“Coronavirus: Scotland drug trials to treat respiratory damage - Daily Mail” plus 2 more

“Coronavirus: Scotland drug trials to treat respiratory damage - Daily Mail” plus 2 more


Coronavirus: Scotland drug trials to treat respiratory damage - Daily Mail

Posted: 23 Apr 2020 09:44 AM PDT

Scotland will soon begin its first clinical trial of a drug to treat the severe respiratory damage caused by lung inflammation in COVID-19 patients.

Researchers from the University of Dundee will conduct trials of brensocatib — formerly known as INS1007 — to tackle lung inflammation caused by the virus.

Although COVID-19 infections are mild in most people, up to 20 per cent of patients develop lung inflammation and may end up needing a ventilator to breathe.

It is the body's own inflammatory response — designed to clear the virus — which causes the lung damage that can even lead to respiratory failure and death.

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Scotland will soon begin its first clinical trial of a drug to treat the severe respiratory damage caused by lung inflammation in COVID-19 patients. Researchers from the University of Dundee will conduct trials of brensocatib to tackle lung inflammation caused by the virus

Scotland will soon begin its first clinical trial of a drug to treat the severe respiratory damage caused by lung inflammation in COVID-19 patients. Researchers from the University of Dundee will conduct trials of brensocatib to tackle lung inflammation caused by the virus

WHAT ARE THE THREE MAIN CORONAVIRUS TRIALS IN THE UK?

Principle 

The Principle trial is studying people aged 50 to 64 who have COVID-19 symptoms and a chronic health condition such as heart disease, asthma or cancer. 

It is unclear how many patients are taking part. 

It is also open to those aged 65 or over, with or without other illnesses.

The first drug that will be trialled is hydroxychloroquine, sold as Plaquenil. Other potential treatments will be used if they show promise in pre-clinical studies.

The study is being run at the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) in Surrey.

It will last until March next year.

Recovery

The Randomised Evaluation of COV-id19 thERapY (RECOVERY) trial is being run by the University of Oxford. 

It will test the HIV drug lopinavir/ritonavir, marketed as Kaletra and Aluvia, hydroxychloroquine, a malaria medication sold as Plaquenil, and dexamethasone, a type of steroid use in a range of conditions to reduce inflammation.

Almost 1,000 patients from 132 different hospitals have been already recruited in just 15 days.

Thousands more are expected to join the trial in the coming weeks, making it the largest randomised controlled trial of potential COVID-19 treatments in the world.

Definitive results on whether the treatments are safe and effective are expected within months and, if positive, they could potentially benefit hundreds of thousands of people worldwide. 

REMAP-CAP

The REMAP-CAP trial is an international effort, with more than 50 research teams around the world taking part. 

It is looking specifically at patients who develop community-acquired pneumonia (CAP) as a result of viral infections.   

The study will test 16 drugs, including  hydroxychloroquine, lopinavir/ritonavir and interferon beta, which have all shown promise in pre-clinical trials.

Between 2,000 and 4,000 patients will be enrolled.

As part of the STOP-COVID19 trial, the team will explore whether brensocatib can reduce the incidence of acute lung injury and the need for mechanical ventilation.

It is hoped that the treatment will lead to patients spending fewer days dependent on oxygen and less time in hospital, reducing the burden on healthcare systems.

STOP-COVID19 is one of the studies into the novel coronavirus that has been given urgent public health research status by the Department of Health and Social Care.

Trials conducted to date have shown that brensocatib reduces inflammation in the lungs of people with underlying lung conditions — so it is hoped that the drug will have a similarly beneficial effect in those suffering from COVID-19.

Beginning in early May, the university will recruit 300 volunteers from ten hospitals across the UK.

Patients will be offered the chance to participate immediately after receiving a positive diagnosis for coronavirus.

Half this number will receive brensocatib in addition to standard hospital care, while the other half will receive a placebo instead.

'High rates of patients requiring ventilation and overwhelming intensive care unit capacity has been a major cause of excess deaths around the world,' said lead researcher James Chalmers of the University of Dundee.

'We hope that brensocatib can put a brake on the devastation this disease causes — to literally stop COVID-19 when it begins attacking the lungs,' added Professor Chalmers, who is also a respiratory physician at Ninewells Hospital, a trial site.

'The medical community has never faced a more urgent need for treatment than the unprecedented situation we face today with COVID-19.'

'The mechanism of action of brensocatib observed in a study in bronchiectasis patients provides a strong rationale for evaluating this novel treatment candidate in other neutrophil-driven inflammatory conditions.'

'It is my hope that it will have applicability in patients at risk of acute respiratory distress syndrome — a devastating outcome of COVID-19 for which there are currently no approved therapies.'

The Dundee researchers will be teaming up with the US-based biopharmaceutical company Insmed, at which Martina Flammer is chief medical officer. 

Although COVID-19 infections are mild in most people, up to 20 per cent of patients develop lung inflammation and may end up needing a ventilator to breathe. It is the body's own inflammatory response ¿ designed to clear the virus ¿ which causes the lung damage that can even lead to respiratory failure and death

Although COVID-19 infections are mild in most people, up to 20 per cent of patients develop lung inflammation and may end up needing a ventilator to breathe. It is the body's own inflammatory response — designed to clear the virus — which causes the lung damage that can even lead to respiratory failure and death

'The global COVID-19 pandemic has generated an extraordinary response from the biopharmaceutical industry to bring to bear all potential means of fighting this disease and preventing its most severe outcomes,' Dr Flammer said.

'At the start of the outbreak, Insmed began pursuing an in vivo mouse model to better understand the potential of brensocatib in preventing acute respiratory distress syndrome.'

'We are very pleased to support Professor James Chalmers and the University of Dundee in leading a controlled clinical trial that will help us evaluate the potential impact of brensocatib on hospitalised patients suffering from severe COVID-19.'

'This is the first Scottish-led drug trial into COVID-19 and it has been prioritised and designated as an urgent public health study,' added study investigator and NHS Tayside R&D director Jacob George.

'Tayside can be justifiably proud of this and we look forward to collaborating with other NHS Boards in Scotland to recruit eligible patients onto the trial.'

REVEALED: THE RECOVERY TRIAL DRUGS IN THE UK

Hydroxychloroquine 

What are the brand versions of the drug?

Plaquenil.

What does it treat?

Malaria, lupus and rheumatoid arthritis. It is a less powerful and, by some experts' accounts, less toxic, version of chloroquine phosphate.

Hydroxychloroquine, sold under the brand name Plaquenil, may treat COVID-19

Hydroxychloroquine, sold under the brand name Plaquenil, may treat COVID-19

Who makes it and where has it already been tested?

Drug giant Sanofi carried out a study on 24 patients, which the French government described as 'promising'. 

French health officials are now planning on a larger trial of the drug, which is used on the NHS. 

What have studies shown?

Results from the French study showed three quarters of patients treated with the drug were cleared of the virus within six days. None of the placebo group were treated. 

How does it work?

It interferes with viral molecules replicating in red blood cells.

Is it being tested in the UK?

Hydroxychloroquine is one of the first drugs to be trialled in the Principle study. It involves high-risk patients in primary care, aged between 50 to 64, who have COVID-19 symptoms and a chronic health condition such as heart disease, asthma or cancer. 

It is unclear how many patients are taking part, and the study will run until March next year. So it will be a while before results are clear.

The study is being at the University of Oxford's Nuffield Department of Primary Care Health Sciences.

Hydroxychloroquine is also thought to be among 1,000 drugs being tested at Queens University Belfast. 

What are its side effects?  

Skin rashes, nausea, diarrhoea and headaches.

What do the experts think?

Chinese scientists investigating the other form of chloroquine penned a letter to a prestigious journal saying its 'less toxic' derivative may also help.

In the comment to Cell Discovery – owned by publisher Nature, they said it shares similar chemical structures and mechanisms.

The team of experts added: 'It is easy to conjure up the idea that hydroxychloroquine may be a potent candidate to treat infection by SARS-CoV-2.' 

Lopinavir/ritonavir 

What are the brand versions of the drug?

Kaletra and Aluvia.

What does it treat? 

Lopinavir/ritonavir, marketed under the brand names Kaletra and Aluvia, is an anti-HIV medicine

Lopinavir/ritonavir, marketed under the brand names Kaletra and Aluvia, is an anti-HIV medicine

It is an anti-HIV medicine given to people living with the virus to prevent it developing into AIDS. HIV patients were prescribed either Kaltra or ritonavir alone around 1,400 times in 2018.

Who makes it?

Illinois-based manufacturer AbbVie donated free supplies of the drug to authorities in China, the US and Europe for tests.

What have studies shown? 

Chinese media reported that the drug was successfully used to cure patients with the coronavirus, but the reports have not been scientifically proven.

A separate Chinese study published in the New England Journal of Medicine found that the lopinavir-ritonavir combination did not improve survival or speed recovery of COVID-19 patients.

However, the authors noted they had enrolled a 'severely ill population' of patients.

In a clinical trial submission, scientists in South Korea said lab studies have: 'In vitro [laboratory] studies revealed that lopinavir/ritonavir [has] antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).'

How does it work? 

It is a class of drug called a protease inhibitor, which essentially stick to an enzyme on a virus which is vital to the virus reproducing. 

By doing this it blocks the process the virus would normally use to clone itself and spread the infection further.

Is it being tested in the UK?

It is not prescribed on the NHS for coronavirus because it hasn't been approved - but will be used in the Recovery trial, a massive study run by the University of Oxford for COVID-19 patients already in hospital.

The trial started enrolling patients on March 23, with the aim of reaching COVID-19 patients in more than 150 UK hospitals within two weeks.  

The drug is also being trialled on coronavirus patients in China and at the University of Nebraska.

What are its side effects? 

Known side effects include diarrhea, headaches, upset stomachs, drowsiness, dizziness, a bad taste in the mouth, and trouble sleeping.

What do the experts think?

The drugs have been described as 'promising' by experts. But there has been some hesitancy about the drug combination due to the NEJM study. 

Dexamethasone is a steroid drug is used to treat allergies and asthma, as well as some types of cancer

Dexamethasone is a steroid drug is used to treat allergies and asthma, as well as some types of cancer

Dexamethasone

What are the brand versions of the drug?

Ozurdex and Baycadron.  

What does it treat? 

The steroid drug is used to treat allergies and asthma, as well as some types of cancer. 

Who makes it?

Baycadron is made by Wockhardt Usa, Llc, while Ozurdex is made by Allergan, the manufacturer of a commonly used textured breast implant.

What have studies shown? 

No studies have yet to prove dexamethasone can treat SARS-CoV-2 - but it has been tested on patients with MERS and SARS, two different coronaviruses. 

One retrospective study of critically-ill patients with MERS found that almost half of the people that received steroids needed additional treatments such as assistance in breathing, drugs to increase blood pressure, and a form of dialysis. 

Those given steroids were found to take longer to clear the virus from their bodies.

Other studies found that the virus was still present in SARS patients who took the drugs up to three weeks after infection.

How does it work?  

Steroids are often used by doctors to reduce inflammation, which is present in the lungs of patients with the coronavirus.  

However, steroids also impair the immune system's ability to fight viruses and other infections that often develop in patients with life-threatening illness.

Is it being tested in the UK?

Dexamethasone is one of the drugs being used in the RECOVERY trial launched by the University of Oxford. It will include patients at more than 130 NHS hospitals across the UK.

What are its side effects? 

The drug is known to cause an increase in appetite and heartburn, as well as muscle weakness and insomnia.

What do the experts think?

In a piece in prestigious medical journal The Lancet, three experts warned: 'No unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids.

'And they might be more likely to be harmed with such treatment. 

'We conclude that corticosteroid treatment should not be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a clinical trial.'

Azithromycin is an antibiotic which has shown signs of promise when used in conjunction with hydroxychloroquine

Azithromycin is an antibiotic which has shown signs of promise when used in conjunction with hydroxychloroquine

Azithromycin 

What are the brand versions of the drug? 

 Z-Pack and Zithromax

What does it treat? 

It's widely used to treat chest infections such as pneumonia, infections of the nose and throat such as sinus infection (sinusitis), skin infections, Lyme disease, and some sexually transmitted infections.

Azithromycin is used in children, often to treat ear infections or chest infections.

Who makes it? 

Pfizer 

What have studies shown?   

Some clinicians have seen limited success in COVID-19 patients when adding it to chloroquine and/or hydroxycholoroquine.

There is little concrete evidence for this however and it remains a controversial topic.  

Last month, big pharma firm Pfizer announced positive data for the use of its azithromycin (Zithromax) drug as a coronavirus treatment.  

Hydroxychloroquine was given to 20 COVID-19 patients, and six also received azithromycin.

The rate of cure was highest in people who received hydroxychloroquine and azithromycin, the study reported. 

How does it work? 

The drug itself is an antibiotic and therefore ineffective against viral infections. 

However,  some experts think combining it with the old anti-malaria drugs can improve the prognosis for the sickest patients. 

It is unknown how or if the drug itself can be effective against a virus directly. 

Is it being tested in the UK? 

Azithromycin is one of the four drugs featured in the University of Oxford's Recovery Trial.

This programme currently ha more than 5,000 participants who are all coronavirus patients currently in British hospitals.  

What are its side effects? 

Common side effects include nausea, diarrhoea or vomiting, losing your appetite, headaches, dizziness or changes to taste.  

More serious side effects which are far rarer include chest pains, yellowing skin/eye whites, tinnitus or vertigo. 

What do the experts think? 

Controversial scientists, such as French doctor Didier Raoult, claim the drug, iwhen used in partnership with hydroxychloroquine can help fight coronavirus. 

However, experts are almost universally of the opinion that the antibiotic on its own will offer no protection from the viral infection.  

 

'Silent hypoxia' may be killing COVID-19 patients. But there's hope. - Livescience.com

Posted: 23 Apr 2020 08:30 AM PDT

As doctors see more and more COVID-19 patients, they are noticing an odd trend: Patients whose blood oxygen saturation levels are exceedingly low but who are hardly gasping for breath.

These patients are quite sick, but their disease does not present like typical acute respiratory distress syndrome (ARDS), a type of lung failure known from the 2003 outbreak of the SARS coronavirus and other respiratory diseases. Their lungs are clearly not effectively oxygenating the blood, but these patients are alert and feeling relatively well, even as doctors debate whether to intubate them by placing a breathing tube down the throat.

Three Ways to Make Coronavirus Drugs In a Hurry - Scientific American

Posted: 23 Apr 2020 04:44 AM PDT

Mark Denison began hunting for a drug to treat COVID-19 almost a decade before the contagion, driven by a novel coronavirus, devastated the world this year. Denison is not a prophet, but he is a virologist and an expert on the often deadly coronavirus family, members of which also caused the SARS outbreak in 2002 and the MERS eruption in 2012. It is a big viral group, and "we were pretty certain another one would soon emerge," says Denison, who directs the division of pediatric infectious diseases at Vanderbilt University Medical Center.

A virus is an unusual beast. Essentially it is a cluster of genetic material that integrates itself into a cell and takes over some of the cell's molecular machinery, using it to assemble an army of viral copies. Those clones burst out of the cell, destroying it, and go on to infect nearby cells. Viruses are hard to kill off completely because of their cellular integration—they hide within their hosts. And they have explosive reproductive rates. Because total eradication is so hard, antiviral drugs instead aim to limit replication to low levels that cannot hurt the body.

In 2013 Denison and Ralph Baric, a coronavirus researcher at the University of North Carolina at Chapel Hill, identified a vulnerable site on a protein common to all coronaviruses they had examined, a spot that is key to the microbe's ability to make copies of itself. If that ability is hindered, a coronavirus cannot cause widespread infection. Four years later researchers in the two laboratories spotted a compound that acted on this protein site. It was sitting, unused, in a large library of antiviral compounds created by the biotech giant Gilead Biosciences. The scientists got a sample and, in test tube and animal experiments, showed that the drug, called remdesivir, shut down the replicating machinery of several coronavirus variants.

So in early January, when the alarms rang about SARS-CoV-2, Denison and Baric alerted colleagues at Gilead that they were sitting on a potential treatment. Largely because of its activity against other coronavirus strains in Denison and Baric's animal studies, remdesivir was made available to patients for "compassionate use" in January. By March, Gilead had rushed the compound into two human trials, planning to test the drug's safety and most effective doses on about 1,000 ill patients over several months; health authorities in China began two similar trials. While that was happening, Denison, Baric and a group of their colleagues at Emory University identified still another compound, called EIDD-2801, that hits the same viral vulnerability. In early April they published results showing that in mice, the new substance helped breathing and reduced the amount of many coronaviruses. In test-tube experiments with human lung cells, it drastically hindered SARS-CoV-2.

Several labs around the world, like Denison's and Baric's, have logged years of experience poking about the inner workings of coronaviruses because of SARS and MERS. By the time the new coronavirus was genetically sequenced and its structure revealed, scientists already had identified the enzymes and proteins that most coronaviruses use to spread from one infected human cell to another and also understood that the body could create an overly aggressive inflammatory response when the virus infected lung airway cells.

Because of this work, three main strategies for impeding the virus have emerged as the labs have turned to the current threat. One strategy is to find compounds like remdesivir and EIDD-2801 that gum up the virus's reproductive machinery when it enters a target cell. A second is to block the virus, like a bouncer outside a bar, from entering and infecting those cells in the first place. The third approach is to muffle the immune system's dangerously overactive response, a "cytokine storm" that can drown a victim in a mass of congestion and dying airway cells.

To find these drugs, researchers have turned to the Food and Drug Administration's list of some 20,000 compounds approved for human use and crawled through drug patent applications looking for compounds with promising mechanisms of action. The goal has been to find drugs that have been at least partly developed, avoiding years of making therapeutic molecules from scratch. The Milken Institute, a health advocacy think tank, counted 133 experimental COVID-19 treatments in mid-April. About 49 of these therapies are being rushed into clinical trials. Their effectiveness in people is not yet known, and scientists caution that such drugs, like other anti-virals, are unlikely to be cures. But they could reduce symptoms enough to give patients' immune systems a chance to beat the virus on their own.

COPY STOPPERS

Because all coronaviruses use the same molecular mechanism to reproduce, Baric says, that mechanism, which involves the enzyme nsp12, was an obvious target. Nsp12 normally corrects mistakes made by the main replication enzyme, RNA polymerase, as it as--sembles new virus particles. But remdesivir appears to work its way into nsp12's structure, disabling it. As a result, the virus's copying factory becomes sloppy and produces fewer new viruses.

EIDD-2801, the compound with promising animal and test-tube results reported in early April, aims at the same viral enzyme. But unlike remdesivir, which much be given intravenously, EIDD-2801 can be taken as a pill. For this reason, Baric and other researchers investigating EIDD-2801, including George Painter, a professor of pharmacology and president of the Emory Institute for Drug Development, which first produced the drug, suspect it may end up being more widely used than remdesivir.

In 2018 Painter and his colleagues identified EIDD-2801's activity during a search for a universal influenza medicine. When SARS-CoV-2 emerged, Painter's group immediately shifted focus. EIDD-2801, like remdesivir, inhibits the coronavirus's self-copying operations, but it also works against virus variants with a mutation that made them resistant to the Gilead drug. In addition, EIDD-2801 is effective against a host of other RNA viruses, so it could serve as a multipurpose antiviral, much as some antibiotics can work against a wide variety of bacteria. For COVID-19, says Wayne Holman, co-founder of Miami-based Ridgeback Biotherapeutics, which has licensed the drug and is planning clinical trials, the goal is to have a pill that can be taken by patients at home early in the course of the disease to prevent it from progressing.

BLOCKING INFECTION

To stop SARS-CoV-2 from penetrating cells in the first place, scientists are trying to develop antibodies that lock onto the viral protein that facilitates cell entry, a part of the virus known as the spike. Some of these neutralizing antibodies, made of a protein called immunoglobulin, may come from the blood of patients who have already cleared the virus. Several medical centers, including Johns Hopkins Hospital and the Mayo Clinic, are harvesting blood plasma from survivors and screening it for antibodies. In a technique known as convalescent therapy, doctors then transfuse it into hospitalized patients with life-threatening acute respiratory distress. Early studies of a few such patients suggest the approach may work—some patients' symptoms improved, and levels of the virus in their bodies dropped—but the work is very preliminary.

Takeda Pharmaceuticals, a Japanese firm, is also collecting plasma from recovered COVID-19 patients to identify antibodies. In that plasma, the company is identifying antibodies that show the most activity against SARS-CoV-2. Using these antibodies as a template, the Takeda researchers plan to synthesize a batch of even more active versions to create a potent cocktail of infection inhibitors, says Chris Morabito, head of research and development of plasma-derived therapies. The therapy—TAK-888—might enter clinical trials by year's end, Morabito says; the number "888" represents "triple fortune" in Chinese. Several other drugmakers, including Regeneron and Vir Biotechnology, are generating their own therapeutic antibodies and say they will also be tested in patients this year.

Another blockade strategy focuses on the cellular docking site that the virus uses. Josef Penninger, a molecular biologist at the University of British Columbia in Vancouver and founder of drug company Apeiron Biologics, is trying to lure the virus away from a chemical receptor called ACE2 in the outer wall of lung cells. The coronavirus spike protein binds to this receptor. Several years ago Penninger's lab synthesized a decoy version of ACE2. In test-tube experiments, the scientists found the synthetic molecule—APN01—attracted coronaviruses away from real human airway cells. The virus locked onto the decoy and was marooned there. "We are blocking the door for the virus and, at the same time, protecting tissues," Penninger says. Apeiron is planning clinical trials later this year for APN01, which must be administered in the hospital as an infusion to sick patients.

OVERREACTIONS

In the sickest COVID-19 patients, a mass of mucuslike fluid accumulates in the lungs, preventing cells from absorbing oxygen. These are the patients that need ventilators. The fluid buildup is the result of an overactive immune response that involves a signaling chemical called interleukin-6 (IL-6). Biotech companies, including Regeneron and Genentech, have manufactured synthetic antibodies that can bind to IL-6 and mute the call to action that it sends out.

Northwell Health, a large system of 23 hospitals based in Long Island, N.Y., is one of more than a dozen centers participating in clinical trials of the IL-6 blockers, says Kevin Tracey, chief executive of the Feinstein Institutes for Medical Research, which is running the trials at Northwell sites. "The hospitals are being inundated with very sick patients suffering from serious pneumonia and acute respiratory distress," Tracey says. "The IL-6 drugs have a plausible mechanism of action. I'm optimistic they'll work."

None of these approaches are cures. Denison says the drugs under development may "reduce the severity" of an advanced COVID-19 episode, especially if they can be administered when initial symptoms—a mild cough, muscle aches or slight fever—first arise. In a hopeful future, a combination of various therapies may be able to thwart the virus on several different fronts, the way a cocktail of antivirals can beat back an HIV/AIDS infection. By limiting symptoms, drugs may be able to keep some patients out of the hospital and keep hospitalized patients off of ventilators. They can serve as a bridge to survival as other scientists rush to develop the real virus slayer: a vaccine. 

Read more about the coronavirus outbreak here.

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