Therapies for COVID19 (C19) fall into three groups: vaccines, anti-viral therapies and therapies that treat the complications of C19 infection. Quellor, INmune Bio’s DN-TNF drug that neutralizes soluble TNF without being immunosuppressive, is being developed to treat complications of cytokine storm in patients with symptomatic C19 infection. Three important questions need to be answered about the Quellor program in patients with C19:
- What is the most important problem in patients sick from C19?
- Why target TNF of the C19 induced cytokine storm?
- What is the design of the Quellor Phase II clinical trial?
The cytokine storm can be described as the real villain in patients sick enough from C19 to seek medical attention. In most patients seeking medical attention for their C19 infection, the coronavirus titer (a measure of the amount of virus in their blood) is already decreasing. This means their immune system is winning the war of eradicating coronavirus; unfortunately, the immunologic response to the virus is making them sick! C19 cytokine storm is most often described as elevated levels of TNF, IL1 and IL6 in the blood. These elevated cytokines are whipping the immune system into an uncontrolled, dysregulated frenzy (the storm). If the cytokine storm is making the patient sick, it makes sense to target the cytokines of the storm to blunt the effects of on the patient. That is what we are trying to do with Quellor. We plan to give patients Quellor, a DN-TNF protein biologic that neutralizes soluble TNF to neutralize blunt the effects of the cytokine storm. Our goal is to help the patient get better fast and stay out of the ICU.
TNF is arguably the “master cytokine” of the cytokine storm for two reasons. First, translation and expression of TNF must occur before there is expression of IL1 and IL6. That is, if you block production of TNF, the levels of IL6 and IL1 will be much lower. Alternatively, if you block production of IL6, you will not have any effect on the production of TNF or IL1. The second reason targeting TNF makes sense goes to the heart of C19 pathology – blood clots. That is, many of the pulmonary, renal, cardiovascular, and neurologic symptoms seen in patients with advanced C19 infections are caused by blood clots getting stuck in the capillary beds of these major organ systems. Where are these blood clots coming from? It appears that the cytokine storm causes endothelial activation (endothelial cells are the cells that line the blood vessels). Activated endothelial cells express Tissue Factor. Tissue Factor causes blood clots to form at the wrong time and the wrong place. These aberrant clots literally gum up the works in the lungs, kidneys, heart, brain and beyond resulting in hypoxia, renal failure, cardiac dysfunction, stroke and more. So far, anti-coagulation therapy is not effective in treating this problem. At INmune Bio, we believe the way to treat the catastrophic complications of C19 is to prevent the aberrant clots from forming. The best way to prevent the formation of aberrant clots is to prevent endothelial cell activation. Of the cytokines that make up the cytokine storm, TNF is the most potent activator of endothelial cells. We believe neutralizing soluble TNF with Quellor may reverse endothelial activation and prevent the formation of aberrant clots. Targeting TNF is a therapeutic strategy that must be tested in patients with C19. That is exactly what we plan to do in the clinical trial.
The clinical trial is a Phase II, blinded, randomized, multicenter trial in hospitalized patients with respiratory symptoms from C19 infection. The goal of the trial is to treat patients with a single dose of Quellor to see if we can prevent the development of the catastrophic complications of C19 infection including progressive respiratory failure, admission to the ICU, renal failure, cardiovascular, neurologic complications and thromboembolic complications. The trial is focused on patients at highest risk of these complications including the elderly, the obese, patients with diabetes or a history of cardiovascular disease, patients who are African American or Hispanic. Success or failure is measured on day 28 with safety is follow-up for 60 days. The trial was designed in close collaboration with the FDA. We plan to enroll 366 patients in two groups. The “first 100” will allow us to determine a GO/NO GO to for the second “confirmatory” phase of the trial (266 patients). The randomization is 1:1 with half of the patients receiving Quellor and half receiving a placebo.