The World’s Largest COVID-19 Drug Trials Take Place in the UK – 4th April 2020

Dr David J Flavell PhD FRCPath
Charity & Scientific Director of Leukaemia Busters

4th April 2020

COVID-19 Cures?

As the global biomedical research community turns its attention to an array of potential treatments for COVID-19 we ask which are the most likely to work and what this will do for bringing the pandemic under control.

  • The global research effort already underway for new and re-purposed drugs
  • The important difference between vaccinate and treat.
  • The different types of drug and how they work.
  • Drug treatments that cure or alleviate
  • How would a successful treatment change the pandemic landscape?

There is an information overload about treatments being developed globally for COVID-19 and the purpose of my blog today is to try to cut through some of the confusion and present a clear picture of what, to the best of my knowledge, is really going on.

Before launching into explanations about the various treatments and how they work let me give you the very comforting news that proper controlled clinical trials are now being co-ordinated globally by a WHO programme called WHO SOLIDARITY  that is trialing dozens of different treatments in hundreds of clinical trials being conducted in many countries around the world. In the UK we also have our own massive clinical trial programme under the banner of the RECOVERY trial  also co-ordinated with the WHO effort.

These are proper very large randomised clinical trials that will examine the benefits of a given treatment compared against best standard of care treatment for seriously ill hospitalised COVID-19 patients. Many of the reports you may have heard about with Chloroquine and others have not been properly controlled randomised trials, have involved only relatively small numbers of patients and have generally not compared outcomes with a control group of patients so it’s not possible to say if the results they reported were truly meaningful or not. That needed to change and the high quality trials now underway globally will once and for all give accurate and believable answers, unlike the smaller anecdotal “trials” that do not.

This blog is not the place for me to go into detail about everything currently underway so for those of you who are interested in the finer detail I recommend that you visit the WHO SOLIDARITY and UK RECOVERY websites for more information.

VACCINATION versus TREATMENT

The first thing to say is that we must make a clear distinction between vaccination and treatment, they are very different things.

Vaccination is a preventative or prophylactic measure designed to prevent COVID-19 infection in the first place. See my blog on “Vaccinating the Herd“.

Treatment on the other hand is the use of drugs or other therapies to treat patients who already have COVID-19 in order to alleviate their severe symptoms and/or eliminate or weaken the virus.

That said you need to be aware that there are broadly three different treatment types, again both very different in their effects on the virus and disease processes. These are:-

  1. Treatments that block the virus from infecting the patients cells.

  2. Treatments that interfere with the viruses ability to replicate inside the patients cells.

  3. Treatments that quell the life-threatening symptoms of COVID-19 by dampening down the dangerously over active immune response to the virus.

So let’s consider the various types of treatments and how they might work but before we do let’s just say something about the SARS-CoV-2 virus itself because it’s important to understand a few basic facts to understand how the various treatments might work. You may remember in my blog “Viral SurvivalI said that viruses aren’t strictly speaking living entities, they are just tiny packages of genetic material enclosed in a fatty (lipid) membrane decorated with specialised proteins on their surface. The genetic material they contain possesses all the information needed by the virus to make new copies of itself. In the case of the SARS-CoV-2 virus it is the “spike” protein decorating the surface that is the key to unlocking the door into the victim’s cells.

The spike protein is so named because it looks like an inverted spike and gives the virus its characteristic crown-like appearance when viewed under a powerful electron microscope. Once inside the victims cell the viruses genetic material is released and immediately hijacks the victim’s normal cellular machinery to make millions of copies of itself filling up those cells, eventually bursting out to infect other surrounding cells, on and on. This is the way that the virus ravages its way through hundreds of millions of cells in our throats, lungs and other organs if left unchecked by our normally efficient immune system.

However, as we know that immune response doesn’t work for everybody and sadly around 20% of people develop serious life-threatening symptoms with some of these dying as the infection causes untold damage to their lungs, blood vessels, kidneys and in some cases even the brain.

The big scientific question then is why do some individuals progress to develop serious symptoms needing ICU support in hospital while for others it is only a mild or moderate infection that is easily brushed off after a week or two? What is a mystery for now will eventually reveal itself as research progresses to uncover the facts to explain this, then we shall be in a much stronger position to develop other new drugs that are designed to target newly discovered mechanism(s) by which the virus causes serious disease in the unfortunate minority. For now we have an armoury of drugs developed for other conditions and viruses that are being re-purposed in the fight against COVID-19. This is not an ideal situation but it is the best we have for now and though these drugs might not be the “best fit” some do show promise in interfering with the viruses savage progress.

How Do the Various Drugs Work?

So now let’s move on to a description of the various types of drug and how they work. This is by no means a comprehensive breakdown of everything that is currently being investigated in clinical trials, there just isn’t room to include that here. I refer you to the WHO SOLIDARITY and UK RECOVERY websites for this. Also bear in mind that the drugs mentioned here are not yet proven, that’s the entire purpose of the trials, to determine a drugs effectiveness and it will be a while before we know the outcomes once the results have been fully analysed and a verdict is reached for each.

1. Treatments that Block the Virus from Entering the Victim’s Cells

The reason that our own antibodies work in rendering us immune to COVID-19 is because they block the entry of the virus into the vulnerable cells in our airway and lungs. They do this by preventing the spike protein on the virus from locking on to a molecule on the surface of the victims cells called ACE-2 which the virus uses as a doorway to get inside the cell. These are the so called neutralising antibodies that do exactly as their name suggests, they neutralise the virus by preventing it from gaining entry into the host cell.

This forms the basis for a treatment that uses of hyper-immune plasma also known as convalescent plasma collected from patients who have recovered from COVID-19 and therefore have produced neutralising antibodies now under investigation at two London hospitals. Some limited studies have shown that infusion of hyper-immune plasma into seriously ill COVID-19 patients has some benefits that includes a quicker recovery time but large scale clinical trials have yet to definitively prove this to really be the case. We should know fairly soon.

The major problem with this approach is the limited amount of convalescent plasma available from recovered patients. There is a potential solution to this though. It is possible to create an artificial hyper-immune plasma using virus neutralising monoclonal antibodies created in a laboratory. These already exist and they appear on the WHO list of potential treatments but as far as I’m aware nobody is pursuing this approach just yet. Before doing so it would be prudent to wait for the results from trials with convalescent plasma from recovered patients. If they show positive benefits then would be the time to consider an artificially created hyper-immune plasma, something that could be assembled fairly quickly and theoretically produced in unlimited quantities.

Then there are other molecules besides antibodies that that can be artificially engineered to block the binding of the virus via its spike protein to the host cell. Molecular biologists can artificially create parts of the spike protein that would bind to the ACE-2 receptor on the host cell and prevent the virus from attaching to the cell to infect it. Whilst this approach is certainly under consideration it is still theoretical and as far as I know is nowhere near ready for clinical trials just yet.

I’m also including the anti-malarial drugs Hydroxychloroquine and Chloroquine here  because these two do theoretically affect the way that the virus gets into the cell. Both have become controversial because certain world leaders have given them their premature endorsement based on their gut reactions to anecdotal evidence but without there being any solid clinical trial data.

Interestingly we use chloroquine in our laboratory to modify the way in which antibody-based drugs enter the leukaemia cell so we are well familiar with its properties in this regard. This drug works by changing the acidity of vesicles inside the cell and the presumption is that this is how chloroquine might work in preventing SARS-CoV-2 virions from escaping from these vesicles and into the cells interior where they can begin their aggressive reproduction. Chloroquine also has some anti-inflammatory properties and can inhibit protein production  protein synthesis inhibitory properties and these might also contribute to any therapeutic effect against COVID-19.

Now that the WHO SOLIDARITY and UK RECOVERY programmes are underway and big scale clinical trials are in progress we should know the answer as to whether or not chloroquine has any useful benefits very soon. One negative effect of the undue publicity that chloroquine has recently received from Trump in the US and Macron in France as an unproven (as yet) treatment for COVID-19 has been that it has led to a shortage for other patients because of panic buying.

2. Treatments that Prevent the Virus from Replicating inside the Host Cells

All of the drugs that are being investigated for their ability to inhibit the reproduction of the virus inside the patients infected cells are repurposed drugs that were originally designed for other viruses. They are therefore not optimised for use against the COVID-19 coronavirus because they are literally not the “best fit” but they may fit sufficiently well enough to have a beneficial effect.

The most famous of these is the drug Remdesivir that interferes with one of the viruses enzymes called RNA polymerase. This drug was originally designed for use against the virus that causes Ebola. In a relatively small scale Chinese clinical trial earlier this it did show that use of the drug did decrease the time to recovery but not to any significant level. Very recently Dr Anthony Fauci director of the US National Institute for Allergy and Infectious Diseases at NIH, most unusually and some would say controversially, announced in the Oval Office of the White House the interim results of a larger scale international placebo controlled clinical trial with remdesivir.

The results he reported showed that remdesivir significantly reduced the average recovery time of seriously ill COVID-19 patients from 15 days to 11 days compared to placebo treated patients and that there was also a reduced though non-significant death rate from 11% down to 8%. Perhaps only small improvements but improvements nonetheless.  But don’t hold your breath until the final results have been fully analysed and scrutinised, only then will we fully understand the true outcome of this trial plus there are other trials with remdesivir taking place elsewhere and it remains to be seen if these will agree.

Two other anti-viral drugs under investigation in clinical trials for COVID-19 are Lopinavir and Ritonavir both originally designed for use against the HIV virus that causes AIDS. Lopinavir attacks essential enzyme called a protease needed by the HIV virus while ritonavir prolongs the activity of lopinavir.  The great hope was that these two drugs may also act against the SARS-CoV-2 virus but there is currently  little evidence that this is the case. Regardless, these two anti-viral drugs have been earmarked for investigation in several large scale ongoing clinical trials. Bear in mind that these anti-HIV drugs are not a best fit for the  SARS-CoV-2 virus  and that eventually new anti-viral drugs designed specifically for COVID-19 will begin to appear on the scene (see section below, Completely New Drugs Specifically Designed for the COVID-19 Coronavirus)

3. Treatments that Dampen Down the Damaging Immune Response

Immunomodulatory treatments are something different again. They are designed to dampen down any damaging effect of an overzealous immune response against the COVID-19 virus. There is some good evidence that at least some of the damage caused to the lungs and other organs by the disease is due to an over active immune response to the virus that causes collateral damage to any tissue or organ the virus is near to or residing in. In the jargon we use as immunologists this is referred to as immunopathology.

In such circumstances chemicals and secreted proteins called chemokines and cytokines are released by the responding immune cells that have the effect of over stimulating the immune response in a vicious cycle referred to as a “cytokine storm”. It is this (and possibly other immunological reactions) that bring about massive amounts of inflammation that then damages the surrounding tissues and organs.

This is where cancer research meets COVID-19 research beautifully demonstrating the interconnectedness of biological systems. Some patients with cancer who receive a relatively new and revolutionary treatment called immune checkpoint therapy to boost immunity against their cancer can develop a type pneumonia that looks very similar to the pneumonia seen with in COVID-19.

Oncologists have pioneered a partially successful treatment for this type of pneumonia in their cancer patients by using antibodies or other protein molecules that either “mop up” or block the action of two different cytokines called IL-6 and IL-1 to treat their patients. The two antibodies in question are Tocilizumab and Siltuximab  for the IL-6 cytokine and Anakinra for IL-1. A clinical trial comparing the effects of these three used in different combinations in seriously sick COVID-19 patients is now underway in Belgium and elsewhere.

The great hope is that these clinical studies designed to reduce the amounts and effects of cytokines released into the patients body because of the virus will also reduce the severity of the disease through the dampening down of any damaging immune response. It certainly works in cancer patients with a similar pneumonia so it is hoped will also work in COVID-19 patients also.

There are other ways in which the immune response can be modulated to reduce the damaging effects it may have in COVID-19 patients. Interferon beta 1a is a cytokine with well-known anti-viral effects (interferon derives its name from three decades ago when it was first discovered that it “interfered” with viral reproduction) through its effects on stimulating the immune system shown to be of benefit for patients with other respiratory disorders such as chronic obstructive airway disease by Southampton led researchers. This forms the rationale for investigating inhaled  interferon beta 1a in a trials in COVID-19 patients in Southampton and elsewhere.

Steroids are another class of drug that suppress the immune response generally and non-specifically and these are also being investigated, for example Dexamethasone, as a potential treatment to quell the cytokine storm that characterises one of the adverse responses to the virus. The problem with steroids is that they suppress the immune system in general and there are concerns that this could make the situation worse for the patient if this allows the virus to run away rampantly if there is they lose any effective immunity. Nothing is clear yet but with time as the data comes pouring in and is fully analysed we shall know what works best.

What about new drugs?

All the drugs mentioned so far already exist and are being repurposed from other indications for other diseases for use in COVID-19 . But what about new drugs specifically designed for the coronavirus that causes  COVID-19? As we learn more about the molecular structure of the SARS-CoV-2 virus, as is already happening, then this will allow the intelligent design of drugs that are taylor made  for this virus. This is already happening but it is a slow process to develop a designer drug from scratch and it will be some time before we see anything available for clinical use. Even so, with the pace of current research it is likely that new drugs will begin to appear fairly quickly of that there is no doubt. What will take the time is their thorough testing for efficacy and safety before they can be used in human beings. Watch this space, I’ll report on new developments here as and when they happen.

My Apologies for the Information Overload

I apologise for the information overload in today’s blog, I know that there’s a lot to take in. Truth is, I have only presented you with a small fraction of what is actually taking place across the globe. The pace of progress is truly breath taking, never before have we seen medical science mobilised on the scale we are observing now.

Each And every day during this crisis I have opened up my PC in the morning to discover another mass of scientific publications has arisen overnight. Many of these are posted as scientific papers on what are called pre-print servers, meaning that these have not yet been checked for accuracy or flaws by the process of peer review, a standard check and balance for any paper published in any reputable science journal. That means unfortunately that some papers emerging are of a poor quality or even in the worse example present data and information that is not necessarily factually correct or has been interpreted in the wrong way.

Foraging through this daily mass of literature is quite a challenge, deciding what is and what is not a worthwhile study. The advantage I have is that I’ve been a reviewer for numerous high quality medical journals for over 30 years and that has given me the advantage of knowing what to look out for that indicates a paper could be a bit dodgy. Even so it is hard work to separate the wheat from the chaff and decide what really is important and what is not. The biosciences can be a minefield!

Combinations of Different Drugs will Likely Make All the Difference

In reality any one single treatment on its own will probably be inadequate to bring about full restoration to health to save the lives of seriously sick COVID-19 patients. Like in many branches of medicine it will almost certainly turn out to be that combinations of two, three or more drugs used together will be needed to fully counter the dangerous life-threatening symptoms of seriously ill COVID-19 patients. Attacking the virus and the root causes of the severe symptoms by aiming at more than one target by using a cocktail of drugs will always work better as we have learned from our own research work with leukaemia treatment.  As more information becomes available on this I’ll make sure to write a blog to inform and give everyone the comfort of knowing that the cavalry that is the biomedical science community will be riding over the hill to the rescue one day soon.

When the Day Finally Comes

Once we have reliably effective treatments for the most serious COVID-19 cases and we learn how best to manage all cases with treatments that ensure serious symptoms never develop in the first place then we shall be well on the road to returning to a normal way of life. Knowing that COVID-19 may no longer be a life-threatening disease and that patients will no longer end up in ICU on ventilators will give us all the confidence to return to a normal way of life even before an effective vaccine become available.

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