Drugs to target COVID-19

A virus is tricky to destroy. This is because they are difficult to find to as they hide within their host's cells, and this can make it difficult for body cells to recognise them as foreign. They also have explosive reproductive rates meaning that they are a fast moving target. Since total eradication is so hard, antiviral drugs instead aim to limit replication of the virus to levels so low that they cannot hurt the body. Scientists around the world are looking at re-purposing existing drugs or coming up with new ways of either eliminating the virus or reducing the severity of the illness.

So far the biggest breakthrough has been with Dexamethasone, an inexpensive steroid that is already easily accessible around the world and looks like it reduces the death rate amongst the severely ill (see below). In addition, Synairgen has just reported that a new treatment, SNG001 in a small trial of 101 people, cut the odds of a patient developing severe disease by 79% .

How Drugs Can Work

There are 3 different ways that the drugs can be used to treat the virus :

1. Block Viral Replication

All coronaviruses use the same mechanism to reproduce which involves an enzyme called viral RNA polymerase. The polymerase makes lots of mistakes as it copies the virus and relies on another enzyme called exonuclease to fix them by "proof-reading" them.

Remdesivir is a drug that appears to disable the proof reading enzyme. When this happens the virus is less able to produce new viruses as it makes too many mistakes. The drug was developed in 2017 and was able to show in test tubes and animal experiments that it could shut down the replicating machinery of several coronaviruses. In March the drug started human trials in 1,000 patients with COVID-19. Remdesivir is taken intravenously.

EIDD-2801 also aims at stopping the same viral enzyme. In April it could be showed that in mice this drug helped breathing and in test tube experiment with human lung cells it drastically slowed SARS COV-2. This drug is taken as a pill which would mean it could more easily used. It also works against other RNA viruses so could work in a similar way as antibiotics do against a variety of bacteria.

2. Prevent Entry into Cells

If a drug could stop SARS COV-2 from getting into the cell in the first place it would stop the virus replicating in the body. Scientists are trying to develop antibodies that lock on to the spike protein of the virus as it is the spike that attaches onto the receptor of the host cell.

Convalescent Plasma

Some of the neutralising bodies that come from the blood people who have had the virus could be transfused into patients with life treating acute respiratory distress. This is in the early stages of trials, but patients have shown some signs that the level of virus in their bodies had dropped.

TAK-888 is a drug that uses modified antibodies against the virus. The company uses the most active antibodies as a template to produce even more active versions to to create a cocktail of infection inhibitors. This therapy might enter clinical trials by the end of the year. There are two other drugs that work on a similar basis that will be tested in patients later this year.

APN01 is a synthetic molecule that attracted coronaviruses away from real human cells. The virus locked on to the decoy and was marooned there. It was a way of luring the virus away from the ACE2 receptor that the virus needs to bind on to in order to gain entry into the cells. Clinical trials are also planned for later this year.

Angiotensin-II Receptor Antagonists

Angiotensin receptor blockers (ARBs) have effects that are similar to angiotensin converting enzyme (ACE) inhibitors. However, ACE inhibitors work by preventing the formation of angiotensin II rather than by blocking the binding of angiotensin II to muscles on blood vessels.

ARBs are used for controlling high blood pressure, treating heart failure, and preventing kidney failure in people with diabetes. Therefore, ARB's such as losartan, valsartan, telmisartan, etc can be a novel therapeutic approach to block the binding and hence, attachment of SARS-CoV-2 RBD to ACE2-expressing cells, thus inhibiting their infection to host cells.

3. Reduce the Hyperimmune Response and Acute Resipratory Distress

Although the majority of people will experience mild symptoms some will need hospitalisation and even in some cases ventilation to help them breathe.

In some patients a mass of mucus like fluid buds up in the lungs which then prevents the cells from absorbing oxygen. In this situation the patient would need a ventilator which is a machine that provides breathable air into and out of the lungs, to deliver breaths to a patient who is physically unable to breathe sufficiently for themselves. This fluid build up is a result of an overactive immune response, a "cytokine" storm that can drown the patient in a mass of congestion and dying airway cells and involves a signalling chemical called Interleukin-6 (IL-6)

So scientists are looking at drugs which can try and dampen the immune systems response by manufacturing synthetic antibodies that can bind to IL-6 and mute the call that it sends out to the body which results in the overactive response. There are 2 drugs being developed which work this way Kevzara (Sarilumab)and Actemra (Tocilizumab), both are in clinical trials .

There are 2 other drugs Remestemcel-L which uses stem cells to modulate the immune system and Xeljanz (tofacitinib) which inhibits inflammatory cells and both of these are also in clinical trials.

Dexamethosone

Dexamethasone is a synthetic glucocorticoid which is usually used to treat illnesses involving inflammation or swelling where the immune system goes into overdrive e.g. arthritis and severe asthma and reduces inflammation by copying the anti-inflammatory hormones produced by the body.

The SARS COV-2 virus triggers inflammation as the body tries to fight it off, but if the patient has a cytokine storm the trial has shown that Dexamethasone can dampen down the body's immune system thus calming the effect of the body attacking its own cells.

However, it has to be used at the right time, those experiencing milder symptoms would not benefit from this drug as suppressing their immune system at this point would not help them. It should be used on those who are receiving oxygen or mechanical ventilation. According to the scientists the trial conducted by the University of Oxford prevented 1 in 3 deaths of those on ventilators and 1 in 5 deaths of those on oxygen.

Scientist hope that Dexamethasone could eventually be used as part of a suite of drugs that could reduce deaths even further.

As the drug has been around since 1957 it is out of patent making it a cheap and widely available drug and so could save many lives around the world.

SNG001

Southampton-based biotech Synairgen has developed the drug SNG001 using a protein called interferon beta 1a (1FN-beta), which the body naturally produces in response to a viral infection. Interferons are a group of signalling proteins which are released by white blood cells to raise the anti-viral defences of nearby cells and alter the immune systems response to infections. Beta interferon protein is released by the body at the end of an immune attack and helps to reduce inflammation and the body's immune reaction.

The way SNF001 works is that the protein is directly inhaled into the lungs of COVID-19 patients using a nebuliser (a device used to inhale medicine) in the hopes that it will stimulate an immune response. Synairgen claims that patients were 2-3 times more likely to recover to the point where everyday activities were not compromised by their illness, and it said also that the trial indicated "very significant" reductions in breathlessness and that it reduced the time spent in hospitals. These claims were drawn from a trial involving 101 COVID-19-infected volunteers, half of whom received SNG001, the other half receiving a placebo (an inactive substance).

The treatment works as the drug is a special formulation of interferon beta delivered directly to the airways using a nebuliser which makes the protein into an aerosol. It is thought that a direct dose of the protein to the lungs will trigger a stronger anti-viral response, even in those with an already-weakened immune system.

SARS COV-2 appears to suppress the reduction of this important protein which results in an overactive immune response that can cause damage to the body.

The drug is commonly used in the treatment of Multiple Sclerosis patients. However, experts say that although positive they would like to see the full results presented and peer-reviewed to make sure that they are robust and the trial conduct was rigorous and a larger trial conducted.

Other ideas

BCG Vaccine

The Bacille Calmette-Guerin (BCG) vaccine is being trialled in some countries as there is some evidence that the vaccination prevents other respiratory tract infections in children and older people mediated by induction of immune memory. However, there isn't any evidence that it is effective against COVID-19.

Vitamin C

High does intravenous vitamin C is being trialled against severe COVID-19.

Vitamin D

Vitamin D supplementation has been shown to reduce the risk of respiratory infections in some studies, it is currently being trialled against COVID-19.

Potential Problems

There are risks in trying to dampen down the immune response in people with a viral infection, one solution is to give them antiviral treatments at the same time.

Hydroxychloroquine has been suggested by President Trump to improve outcomes but there is no evidence of that and if fact it can have some serious side effects. Remdesivir trials showed that patients recovered faster and were slightly less likely to die, but the reduction in mortality wasn't statically significant. It could be that some antiviral drugs might work if given soon enough after a person contracts COVID-19 but the trials currently involve those who are seriously ill. Widespread use would depend on being able to detect infections early and treating those who are at highest risk.

Some scientists say that a lot of progress has been made in a very short space in time and that the solution is likely to lie in a cocktail of existing drugs, but others say that the fact that nothing has been discovered so far means that there isn't a magic bullet and it might mean starting from scratch which could take years.