15/09/2020

Bart Lambrecht (VIB-UGent Center for Inflammation research) has taken the lead in several clinical trials that are running under the promotorship of University Hospital Ghent across Belgium, in partnership with VIB. Some trials repurpose existing drugs to treat patients infected with COVID-19. A first trial is evaluating the effect of inhaled Leukine® on lung function and patient outcomes. A second approach focuses on several existing rheumatism medications to alleviate the excessive inflammatory reaction in severely affected COVID-19 patients. Two other trials employ new drugs to target the pro-inflammatory and pro-coagulant complement system. 

 

Leukine® against COVID-19
Alveolar macrophages, a cell type in the lungs, depend on the growth factor GM-CSF for differentiation and normal functioning. GM-CSF plays a critical role in the defense against viruses and maintaining proper function of the immune system and gas exchange of the lungs.

The growth factor provides resistance to influenza and, in animal studies, GM-CSF reduced mortality due to viral pneumonia. Recent data highlight the importance of understanding the immune status of patients and the activation of the immune system to help clear viruses
and reduce the risk of secondary infections.

Leukine® is a yeast-derived version of GM-CSF, developed by Partner Therapeutics. It was initially approved in the United States in 1991 and has been approved for use in five clinical indications. Its safety and tolerability profile are well understood. 

“Patients with COVID-19 who progress to acute hypoxic respiratory failure due to COVID-19 have very limited treatment options and a high mortality rate,” says Bart Lambrecht. “We rapidly initiated this study with Leukine® because GM-CSF has profound effects on antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung, and can promote lung repair mechanisms.”

For the treatment of COVID-19 associated acute hypoxic respiratory failure, Leukine® is used as a nebulized form for direct inhalation. Nebulized Leukine® has previously been studied in phase 2 and phase 3 randomized trials in lung conditions that affect alveolar macrophages.
IV administration of Leukine® has been investigated extensively in other conditions, including sepsis, and was found to be safe. Currently, more than 60 patients are enrolled in this Leukine® trial in Belgium. 

Rheumatism medication against COVID-19
University Hospital Ghent, VIB and the Belgian Heath Care Knowledge Centre (KCE) are testing existing biologicals normally used to treat rheumatic diseases for their potential to also mitigate the excessive inflammatory reaction in COVID-19 infections. In doing so, they could prevent or limit lung damage. 

In about 20% of hospitalized COVID-19 patients the infection leads to severe lung damage. The patient cannot take up sufficient oxygen into the blood due to the excessive inflammation in the lung alveoli, which leads to shortness of breath and confusion. This type of severe lung inflammation is initiated by cytokines (inflammatory molecules that also play an important role in rheumatism and gout).

“Research from China and Italy shows that more cytokines are present in patients that are being ventilated on intensive care,” says Bart Lambrecht (VIB-UGent Center for Inflammation Research) who coordinates the study. “Sometimes these cytokines are present in such
great numbers that we call it a ‘cytokine storm’.”

The new treatment aims to use medication for rheumatism to mitigate the excessive inflammatory reaction and resulting lung damage. In the study, 342 patients with severe COVID-19 infection and early signs of a cytokine storm will be treated with the medication anakinra (Kineret®, an inhibitor of interleukine-1), tocilizumab (Roactemra®, an inhibitor of the interleukin-6 receptor) or siltuximab (Sylvant®, an inhibitor of
interleukin-6). 

A group of control patients (1 in 5 of the study’s participants) only receive the current standard treatment, which can even includeexamethasone, a proven anti-inflammatory agent. “The studies from abroad show that up to 75% of the patients with this severe
form of COVID-19 experience a favorable effect when given medication against rheumatism, but this was not compared to the standard treatment. We have to find out which of the rheumatism medications works best and whether combination therapy might work even better.
At the moment, there is too much experimentation with these treatments. We hope our study brings clarity about the mechanisms and possible side effects,” says Bart Lambrecht.

The study was financed by the KCE, which co-designed the study. “Our clinical research teams have worked day and night to get this on the rails as quickly as possible. Everyone felt the urgency. Procedures that normally take weeks, were now completed within 48 hours. We
currently have more than 90 patients enrolled in the trial,” says Bart Lambrecht.

Complement system as a new target
The complement system is a complicated cascade of proteins that gets activated in response to infection and tissue damage. Autopsy studies from severe COVID-19 patients have revealed that the complement system is activated early in disease and could be responsible for causing coagulation problems in the lungs and recruitment of the inflammatory cells that are responsible for the cytokine storm, late in the disease.

Studies from the Lambrecht preclinical lab have shown that blocking complement can stop some of the most severe lung damage caused by lung viruses and improve survival. Two clinical trials launched by the Lambrecht team tap into the complement system. In a first study,
81 patients will be treated with Zilucoplan, a small molecule C5 complement inhibitor from UCB Pharma. Another study will check the safety and feasibility of targeting C2 complement with monoclonal antibody Argx117 from Biotech company argenx. “The complement is such an upstream regulator of lung inflammation during COVID-19, that we believe that blocking it early could have a profound impact on disease progression in patients with moderate disease”.

Finally, Bart Lambrecht stresses that VIB has been instrumental in setting up these trials in the hospital setting. The VIB-UGent Center for Inflammation Research, within the framework of the Grand Challenges Program, is doing molecular research to see who will most benefit
from these new and existing treatments, so that the cytokine storm can be better prevented in future infections. 

“There is extensive collaboration between all the basic science labs and VIB Core facilities. With the Singularity platform, we are doing scRNA sequencing, CITESeq
analysis and 30 color flow panels. “This is VIB at its best,” says Bart Lambrecht. “All the MDs that work in our center as basic scientists in the MD/PhD track, have volunteered to become the clinical trial doctors, returning to their posts in the hospital. They are the real heroes who made these clinical studies possible.”

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