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Roivant Sciences announced today that the first patient was dosed at Temple University Hospital in Philadelphia in an adaptive, randomized, double-blind, placebo-controlled, multi-center pivotal trial evaluating the impact of intravenous (IV) treatment with gimsilumab on mortality in COVID-19 patients with lung injury or ARDS. Dosing will commence at Mount Sinai Hospital in New York City and other trial sites imminently.

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many hospitalized COVID-19 patients experience an overactive immune response consisting of cytokine dysregulation and increased inflammatory myeloid cells that infiltrate the lung, leading to lung injury, ARDS, and ultimately death.¹ Granulocyte macrophage-colony stimulating factor (GM-CSF), a myelopoietic growth factor and pro-inflammatory cytokine, is believed to be a key driver of lung hyper-inflammation and to operate upstream of other pro-inflammatory cytokines and chemokines. Previous evidence from SARS-CoV-1 animal models and emerging data from COVID-19 patients suggest that GM-CSF contributes to the immunopathology caused by SARS-CoV-2 infection in patients with or at risk of developing ARDS.^2-5

Gimsilumab is a fully human monoclonal antibody targeting GM-CSF. Gimsilumab has been tested in numerous non-clinical studies and two prior clinical studies, including a 4-week Phase 1 study in healthy volunteers conducted by Roivant which completed dosing in February. Gimsilumab has demonstrated a favorable safety and tolerability profile based on data collected to date.

“GM-CSF-targeted immunomodulation to address the aberrant host immune response in COVID-19 appears promising for reducing lung injury and death in this aggressive illness,” said Dr. Mandeep Mehra, Professor of Medicine at Harvard Medical School and William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital. “The rapid initiation of this pivotal trial with gimsilumab is impressive given the pressing need for effective therapies that reduce the morbidity encountered with COVID-19.”

“Emerging evidence suggests that GM-CSF may contribute to clinical worsening in COVID-19,” said Dr. Gerard Criner, Professor, and Chair of the Department of Thoracic Medicine and Surgery at the Lewis Katz School of Medicine at Temple University and Principal Investigator for the BREATHE Study at Temple University Hospital. “We are proud to participate in this clinical trial testing gimsilumab in this vulnerable patient population.”

About the BREATHE Study

Roivant’s clinical trial is expected to enroll up to 270 patients with a confirmed diagnosis of COVID-19 and clinical evidence of acute lung injury or ARDS. Subjects will be randomized 1:1 to receive either gimsilumab or placebo. The primary endpoint of the study is the incidence of mortality by Day 43. Key secondary endpoints include the incidence and duration of mechanical ventilation use during the study, the number of days in the ICU, and the number of days of inpatient hospitalization. The study is being conducted with an adaptive design and includes a planned interim analysis.

About GM-CSF & COVID-19

COVID-19 is an infectious disease caused by SARS-CoV-2. COVID-19 has become a global pandemic, with over 2 million confirmed cases and over 125,000 deaths reported to date. Patients with severe cases of COVID-19 experience severe viral pneumonia that often persists despite a decrease in viral load and can progress to lung injury, ARDS, and death.

GM-CSF is a cytokine implicated in many autoimmune disorders that acts as a pro-inflammatory signal, prompting macrophages to launch an immune cascade that ultimately results in tissue damage. GM-CSF has been found to be up-regulated in the serum of COVID-19 patients according to recent data from patients in China.2 The percentages of GM-CSF-expressing CD4+ T cells (Th1), CD8+ T cells, NK cells, and B cells have been observed to be significantly higher in the blood of ICU-admitted COVID-19 patients when compared with healthy controls.3 These reported immunological changes also appear to be more pronounced in ICU-admitted COVID-19 patients versus non-ICU patients.3

GM-CSF boosts the expression of pro-inflammatory cytokines such as TNF, IL-6, and IL-23 in addition to promoting the differentiation of Th1/17 cells and the polarization of macrophages to an M1-like phenotype.4 Increased levels of GM-CSF result in positive feedback which further elevates these inflammatory mediators. In severe COVID-19 patients, it has been suggested that GM-CSF could be the key link between the ‘pulmonary syndrome-initiating capacity’ of pathogenic Th1 cells and the feedback loop of inflammatory monocytes – which in turn secrete additional GM-CSF and IL-6.3 Taken together with the differentially elevated levels of GM-CSF observed in seriously ill COVID-19 patients, GM-CSF’s breadth of activity and its potential role as a central driver of pathology makes it a promising target for clinical research.