Partner Therapeutics Announces Initiation of Clinical Trial to Evaluate Leukine® in Respiratory Illness in Patients with COVID-19 at Singapore General Hospital

 

LEXINGTON, Mass., May 28, 2020 /PRNewswire/ --Partner Therapeutics, Inc. (PTx)  a commercial biotech company, announces the initiation of an investigator-initiated randomized, double-blind, placebo-controlled clinical trial of Leukine (sargramostim, rhu-GM-CSF) in patients with acute respiratory failure associated with COVID-19, conducted at Singapore General Hospital (NCT04400929). The study will evaluate the effect of Leukine on lung function and other important patient outcomes.

"There is large body of data regarding the important role GM-CSF plays in lung health. Emerging data clearly suggest that a deficiency of alveolar macrophages and GM-CSF is potentially driving the initial evolution of the disease and that replacement of GM-CSF could lead to a beneficial effect," said Prof. Jenny Guek Hong Low, senior consultant, Department of Infectious Diseases, Singapore General Hospital and principal investigator of the study. "Given the lack of proven effective treatment options and the high morbidity we are seeing in COVID-19, we are very anxious to advance this important research in the weeks ahead," she added.

The Singapore study will be open to patients hospitalized for COVID-19 who are experiencing acute hypoxic respiratory failure. Patients will be randomized to receive intravenous Leukine for five days in addition to local standard of care or to receive placebo plus standard of care. The primary endpoint evaluates Leukine's impact on lung homeostasis by evaluating the difference in oxygenation measures between the two groups.

In March 2020, Partner Therapeutics (PTx) announced that Leukine is being assessed in the SARPAC (sargramostim in patients with acute hypoxic respiratory failure due to COVID-19) clinical trial currently underway at five hospitals in Belgium to treat patients with respiratory illness associated with COVID-19 (NCT04326920). The SARPAC study is the first randomized, controlled clinical trial to assess the benefits of Leukine in the treatment of COVID-19 and is nearing completion.

"GM-CSF is critical for the normal functioning of the lungs. Infections such as COVID-19 damage the components of the lung most dependent on GM-CSF. The increasing number of sites now investigating the use of GM-CSF in these patients is a testimony to the sound scientific rationale that includes the ability of GM-CSF to repair the lung, boost the immune system and clear the infection," said Dr. Debasish Roychowdhury, chief medical officer at Partner Therapeutics. "We continue to work with academic and government agencies in the U.S. to initiate clinical research here."

Leukine was first approved by the FDA in 1991 and has an established safety profile based on treatment in more than 500,000 patients. The use of Leukine to treat respiratory disorders associated with COVID-19 is investigational and has not been fully evaluated by any regulatory authority.

ABOUT LEUKINE
LEUKINE® (sargramostim) is a recombinant human granulocyte-macrophage growth factor (rhuGM-CSF) that stimulates the differentiation, maturation and mobilization of cells involved in the innate and adaptive immune response. It has been shown to facilitate cellular signaling, epithelial repair, and other critical processes that enhance the immune response and help defend the body against infection and cancer. Partner Therapeutics acquired the rights to Leukine in 2018.  Leukine is held by the U.S. Government in the Strategic National Stockpile for use during public health emergencies.  Leukine is available outside of the United States through a Named Patient Program administered by Tanner Pharma Group.

ABOUT GM-CSF IN THE LUNG 
GM-CSF is a naturally occurring protein that is essential for maintaining healthy lungs.  GM-CSF intrinsically controls the differentiation and maturation of monocytes into alveolar macrophages.  Alveolar macrophages function like the vacuum cleaners of the lung by removing cellular debris, particulate material and pathogens. They maintain the homeostasis of surfactant, a substance that coats the inside of alveoli (air sacs) to prevent them from collapsing.  Alveolar macrophages also play an anti-inflammatory role by removing dying neutrophils that infiltrate the space and reducing pro-inflammatory cytokine secretion by macrophages.1,2  Alveolar macrophages can limit the antigen-specific functional responsiveness of T cells in the lung, reducing local pulmonary inflammation.3   In addition to having an effect on the alveolar macrophages, GM-CSF plays a key role in lung repair processes through its direct effect on alveolar epithelial cell proliferation during lung injury. 

GM-CSF has a different mechanism of action from G-CSF (granulocyte colony stimulating factor) and the drugs should not be used interchangeably.

ABOUT GM-CSF IN COVID-19
Viruses causing COVID-19 infect and kill the cellular lining of the lung.4-6 The injury and breakdown of the epithelial barrier due to the infection leads to a cascade of events in the lung that is characterized by accumulation of cellular debris, leakage, flooding of the air sacs and eventual build-up of a sustained hyperinflammatory response. Gas exchange is severely compromised in the lung and COVID-19 patients can develop acute respiratory distress. Alveolar macrophages that are crucial for the removal of dead cells and debris have been found to be completely lost in the severely infected lungs of COVID-19 patients.7 GM-CSF is critical for the growth, maturation and function of alveolar macrophages.8,9 Unchecked viral replication in the respiratory tract could also be a result of inefficient innate anti-viral immune response.10,11 There are reports of additional immune dysfunction, as low levels of both eosinophils and functional lymphocytes have been reported in the COVID-19 patients.12,13  GM-CSF has been shown to accelerate respiratory viral clearance.14,15  Systemic elevation of pro- and anti-inflammatory cytokines in severe illnesses can sometimes lead to suppression of circulating leukocyte function, or "immunoparalysis."16-18 GM-CSF has been shown to overcome the immune dysfunction observed in critically ill patients.19,20 Therefore, GM-CSF treatment may exert a local effect on restoration of normal lung health and function and a systemic effect by returning the immune homeostasis.

ABOUT LEUKINE CLINICAL TRIALS IN COVID-19
Leukine currently is being evaluated in clinical trials in Belgium and Singapore. 

The SARPAC study (Sargramostim in Patients with Acute Hypoxic Respiratory Failure and Acute COVID-19) is a prospective, randomized, open-label controlled study designed to assess whether inhaled Leukine (sargramostim) can restore lung function and other clinical outcomes in COVID-19 patients experiencing acute hypoxemia (NCT04326920).  The study is open to hospitalized patients age 18-80 with a confirmed diagnosis of COVID-19 infections and symptoms of low oxygenation (O2 saturation <93% on minimal 2 L/min O2 and/or PaO2/FiO2 <350). The primary endpoint is improvement in oxygenation following five days of Leukine + standard of care (SOC) or with SOC alone, as measured by pre- and post- treatment PaO2/FiO2 ratios and the alveolar-arterial (P(A-a)) gradient. This study is underway at multiple sites in Belgium and is led by Dr. Bart Lambrecht at University Hospital Ghent in Belgium.

The Singapore trial, titled "Using GM-CSF as a host directed therapeutic against COVID-19 - a Phase 2 Investigator Initiated Trial" is open to hospitalized patients ages 21-80 with acute hypoxic respiratory failure (O2 saturation <94% on minimal 2 L/min O2 and/or PaO2/FiO2 <350) due to COVID-19 who are randomized to receive Leukine intravenously for five days in addition to local SOC (treatment arm) or SOC alone (placebo group) for five days (NCT04400929).  The primary endpoint is the difference in the mean change in oxygenation (P[A-a]O2 gradient) between the two groups at day six compared to day one.  The study is led by Dr. Jenny Guek Hong Low, Senior Consultant, Department of Infectious Diseases, Singapore General Hospital.

ABOUT PARTNER THERAPEUTICS
PTx is an integrated biotechnology company focused on the development and commercialization of late-stage therapeutics that improve health outcomes in the treatment of cancer and other serious diseases. The company believes in delivering products and supporting medical teams with the purpose of achieving superior outcomes for patients and their families. Visit www.partnertx.com

REFERENCES
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3Blumenthal RL, et al. "Human alveolar macrophages induce functional inactivation in antigen-specific CD4 T cells." Journal of Allergy and Clinical Immunology 2001; 107(2): 258-264
4Xu H et al. "High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa." International Journal of Oral Science (2020) 12:8
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Liao M et al "The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing."  medRxiv. February 23, 2020.
8 Rösler & Herold. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia – a new therapeutic strategy? Mol Cell Pediatr. 2016; 3(1):29. 
9 Tazawa et al., Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 181, 1345-1354 (2010).
10Blanco-Melo D. et al. SARS-CoV-2 launches a unique transcriptional signature from in vito, ex vivo and in vivo systems. https://doi.org/10.1101/2020.03.24.004655.
11Chu H, Chan JF, Wang Y, Tsz-Tai Yuen T, et al. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19. Clinical Infectious Diseases, ciaa410, https://doi.org/10.1093/cid/ciaa410
12 Du Y. et al. "Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study." Am J Respir Crit Care Med. 2020 Apr 3.
13Zheng, M., Gao, Y., Wang, G. et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol (2020). https://doi.org/10.1038/s41423-020-0402-2
14 Unkel B, et al. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. J Clin Invest. 2012; 122(10):3652–3664. doi: 10.1172/JCI62139
15 Huang F-F, et al. GM-CSF in the Lung Protects against Lethal Influenza Infection. Am J Respir Crit Care Med. 2011;184(2):259-68. doi: 10.1164/rccm.201012-2036OC
16Cohen J. 2002. The immunopathogenesis of sepsis. Nature 420:885-891.
17Fowler AA, et al. Development of the adult respiratory distress syndrome: progressive alteration of neutrophil chemotactic and secretory processes. Am. J. Pathol. 116:427– 435.
18Munford RS, et al. 2001. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am. J. Respir. Crit. Care Med. 163:316 –321
19Herold S, et al. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Resp Crit Care Med 2014; 189(5):609-11. doi:10.1164/rccm.201311-2041LE
20Hall et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011; 37:525–532. doi:10.1007/s00134-010-2088-x

 

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