Partner Therapeutics Initiates Patient Enrollment in U.S. Clinical Trial Evaluating Leukine® (rhuGM-CSF, sargramostim) in COVID-19 Patients

LEXINGTON, Mass., Aug. 25, 2020 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx), a commercial biotechnology company, announced today that the first patient has been enrolled in the iLeukPulm clinical trial, a randomized phase 2 study of inhaled Leukine (sargramostim, rhu-GM-CSF) in hospitalized COVID-19 patients with acute hypoxemia [NCT04411680].  This study will evaluate the safety and efficacy of sargramostim in combination with institutional standard of care on clinical outcomes in these patients. A majority of patients hospitalized for COVID-19 experience respiratory distress, also known as acute hypoxemia, that requires oxygen support. 

Dr. Robert Paine, chief of the division of pulmonary medicine at the University of Utah, and Dr. E. Scott Halstead, associate professor of pediatrics at Penn State College of Medicine, are principal investigators of the study.  The iLeukPulm study is supported by the U.S. Department of Defense's (DoD) Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), as part of a $35 million contract for the advanced development and emergency use of Leukine for COVID-19 treatment.  The U.S. Food and Drug Administration (FDA) has agreed to the study design.  The study is currently enrolling patients at University of Utah Health.  Additional sites are expected to join the study in the coming weeks.

"Prior research in patients with acute respiratory distress syndrome has shown that sargramostim administered intravenously is safe and associated with a trend toward a reduction in mortality.¹  These findings provide strong support for clinical research to assess the safety and efficacy of sargramostim in the treatment of COVID-19 infection," stated Dr. Paine, adding, "I believe that administering sargramostim by inhalation as soon as patients are hospitalized and require oxygen due to COVID-19 could improve time to recovery, facilitate long-term healing of the lung, and reduce the need for invasive procedures such as mechanical ventilation."

"GM-CSF is a naturally occurring protein that is essential for healthy lung function," said Dr.  Halstead. "More specifically, research shows that sargramostim can reduce the risk of secondary infection, accelerate the removal of debris caused by pathogens, and stimulate alveolar epithelial cell healing during lung injury. The iLeukPulm study is an important clinical trial to assess whether inhaled sargramostim can help COVID-19 patients who have progressed to the point of requiring oxygen."

Sargramostim also is being studied in the SARPAC (sargramostim in patients with acute hypoxic respiratory failure due to COVID-19) clinical trial, an investigator-led study currently enrolling patients at five treatment centers in Belgium.  The SARPAC trial of inhaled sargramostim includes extensive immune profiling and biomarker analyses [NCT04326920].  A separate investigator-initiated study of intravenous sargramostim to treat COVID-19 was initiated in June at Singapore General Hospital [NCT04400929].

"iLeukPulm is designed to evaluate the utility of sargramostim in COVID-19, including the ability to prevent critical illness and need for ICU care as well as its effectivess in improving clinical outcomes including delayed pulmonary damage," said Fiona Garner, executive director of clinical development at PTx. She added, "We are very grateful to the investigators and their teams for their focus on gathering data from well-conducted research, even in these difficult and trying times for the health care system, and to Department of Defense and FDA for their support."

ABOUT LEUKINE
LEUKINE® (sargramostim) is a recombinant human granulocyte-macrophage colony stimulating 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 approved by the FDA. Leukine also is held by the U.S. Government in the Strategic National Stockpile and 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 resident alveolar macrophages as well as 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.^2,3  GM-CSF leads the immune functions of alveolar macrophages and dendritic cells through activation of both the innate and adaptive immune responses. Following a pulmonary viral infection, activation of both immune systems accelerates viral clearance. Through direct interaction with alveolar epithelial cells, GM-CSF also improves epithelial repair processes during lung injury. In response to infection, GM-CSF is released from alveolar epithelial cells in an autocrine manner to stimulate epithelial repair and barrier restoration.⁴ Additionally, alveolar macrophages maintain the homeostasis of surfactant, a substance that coats the inside of alveoli (air sacs) to prevent them from collapsing, and play an anti-inflammatory role by removing dying neutrophils that infiltrate the space and reducing pro-inflammatory cytokine secretion by macrophages.^2-4  Alveolar macrophages can limit the antigen-specific functional responsiveness of T cells in the lung, reducing local pulmonary inflammation.⁵

Of note, rhuGM-CSF has a different mechanism of action from recombinant G-CSF (granulocyte colony- stimulating factor) products and the drugs should not be used interchangeably.

ABOUT GM-CSF IN COVID-19
The SARS-CoV-2 virus infects and damages the cellular lining of the lungs.^6-8 This is associated with diffuse alveolar damage, severe endothelial injury with the presence of intracellular virus and disrupted cell membranes.⁹ The alveolar macrophages that are crucial for the removal of cellular debris are almost completely destroyed in the severely-infected lungs of patients with COVID-19.¹⁰ Breakdown of the epithelial barrier promotes capillary leakage and further lung damage.^6-8 Control of viral spread depends on interactions between epithelial cells and immune cells, mediated by cytokine signaling and cell–cell contacts. After viral clearance, activated immune cells and debris must be eliminated to avoid hyperactivation of the immune system that can further exacerbate lung epithelial damage.¹¹ The extensive lung epithelial damage observed in patients with COVID-19 compromises gas exchange which may progress to acute respiratory distress.¹⁰   

GM-CSF is an immune mediator that drives pulmonary host defense function and stimulates epithelial repair.⁴  GM-CSF is critical for the growth, maturation, replenishment and function of alveolar macrophages.^4,12  GM-CSF, through its effects on alveolar macrophages, has been shown to accelerate respiratory viral clearance.^4,13,14  Unchecked viral replication in the respiratory tract could be a result of inefficient innate anti-viral immune response.^15,16 Further cases of immune dysfunction, marked by low levels of both eosinophils and functional lymphocytes, have been reported in patients with COVID-19.^17,18 Systemic elevation of pro- and anti-inflammatory cytokines in severe illnesses can sometimes lead to suppression of circulating leukocyte function, or "immunoparalysis."^19-21 GM-CSF has been shown to overcome the immunoparalysis observed in critically ill patients.^22,23 Therefore, GM-CSF treatment may exert a local effect on restoration of lung health and function and a systemic effect by resuming immune homeostasis.^4,24

ABOUT LEUKINE CLINICAL TRIALS IN COVID-19
In addition to the U.S. study described in this press release, Leukine 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) (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
¹Paine R, Standiford TJ, Dechert RE, Moss M, Martin GS, Rosenberg AL, et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med. 2012;40(1):90–97.

²Haslett C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med. 1999;160:S5–S11. doi: 10.1164/ajrccm.160.supplement_1.4

³Knapp S, Leemans JC, Florquin S, et al. Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia. Am. J Respir Crit Care Med. 2003;167:171–179. doi: 10.1164/rccm.200207-698OC

⁴Rösler B, Herold S. 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. doi: 10.1186/s40348-016-0055-5

⁵Blumenthal RL, Campbell DE, Hwang P, et al. Human alveolar macrophages induce functional inactivation in antigen-specific CD4 T cells. J Allergy Clin Immunol. 2001;107(2):258-264. doi: 10.1067/mai.2001.112845

⁶Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8. doi: 10.1038/s41368-020-0074-x

⁷Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14(2):185-192. doi: 10.1007/s11684-020-0754-0

⁸Zhao Y, Zhao Z, Wang Y, et al. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med. 2020. doi: 10.1164/rccm.202001-0179LE. Online ahead of print.

⁹Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-128. doi: 10.1056/NEJMoa2015432

¹⁰Liao M, Liu Y, Yuan J, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020;26(6):842–844. doi: 10.1038/s41591-020-0901-9

¹¹Branchett WJ, Lloyd CM. Regulatory cytokine function in the respiratory tract. Mucosal Immunol. 2019;12(3):589–600. doi: 10.1038/s41385-019-0158-0

¹²Tazawa R, Trapnell BC, Inoue Y, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2010;181(12):1345-1354. doi: 10.1164/rccm.200906-0978OC

¹³Unkel B, Hoegner K, Clausen BE, et al. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. J Clin Invest. 2012; 122(10):3652–3664. doi: 10.1172/JCI62139

¹⁴Huang FF, Barnes PF, Feng Y, et al. GM-CSF in the lung protects against lethal influenza infection. Am J Respir Crit Care Med. 2011;184(2):259-268. doi: 10.1164/rccm.201012-2036OC

¹⁵Blanco-Melo D, Nilson-Payant BE, Liu W, et al. SARS-CoV-2 launches a unique transcriptional signature from in vito, ex vivo, and in vivo systems. doi: 10.1101/2020.03.24.004655. Preprint.

¹⁶Chu H, Chan JF, Wang Y, 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. Clin Infect Dis. 2020;ciaa410. doi: 10.1093/cid/ciaa410. Online ahead of print.

¹⁷ Du Y, Tu L, Zhu P, et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study. Am J Respir Crit Care Med. 2020;201(11):1372-1379. doi: 10.1164/rccm.202003-0543OC

¹⁸Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020 ;17(5) :533-535. doi: 10.1038/s41423-020-0402-2

¹⁹Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420(6917):885-891. doi: 10.1038/nature01326

²⁰Fowler AA, Fisher BJ, Centor RM, Carchman RA. Development of the adult respiratory distress syndrome: progressive alteration of neutrophil chemotactic and secretory processes. Am J Pathol. 1984;116(3):427-435.

²¹Munford RS, Pugin J. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med. 2001;163(2):316-321. doi: 10.1164/ajrccm.163.2.2007102

²²Herold S, Hoegner K, Vadasz I, 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):609-611. doi:10.1164/rccm.201311-2041LE

²³Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37(3):525–532. doi:10.1007/s00134-010-2088-x

²⁴Hall MW, Joshi I, Leal L, Ooi EE. Immune modulation in COVID-19: Strategic considerations for personalized therapeutic intervention. Clin Infect Dis. 2020;ciaa904. doi:10.1093/cid/ciaa904. Online ahead of print.

View original content to download multimedia:http://www.prnewswire.com/news-releases/partner-therapeutics-initiates-patient-enrollment-in-us-clinical-trial-evaluating-leukine-rhugm-csf-sargramostim-in-covid-19-patients-301117592.html

SOURCE Partner Therapeutics, Inc.