In a nutshell we are testing an emerging theory that an over-exuberant response of an immune function known as the STING signalling pathway is a key cause of much death and disability of COVID-19 patients and that blocking this pathway will help reduce the need for hospitalisation and reduce the severity of the COVID-19 disease.
We are not looking to stop people succumbing to the disease in the first place (that is the role of vaccines, something we have yet to find out if that will be possible, as well as being safe).
Our aim is to shorten the course of the infection or reduce its severity. The anti-viral drug, remdesivir, can provide some benefit if taken early enough, and the anti-inflammatory drug, dexamethasone, can reduce the severity of the disease when given to people with advanced disease, but with the number of deaths from this pandemic approaching the one million mark and a growing number of people, including children, experiencing long-term disabilities, there remains a very significant need for more and better therapies.
Much of the death and disability from COVID-19 is being blamed on an inappropriately strong immune response to the infection. In the overwhelming majority of people, the immune system responds in a normal, well-controlled way, eradicating the virus and resulting in little or no long-term adverse consequences. Unfortunately, in between about 5-10% of people, the immune system responds in an over-exuberant way, resulting in most of these patients requiring hospitalisation and carrying with it a high risk of either dying or recovering with a range of long-term disabilities. It is for these latter patients that we urgently need better treatments to augment remdesivir and dexamethasone.
Apart from mounting a defence against the SARS-CoV-2 virus, one of the roles of the immune system is to repair the damage caused by the virus. That repair process is mediated by molecules known as cytokines, involving a modest rise in their levels in the damaged tissue, quickly falling once the repair process is complete. The inappropriate immune response in some COVID-19 patients is associated with cytokine levels completely out of proportion to what is required. This over-the-top response is known as a cytokine storm, with a raft of cytokines being produced at very high levels in the lungs. What should be a normal local inflammatory response meant to repair damaged lung tissue, turns into an overwhelming, whole-of-body response that pushes the patient into risk of multiple organ failure known as septic shock.
At this time, we do not have a clear idea what determines whether a patient is likely to have a normal immune response or an inappropriately high response.
Treating the cytokine storm
Dampening down the cytokine storm before it gets a hold is an obvious treatment strategy, with a
number of approved and experimental drugs currently under testing.
One of the challenges in this approach is knowing which of the several dozen different cytokines involved in inflammation needs to be targeted, with more and more clinical studies reporting that not all cytokines appear to be involved in the COVID-19 cytokine storm.
The finger increasingly is being pointed at a small number of cytokines consistently being associated with poorer outcomes in COVID-19 patients:
Trying to second-guess which cytokines are the main suspects and then target them after they have been produced is a high-stakes strategy which so far has not worked. For example, large trials in COVID-19 patients of drugs that specifically inhibit the prominent cytokine, interleukin-6, have failed to provide any clinical benefit:
This leaves the strategy of blocking the cytokine storm in the first place as arguably the preferred strategy.
Why Veyonda offers a unique and important approach
We believe that the value of Veyonda lies in its potential ability to block the cytokine storm at its roots, offering the prospect of blocking the production of a range of cytokines, among them those so far ‘incriminated’ in the onset of severe COVID-19 cases.
One of the key triggers of a cytokine storm is a front-line defence mechanism known as the STING pathway. One of the roles of STING is to detect and respond to tissue damage caused by the virus, and this is where we believe Veyonda may have a role to play in COVID-19.
Noxopharm has been fortunate to have collaborated with Dr Michael Gantier of the Hudson Institute of Medical Research in Melbourne, a scientist at the forefront of STING research and with a personal reason to follow the COVID-19 story.
What Dr Gantier has shown is that the active ingredient in Veyonda, idronoxil, is a potent inhibitor of the STING pathway, in the laboratory blocking the STING response of human tissues to the same sort of damage inflicted upon COVID-19 patients. A discovery which is thought also to help explain some of the anti-cancer effects of Veyonda.
It is a long jump from the lab to the bedside, but this is a good start because (as far as we know based on public data) it puts Veyonda in the unique position of being the only inhibitor of the STING signalling pathway in the clinic and ready to go into a clinical study in COVID-19 patients.
The NOXCOVID-1 study
We are asking 3 main questions.
The first question is whether Veyonda is safe in patients whose lung function is compromised. After being used without any serious safety issues in over 100 patients with end-stage cancer, including patients with secondary cancers in their lungs, we don’t have any particular concerns. But that still is a question that needs to be asked.
The second question is whether we can achieve improvements in the patients’ clinical state. The World Health Organisation has developed a scale for clinical improvement in COVID-19 patients:
||No evidence of infection
||No limitation of activities
|Limitation of activities
||Hospitalised, no oxygen therapy
||O2 by mask of nasal prongs
||Non-invasive ventilation or high-flow O2
||Intubation and mechanical ventilation
|Ventilation + additional organ support
The 40 or so patients we are targeting with Veyonda in our NOXCOVID-1 study will start with a Score of 3 and 4. Our aim is to get them to Score of 1 or 2.
The third question is what effect this treatment is having on blood cytokine levels.
We anticipate having an answer to these three questions within a matter of months.
In a nutshell we are testing an emerging theory that an over-exuberant response of an immune function known as the STING signalling pathway is a key cause of much death and disability of COVID-19 patients and that blocking this pathway will reduce the severity of the disease and whether any change in a patient’s condition correlates with blood cytokine levels
Previous Noxopharm NOXCOVID-1 ASX announcements:
1 April 2020
21 April 2020
19 June 2020
1 September 2020