We are still trying to understand so much about COVID-19, to learn about the workings of the virus that causes it (SARS-Cov-2) and marshal our defences accordingly. While many infected people have mild symptoms, or even none whatsoever, others see their body's defence systems go into overdrive, which poses a serious threat to their ability to recover. As such, the pharmaceutical industry is working at speed to find solutions. In this article I will look at what the virus does to an organism once it has entered it, and then look at the research we in drug development are doing to try to stop, delay or lessen the impact of the disease.
Once any pathogen or toxin enters an organism, the body sends out a distress call to its internal emergency services, the immune system. The first responders are part of the innate immune system, the immunity we are born with and is written into our genes. They are fast acting and non-specific, arriving at the scene armed with the same arsenal of molecular weapons regardless of whatever the threat is, chief among which are macrophages, which target and destroy microbes.
At this point, specific antiviral medications could attempt to reduce the viral entry, suppressing its ability to multiply and reproduce. Remdesivir is an antiviral agent that has been shown to reduce replication of other human coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). It is also the first medicine to have an Early Access Medicine Scheme for treating SARS-Cov-2-infected patients in the UK, with the potential to shorten recovery time by approximately four days.
In reserve is our body's adaptive immune response, a more sophisticated armed response unit to innate immunology's standard patrol car. Adaptive immunology weapons are antibodies and immune cells – such as B and T cells – which it uses to seek and destroy the threat to the body.
Cytokines are the messengers of the immune system - both innate and adaptive. They are small proteins cells that help to regulate the development of the immune response to address the invading threat and trigger inflammation. However, with some COVID-19 patients we are seeing a massive release of cytokines in what is called a 'cytokine storm'. This can go on to trigger more immune cells and result in hyperinflammation, which can seriously harm or even kill patients. The antiviral immune response to the novel coronavirus therefore represents a balancing act between suppressing or killing the virus and immune-mediated injury.
As researchers understand more about the brakes and accelerators of the immune system, drug developers are able to test and trial treatments to adapt our immunity to meet specific threats. Although that is difficult with a pathogen as new as SARS-Cov-2, there are now more than 500 clinical studies recruiting across the globe. Many of these are immunomodulators – medications used to help regulate or normalise the immune system. Glucocorticoids, for example, are secreted naturally by our adrenal gland in response to stress and have numerous effects on our bodies that are essential for life. They are traditionally associated with immune suppression so were initially not seen as viable in treating COVID-19, fearing that they may diminish innate immunity by enabling viral propagation. However, as a type of corticosteroid hormone they are also very effective at reducing inflammation and dampening down the response of a cytokine storm - as the recent trials of dexamethasone, which cut the risk of death for COVID-19 patients on ventilators by approximately a third, have shown.
Researchers have recently identified part of the cytokine storm known as a 'burning point'. In a paper submitted toThe Lancet1the study identified a burning point as the start of the cytokine storm. The research shows that this occurs five days before what the authors describe as a 'composite end point event' or CEPE. This could be the need for the patient to be intubated or other organ failure requiring an admission to the intensive care unit. This research offers clinicians the chance to identify those most at risk of CEPE at admission and intervene before a CEPE develops, thereby reducing the likelihood of fatality. It also provides the drug development world with a specific point of disease progression to focus on, to see the burning point as an opportunity to intervene and halt the acceleration of the virus or the tsunami of cytokines.
In this burning point, hyperinflammation occurs due to an over stimulation of T Cells resulting in a huge release of cytokines. More research has identified those cytokines most commonly observed in patients, in particular Interleukin-6 (IL-6), a multifunctional cytokine that plays an important role in the regulation of the immune response and inflammation. IL-6 was one of only two cytokines higher in patients infected with the novel cornavirus than those infected with influenza viruses, and higher levels of IL-6 also increased a COVID-19 patient's odds of being intubated2so can be used to predict and mitigate potential respiratory failure.
Another marker identified by researchers is a deficiency of vitamin D3. Low vitamin D levels have been associated with thrombotic episodes (which have been noted in COVID-19); an increase in inflammatory cytokines; a greater risk of pneumonia and viral upper respiratory tract infection. Vitamin D supplements can also increase Treg levels (T regulatory lymphocytes), which are known to defend against unchecked inflammation and viral infection and have been reported to be low in many patients with COVID-19. Research has been mainly exploratory and additional studies are ongoing such as in the UK.
There are also preclinical models that help us understand this hyperinflammatory state and how we can approach it, including acute respiratory distress syndrome (ARDS) mouse models and a knock-out mouse model that inactivates the enzyme ACE2.
This is interesting, as the coronavirus that causes COVID-19 enters human cells by using ACE-2 as a gateway and disrupts the enzyme’s usual role of balancing two opposing pathways in the Renin-Angiotensin System (RAS), – one of which activates inflammation (Type 1), with the other having a more healing, protective, anti-inflammatory arm (Type 2). In some patients, this causes a major RAS imbalance, acute inflammation, and can contribute to the creation of a cytokine storm in the lungs. So, by knocking out ACE2 altogether, although the virus may struggle to enter the cells and the viral titre levels might stay very low, you can also make the ARDS worse.
At Vicore we have been researching the RAS for nearly 20 years, and more recently our attention has been focussed on what happens when the lung is injured. This has serendipitously led us to start thinking about COVID-19.
We are triallingVP01, an experimental first in class low molecular weight angiotensin II receptor type 2 (AT2R) agonist, as a potential COVID-19 treatment.Our hope is that VP01 might ‘rebalance’ the RAS by directly stimulating the protective Type 2 system (rather than knocking out both arms), which may help bring the body back to normal function.
With more than 500 clinical trials currently ongoing to find treatments for COVID-19, it is critical that we as an industry we work together to ensure we find the fastest route to creating the pandemic armamentarium. It is rare for so much research with similar goals to run concurrently, and with so much happening it would be easy to lose sight of the bigger picture by working in isolation. That is dangerous and risks work being repeated and time wasted. Academia and biotech companies need to come together, regardless of size or stature, and ensure we collectively contribute to the whole landscape of this urgent work.
Rohit Batta is chief medical officer of Vicore.
1. A 'Burning Point' Is Found Before the Composite End Point Event Happened in Critically Ill Patients with COVID-19: A Multicenter Retrospective Study, Jin Yang et al, PREPRINT
2. Targeted Immunosuppression Distinguishes COVID-19 From Influenza in Moderate and Severe Disease, Mudd et al, PREPRINT
3. Does Vitamin D Deficiency Increase the Severity of COVID-19? Weir et al, Online ahead of print