To date, just under 961,000 people have tragically died from Covid-19, according to John Hopkins University’s Covid-19 dashboard. Covid-19 deaths have been found to be mainly linked to an over-reaction of the immune system, known as the cytokine storm.
As a result, there has been a lot of research looking into how we can effectively treat this cytokine storm and, therefore, save thousands of lives across the world. This is particularly imperative given that many countries in the world are now experiencing a second wave of the pandemic.
One possible therapeutic target that has emerged is tumour necrosis factor (TNF). According to a paper published in The Lancet in early September, it is believed that as TNF is a major component of the cytokine storm, that neutralising this target with anti-TNF drugs might mediate the hyper-inflammatory response of the immune system that is killing Covid-19 patients.
It is hoped that anti-TNF drugs might work where anti-interleukin-6 (IL-6) therapies have struggled – IL-6 is another component of the cytokine storm. For instance, Roche’s Actemra (tocilizumab) failed to meet its primary or second endpoints of improved clinical status and reduced death in a global Phase III trial.
California-based INmune decided to leverage its TNF platform and launch a Phase II trial of its selective inhibitor of soluble TNF (sTNF), Quellor, in hospitalised Covid-19 patients. Quellor differs from the existing TNF inhibitors on the market, which are prescribed for inflammatory conditions ranging from rheumatoid arthritis, inflammatory bowel disease and psoriasis, because it only inhibits sTNF, and not transmembrane TNF (tmTNF) as well.
In the study, Quellor will be combined with standard of care and compared to standard of care alone to make sure medical teams and patients are happy with being in a clinical trial for an experimental drug . INmune is hoping to have completed the trial by the middle of next year if recruitment is successful.
INmune CEO and president Dr RJ Tesi explains the promise of anti-TNF drugs in treating the cytokine storm and how Quellor can optimise this approach by only inhibiting sTNF.
Allie Nawrat: Why is there such an urgent need to treat the cytokine storm caused by Covid-19?
RJ Tesi: At the end of the day, it’s the cytokine storm that is causing hospitalisation and death. Only 20% of patients who get infected with Covid-19 end up in the hospital, about half of the remaining 80%, so 40%, are asymptomatic and the other 40% get flu-like symptoms. It is the 20% that go into the hospital that are the cause of why we’ve had to really treat this so differently from flu; we don’t do social distancing or close restaurants during the [annual] influenza season. But we have been doing that during the Covid-19 pandemic.
By the time someone is sick enough to go to the hospital with Covid-19, their viral titre is actually decreasing. So the infection is becoming less important in the body because their immune system is clearing the virus. The problem is the immune system has gone wild, and [so] it’s the immune system that’s making them sick. [Put simply], the virus makes you sick, but the immune response and the cytokine storm is what kills you.
So it is very important that we treat the cytokine storms in patients that have declared themselves sick enough that they need to see a doctor.
AN: What promise do TNF-targeting therapies have in regulating the cytokine storm associated with Covid-19?
RJT: The cytokine storm is this tidal wave of inflammatory cytokines that are caused by the immune system’s response to the virus. There are three main cytokines: TNF, IL-1 and IL-6. So if we’re going to treat the immune system’s response, because it’s killing you, one of the things we could do is target one of these cytokines.
In doing so, people made the assumption that all cytokines were created equal under Covid-19, and they aren’t. TNF is what we call the master cytokine [as it is] the most important of those three. There are a few reasons for this.
sTNF is the first cytokine that is expressed by inflammatory cells. It has to be expressed before you get production of IL-1 and IL-6. So, if you cut off the production of TNF, you never get production of IL-1 or IL-6. So, targeting TNF, as the master cytokine, allows you to prevent the cytokine storm.
The second reason is linked to what the cytokines are doing; they’re obviously revving up the immune cells to attack the virus, but why are they killing us? What is the common denominator?
Unfortunately, it took a high-profile event for [this to become clear]. There was a Broadway actor [called Nick Cordero] who developed neurologic problems from Covid-19 and he then lost his leg because of blood clots. [It has become clear that] the blood clots are the common denominator.
[This is because] the cytokine storm activates endothelial cells, [which] line the inside of the blood vessel. Usually they allow the blood to just slide through without any problem, but when they become activated, they begin to have all these rough edges and they express a protein called tissue factor that sticks out from the endothelial cell and stimulates blood clots.
TNF is the cause of this endothelial cell activation. IL-1 also activates the endothelial cells, but IL-6 does not. That probably explains why IL-6 inhibitors didn’t work.
We are quite optimistic that this [anti-TNF approach] will be able to really stop the pathology in its tracks, get the immune system under control, so the patient gets better quickly without requiring respiratory support and the risk of death.
AN: How does Quellor differ from other anti-TNF therapies? Why is it important in treating Covid-19 that the drug is selective and does not block transmembrane TNF?
RJT: There are two types of TNF – there’s sTNF, which we call bad TNF, and tmTNF, which is good TNF.
sTNF is the TNF that is most important in autoimmune diseases, like rheumatoid arthritis and inflammatory bowel disease. Whereas tmTNF, or good TNF, does a number of things; it improves the immune response to infection and cancer, and it is important for myelination and nerve cell function. It turns out that currently approved non-selective TNF inhibitors are immuno-suppressive; they dampen down the immune system so it can’t fight infection or cancer.
So blocking tmTNF is a problem. Our drug, Quellor, only blocks sTNF so it gets rid of the inflammation, but it does not immuno-suppress the patient and that’s what’s relevant to Covid-19. If someone has a life-threatening viral infection, you do not want to undermine their immune system so they can’t get rid of the virus.
We don’t believe patients should be getting the current anti-TNF drugs, because it will cause immune-suppression. But they will benefit from a drug that gets rid of the bad TNF without affecting the good TNF.