COVID-19 patients mostly die of respiratory failure caused by „cytokine storm“, the uncontrolled, auto-aggressive inflammatory reaction of their immune system. There is currently no specific drug to combat cytokine storm. The poor efficacy of anti-inflammatory drugs and biologics is due to their dominant immunosuppressive action being unsuitable for a causal therapy of cytokine storm.

Inflammation is a vital defense reaction in vertebrates to combat pathogenic microbes and other harmful effects. Microbes are attacked by aggressive reagents (cytokines, ROS, AMP) of the innate immune system and largely destroyed. If this only partially succeeds, adaptive immunity is also activated to break down harmful agents using specific antibodies. After the work is done, the activated protective inflammation must be shut down, otherwise chronic inflammatory diseases with self-tissue damage can result.

The course of the immune defense process, from activation of innate immunity to resolution of adaptive immunity, must be tightly controlled. According to current knowledge, these highly complex defense mechanisms are controlled by the concerted interaction of countless immune cells, receptors, mediators and signaling molecules. The sophisticated intracellular, intercellular and systemic regulatory mechanisms of innate and adaptive immunity usually ensure that immune defense processes run optimally. In truth, the entire regulatory mechanism has become unmanageably complex, or as the saying goes: “You can’t see the forest for the trees”. And just as a forest is characterized today using terms such as “CO₂ uptake” or “ecological balance”, similar novel concepts are needed to make immune regulation mechanisms more tangible.

Due to the fundamental role of innate immunity in initiating and regulating defense mechanisms, the Innate Balance of Activation Resolution (IBAR) could be a useful term for characterizing the inflammatory status of an organism. According to this concept, the innate equilibrium can be disturbed by excessive activation or incorrect resolution, and becomes pathological if this damages one’s own tissues. Treatment by restoring the balance also needs some “innate resolution factors” that have not been identified so far.

DoNatur has isolated the arthritis drug substance MCS-18 from medicinal plants and has proven its novel anti-rheumatic mechanism on cells and receptors involved in innate immunity. The resolution of pathological inflammation by MCS-18 has been largely confirmed on dendritic cells and macrophages, as well as in animal models of arthritis, multiple sclerosis, type 1 diabetes, and atherosclerosis. The clinical efficacy of MCS-18 in arthritis has already been confirmed in a Phase II trial.

“MCS-18 has achieved survival rates of up to 80 per cent in animal models of septic shock (by endotoxin or by cecal ligation) compared with 0 per cent in control groups after 36 hours. These results are very promising for application of MCS-18 in COVID since septic shock is assumed to be a cytokine storm related to bacterial infections”, said Dr. Franz Kerek, managing director Donatur GmbH.

The virus-invaded lungs trigger a panic attack to regain control. Overactivated macrophages apply immune defense reagents with low protection for self. Destroyed lung cells release DAMPs, alarmins, which reinforce hyperinflammation through feed-back loops, resulting in respiratory failure and death. MCS-18 is expected to intervene along the process (Fig. 1) at ‘C‘ by silencing the uncontrolled activation, and at ‘L’ by resolution of DAMPs, alarmins.

DoNatur is working intensively on the therapeutic application of the active ingredient MCS-18 for the efficient resolution of cytokine storms in COVID-19. First, the inhalation tolerance will be tested on healthy volunteers and the effectiveness and safety will be investigated in phase I / II clinical trials.

CONCLUSION: Efficient control of the cytokine storm could reduce mortality from the current rate of 21 in 1000 CoV patients to the level of a seasonal influenza epidemic, i.e. ~ 4 in 1000 patients. With the main risk of COVID being efficiently reduced, mutant derivatives and future pandemics can be combated more efficiently by vaccination or other means with significantly less burdensome restrictions. DoNatur is open for license-based and scientific co-operations.