Gimsilumab trial starts in first US patient with ARDS and COVID-19

By Dr. Liji Thomas, MDApr 16 2020

The first American patient with COVID-19 and acute respiratory distress syndrome (ARDS) has been put on the drug gimsilumab at Temple University Hospital, as part of the BREATHE clinical trial. The trial, sponsored by Roivant Sciences, will evaluate the effectiveness of intravenous gimsilumab in preventing death in patients with COVID-19 and ARDS.

Several human coronavirus infections, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), are associated with a high incidence of disease and death. The latest coronavirus infection is the so-called COVID-19, caused by the SARS-CoV-2, which has spread from China's Wuhan city to almost all regions of the world.

Novel Coronavirus SARS-CoV-2: This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. The virus shown was isolated from a patient in the U.S. Credit: NIAID-RML

How does the coronavirus cause COVID-19 features?

SARS-CoV-2, the virus responsible for COVID-19, triggers respiratory illness in patients, causing a cytokine storm - an exaggerated immune response - that spirals into lung injury, ARDS, and death. ARDS is a lethal lung complication associated with inadequate oxygenation of the lung tissues and stiffening of the lungs. It requires hospitalization and mechanical ventilation. Even with accepted standards of care, the condition is associated with a high overall mortality rate of 41.6%. Serious sequelae include scarring or a punctured lung.

CD4+ T cells are one type of immune cell in the blood and tissues, that quickly become active after the onset of the COVID-19 infection. This activation is followed by their differentiation into pathogenic T helper cells, releasing a flood of cell signaling molecules such as GM-CSF (granulocyte macrophage-colony stimulating factor).

GM-CSF and acute lung injury

This molecule is a growth factor that is known to play a critical role in producing inflammation in autoimmune diseases. It is also believed to be the reason for the excessive lung inflammation in ARDS. SARS-CoV-1 animal experiments and data from other trials suggest that GM-CSF influences the immune response to SARS-CoV-2 in patients who have or are likely to develop ARDS, thus increasing inflammation in the respiratory system.

GM-CSF levels are high in the serum of COVID-19 patients according to recent Chinese studies. This surge of GM-CSF and similarly inflammation-inducing cytokines cause the recruitment of inflammatory monocyte lineages that produce high levels of IL-6. Thus, many researchers suggest that GM-CSF could be the critical link between the capacity of the Th1 cells to trigger an acute lung injury syndrome, and the feedback loop of inflammatory monocytes, which releases still more GM-CSF and IL-6, to cause a vicious cycle.

Investigators think these monocytes, that are produced at very high levels, enter the lung circulation by the thousands, and potentiate the lung damage, causing respiratory failure and death in short order. "Emerging evidence suggests that GM-CSF may contribute to clinical worsening in COVID-19," Dr. Criner said.

The evidence that the illness is typically mild to moderate in children but more severe in elderly individuals supports the role of the mature immune response in the latter in inducing severe lung injury and organ failure.

How is the trial being carried out?

The enrollment criteria for the study include a confirmed diagnosis of COVID-29 and clinical evidence of acute lung injury or ARDS. The trial is a randomized, double-blinded, placebo-controlled study. Patients are randomized to either gimsilumab or a placebo.

With up to 270 patients being enrolled, the study aims to study the incidence of mortality by Day 43, as well as the number of patients who require to be put on mechanical ventilators, the duration of ventilation, the number of days in the intensive care unit, and the number of days of inpatient hospitalization, within the study period. The trial is being conducted at multiple sites.

What is gimsilumab?

Gimsilumab is a fully human monoclonal antibody that is being evaluated for its potential to treat inflammatory diseases and cancer. It works by targeting

The trial builds on earlier work, including several non-clinical studies and two clinical studies. One of these was a four-week Phase 1 study in healthy volunteers, which ended dosing in February 2020. All available data indicate that gemsilumab is both safe and well-tolerated.

Pulmonary research specialist Dr. Elizabeth Volkmann says, "Targeting GM-CSF represents a promising strategy for curbing lung damage while allowing time for the virus to clear. It is my hope that gimsilumab will reduce mortality from COVID-19 and help improve the lives of those affected by this emerging public health crisis."