- BREATHE is an adaptive, randomized, double-blind, placebo-controlled trial expected to enroll up to 270 patients, with a planned interim analysis
- FDA has agreed that this study could support registration if successful
- This is the first pivotal study for an anti-GM-CSF therapy known to initiate dosing in COVID-19 patients
- GM-CSF is a pro-inflammatory cytokine up-regulated in COVID-19 patients at risk of developing Acute Respiratory Distress Syndrome (ARDS)
NEW YORK and BASEL, Switzerland, April 15, 2020 / PRNewswire — 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 incidence of mortality by Day 43. Key secondary endpoints include the incidence and duration of mechanical ventilation use during the study, number of days in the ICU, and number of days of inpatient hospitalization. The study is being conducted with an adaptive design and includes a planned interim analysis.
About GM-CSF and 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.3GM-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 a 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 make it a promising target for clinical research.
ARDS is an acute, life-threatening inflammatory lung injury characterized by hypoxia – a lack of oxygen to the tissue – and stiff lungs due to increased pulmonary vascular permeability. ARDS necessitates hospitalization and mechanical ventilation. A rapid increase in patients with ARDS presents a major challenge for the global public health system given limited hospital beds and ventilators. When implementing standard of care, including mechanical ventilation, ARDS has an overall mortality rate of 41%.6
About Roivant Sciences
Roivant Sciences aims to improve health by rapidly delivering innovative medicines and technologies to patients. Roivant does this by building Vants – nimble, entrepreneurial biotech and healthcare technology companies with a unique approach to sourcing talent, aligning incentives, and deploying technology to drive greater efficiency in R&D and commercialization. For more information, please visit www.roivant.com.
Clinical Trial Contact
Siddiqi HK and Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal, J Heart Lung Transpl. 2020. https://doi.org/10.1016/j.healun.2020.03.012.
H... C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/s0140-6736(20)30183-5.
Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. Pre-Print. 2020. https://doi.org/10.1101/2020.02.12.945576.
Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm. 2015;2015:568543. doi:10.1155/2015/568543.
Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016;19(2):181-193. doi:10.1016/j.chom.2016.01.007.
Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. New England Journal of Medicine. 2005 Oct 20;353(16):1685-93.