Roivant Provides Updates for Pivotal BREATHE Clinical Trial Evaluating Gimsilumab in COVID-19 Patients for the Prevention and Treatment of Acute Respiratory Distress Syndrome

NEW YORK and BASEL, Switzerland, May 13, 2020 /PRNewswire/ -- Roivant Sciences today announced several updates for its adaptive, randomized, double-blind, placebo-controlled, multi-center pivotal BREATHE trial evaluating the impact of intravenous (IV) treatment with gimsilumab on mortality in COVID-19 patients with lung injury or ARDS.

The independent Data Monitoring Committee (DMC) for BREATHE unanimously recommended that the trial continue after a pre-specified safety assessment evaluating data from the first 10% of randomized subjects after six days of follow-up.

In addition, Roivant recently amended the protocol to permit the use of investigational antivirals (e.g. remdesivir) during the study, as well as treatment with convalescent plasma prior to enrollment. 56 patients have been enrolled in the study to date, and a total of 7 sites have been initiated in New York, Philadelphia, Detroit, New Orleans, Dallas, and Atlanta.

"We are pleased with the rapid progress we have made to date on the BREATHE program. The adjustments to our protocol reflect our desire to ensure patients receive the best possible treatment.  We believe gimsilumab may prove to be complementary with antivirals and convalescent plasma and anticipate providing a definitive answer to the question of whether an anti-GM-CSF antibody can provide benefit to COVID-19 patients," said Simon Lowry, MD, the program's lead.

"We believe an anti-GM-CSF treatment may help manage the hyperactive immune response observed in the most severe cases of COVID-19.  We are pleased to be participating in this important program and look forward to further enrollment," said Kusum Mathews, MD, Assistant Professor, Division of Pulmonary, Critical Care, & Sleep Medicine, Department of Medicine at Mount Sinai.

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. 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 blocking GM-CSF could reduce the immunopathology caused by SARS-CoV-2 infection in patients with or at risk of developing ARDS.

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.

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. Work on the trial is being conducted by Kinevant Sciences, a wholly owned subsidiary of Roivant Sciences. Additional information is available at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT04351243).

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 4 million confirmed cases and over 290,000 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.¹ 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.² These reported immunological changes also appear to be more pronounced in ICU-admitted COVID-19 patients versus non-ICU patients.²

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 a M1-like phenotype.³ 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-6.² 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.

About ARDS
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%.⁴

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 https://roivant.com.  

1. Huang 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.
2. 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.
3. Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm. 2015;2015:568543. doi:10.1155/2015/568543.
4. 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.

SOURCE Roivant Sciences

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