominal or thoracic cavities. There were only 3 cats in the study with izability to the virus underlying the current pandemic because of the
abdominal non-effusive (“dry”) FIP, which is a more chronic condition, high genetic diversity of the Coronaviridae family, although broad-
and another 4 cats initially had dry FIP that progressed into wet FIP. spectrum drugs tend to be directed at well-conserved targets [11,40]. In
One cat in the dry FIP group and one in the dry-to-wet group did not addition to this issue, there are a number of factors that can impact how
survive. Because of the small number of cats with dry FIP, conclusions predictive findings from in vitro or in vivo models may be of clinical
cannot be drawn about whether remdesivir has greater efficacy in the efficacy against SARS-CoV-2. For example, drugs that may be effective
treatment of some clinical manifestations of FIP than others. A strength in vitro may not have clinical utility if the therapeutic dose induces
of this study is that it was conducted among animals with naturally- severe adverse events in the patient. Alternatively, if the treatment dose
occurring CoV infection as a field trial, better representing real-world does not attain an effective serum concentration in patients, or if EC50 is
circumstances. greater than the achievable maximum serum concentration (Cmax), then
the drug is less likely to have therapeutic utility. With regard to animal
4.3. Human data models, how closely the model represents disease pathogenesis and
drug metabolism in humans can be challenging to gauge.
The first patient to present with COVID-19 in the U.S. was treated
with intravenous remdesivir under the compassionate use clause after 4.4. Clinical trials
developing pneumonia in January 2020 [37]. This 35-year-old male
had been infected during travel to Wuhan and returned to the U.S. Multiple clinical trials are underway on the use of remdesivir for
where he was hospitalized for more than 12 days. He was treated with treatment of COVID-19 [41]. The NIH-sponsored clinical trial, ongoing
intravenous remdesivir on the seventh day, and his condition was re- in the U.S. and the Republic of Korea, is a double-blinded, placebo-
portedly improving on the eighth day. No adverse events related to controlled trial in which patients are randomized to receive either
remdesivir use were noted. The case report was written prior to the placebo or an initial dose of 200 mg of intravenous remdesivir on the
patient's discharge. first day, followed by a maintenance dose of 100 mg per day, through
discharge up to a maximum of 10 total treatment days [20]. The pri-
Human data on remdesivir use for COVID-19 will likely continue to mary outcome of the trial, as described in the U.S. National Library of
become available from compassionate use cases before the clinical trial Medicine clinical trials registry, will be expressed as the proportion of
is completed. In fact, there are many anecdotal reports already circu- patients in each category of a seven-category clinical severity scale on
lating about treatment of COVID-19 patients with remdesivir. the fifteenth day post treatment initiation (Table 2) [42]. Additionally,
According to a recent newspaper article, 17 passengers on the Diamond Gilead Sciences is sponsoring a remdesivir study among patients with
Princess cruise ship were treated with intravenous remdesivir for severe COVID-19 with a composite primary outcome measure of fever
10 days and were alive at the time of article release. One of the phy- normalization and oxygen normalization [43].
sicians involved in their treatment, who is affiliated with the U.S.
National Institutes of Health (NIH), felt that the patients were less de- Table 2
pendent on ventilators after receiving the drug. Nevertheless, no con- Ordinal seven-point scale used as primary outcome in the U.S. National
clusions can be drawn based on such reports. Institutes of Health sponsored clinical trial (NCT04280705) on remdesivir⁎.

A preprint of a case series on the first 12 COVID-19 patients in the Outcome: proportion of participants in each of the below ratings (Day 15)
U.S. (who had disease onset between January 14 and 29, 2020) recently
became available, though it had not been peer-reviewed at the time of Severity rating Category description⁎
writing [38]. This report, authored by a team from the Centers for
Disease Control (CDC), described the demographic and clinical char- 1 Death
acteristics of the patients, as well as information on course of disease 2 Hospitalized, on invasive mechanical ventilation or
and clinical management. Seven of the 12 patients (58%) were hospi-
talized, and three of these patients received remdesivir intravenously at extracorporeal membrane oxygenation
the onset of worsening symptoms (two on the eleventh day of illness 3 Hospitalized, on non-invasive ventilation or high flow oxygen
and one on the seventh day). Treatment with remdesivir was tolerated,
though temporary gastrointestinal upset and elevated aminotransferase devices
levels were observed in all three patients after administration. Treat- 4 Hospitalized, requiring supplemental oxygen
ment was discontinued after respiratory symptoms improved (total 5 Hospitalized, not requiring supplemental oxygen
treatment durations of 4 days, 5 days, and 10 days). It should be noted 6 Not hospitalized, limitation on activities
7 Not hospitalized, no limitations on activities

⁎ Please note that information is taken verbatim from the U.S. National
Library of Medicine clinical trials registry [42].

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E.S. Amirian and J.K. Levy One Health 9 (2020) 100128

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evaluation is strongly warranted. In general, there are many reasons
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Funding statement Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the
viral polymerase and the proofreading exoribonuclease, mBio 9 (2) (2018), https://
This work did not receive any specific grant from funding agencies doi.org/10.1128/mBio.00221-18.
in the public, commercial, or not-for-profit sectors.
[14] B.G. Murphy, M. Perron, E. Murakami, K. Bauer, Y. Park, C. Eckstrand, et al., The
Declaration of Competing Interest nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP)
virus in tissue culture and experimental cat infection studies, Vet. Microbiol. 219
The authors report no relevant conflicts of interest. E.S. Amirian was (2018) 226–233, https://doi.org/10.1016/j.vetmic.2018.04.026.
previously employed by McKesson Specialty Health, where she con-
ducted health economics and outcomes research contract studies. [15] A. Cho, O.L. Saunders, T. Butler, L. Zhang, J. Xu, J.E. Vela, et al., Synthesis and
However, none of these studies involved Gilead Sciences. antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nu-
cleosides, Bioorg. Med. Chem. Lett. 22 (8) (2012) 2705–2707, https://doi.org/10.
Acknowledgements 1016/j.bmcl.2012.02.105.

The authors acknowledge Megan Rafferty for her technical assis- [16] N.C. Pedersen, M. Perron, M. Bannasch, E. Montgomery, E. Murakami,
tance. M. Liepnieks, et al., Efficacy and safety of the nucleoside analog GS-441524 for
treatment of cats with naturally occurring feline infectious peritonitis, J. Feline
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