Partner Therapeutics Announces $35 Million Contract with U.S. Department of Defense for Advanced Development and Emergency Use of Leukine® (rhuGM-CSF) for COVID-19 Acute Hypoxemic Respiratory Failure (AHRF)
Funding will support two randomized, multi-center clinical trials in COVID-19 patients, expansion of manufacturing capacity and potential Emergency Use Authorization (EUA) filing
LEXINGTON, Mass., Aug. 4, 2020 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx), a commercial biotechnology company, today anounced a $35 million milestone-based Other Transaction Agreement (OTA) with the U.S. Department of Defense (DOD) to fund two clinical studies of inhaled Leukine® (sargramostim, rhu-Granulocyte Macrophage-Colony Stimulating Factor "GM-CSF") in patients with COVID-19 associated acute hypoxemia. Through the DOD's Chemical Biological Defense Program COVID-19 efforts, the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense's (JPEO-CBRND) will evaluate the effect of Leukine in improving clinical outcomes, including oxygenation and percent of patients intubated. The first of the two clinical studies (NCT04411680) will be initiated in August 2020 in centers in the U.S., and will be conducted under an Investigational New Drug (IND) Application, approved by the U.S. Food and Drug Administration (FDA) on May 20, 2020.
The milestone-based Firm Fixed Price (FFP) agreement with the JPEO-CBRND will fund two Phase 2 studies to assess the benefits of Leukine in the treatment of patients with acute hypoxemia due to COVID-19. Funding will also support regulatory filings for a potential EUA and expansion of production capacity to meet increased demand. The first of the two clinical studies will commence in August 2020 and will supplement data from more than 60 patients who have completed treatment in the SARPAC study (sargramostim in patients with acute hypoxic respiratory failure due to COVID-19) clinical trial, currently underway at five hospitals in Belgium (NCT04326920).
"GM-CSF is essential for lung health. Emerging data suggest that COVID-19 is associated with immune dysfunction including deficiency of alveolar macrophages and GM-CSF," said Dr. Debasish Roychowdhury, chief medical officer at PTx. "Treatment with Leukine may confer benefit to patients with acute respiratory distress and potentially reduce long term complications. We are grateful to the DOD's JPEO-CBRND for supporting this effort to assess the potential role of Leukine to treat patients with severe COVID-19 infection. Effective, safe and easily administered treatments that halt or reverse the progression of the disease and reduce the risk of long term complications represent an area of significant unmet need in treatment of COVID-19."
In March 2020, PTx announced that Leukine is being assessed in the SARPAC clinical trial currently underway 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 via inhalation in the treatment of COVID-19. In May, Singapore General Hospital also initiated a study of intravenous Leukine in COVID-19 patients (NCT04400929).
"The DOD's support enhances Partner Therapeutics' efforts to rapidly advance the study of Leukine as a treatment to halt COVID disease progression and mitigate long-term organ damage and other complications," said John McManus, chief business officer of PTx. "Leukine has a proven safety profile and there is clinical evidence indicating that it could confer benefit to patients with acute hypoxemia from COVID-19 infection. We look forward to working with JPEO-CBRND to deliver our milestones expeditiously under this agreement."
"We are pleased to work with Partner Therapeutics and excited about the prospects of repurposing already FDA-approved medical countermeasures for the fight against COVID-19," said the JPEO-CBRND's Joint Project Manager for CBRN Medical, Col. Ryan Eckmeier. "Proving a repurposing framework for treating acute hypoxemic respiratory failure is particularly useful to our core mission of protecting our nation's warfighters from CBRN threats, as AHRF is a condition which can also occur with exposure to other CBRN agents."
Leukine is FDA-approved for the treatment of acute radiation syndrome (ARS) and is held in the Strategic National Stockpile. "The potential utility for COVID patients highlights Leukine's promise as a broad-spectrum, dual-use medical countermeasure," added McManus.
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 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.1,2 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.3 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.1-3 Alveolar macrophages can limit the antigen-specific functional responsiveness of T cells in the lung, reducing local pulmonary inflammation.4
Of note, 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 The SARS-CoV-2 virus infects and damages the cellular lining of the lungs.5-7 This is associated with diffuse alveolar damage, severe endothelial injury with the presence of intracellular virus and disrupted cell membranes.8 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-19.9 Breakdown of the epithelial barrier promotes capillary leakage and further lung damage.5-7 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.10 The extensive lung epithelial damage observed in patients with COVID-19 compromises gas exchange which may progress to acute respiratory distress.9
GM-CSF is an immune mediator that drives pulmonary host defense function and stimulates epithelial repair.3 GM-CSF is critical for the growth, maturation, replenishment and function of alveolar macrophages.3,11 GM-CSF, through its effects on alveolar macrophages, has been shown to accelerate respiratory viral clearance.3,12,13Unchecked viral replication in the respiratory tract could be a result of inefficient innate anti-viral immune response.14,15 Further cases of immune dysfunction, marked by low levels of both eosinophils and functional lymphocytes, have been reported in patients with COVID-19.16,17 Systemic elevation of pro- and anti-inflammatory cytokines in severe illnesses can sometimes lead to suppression of circulating leukocyte function, or "immunoparalysis."18-20 GM-CSF has been shown to overcome the immunoparalysis observed in critically ill patients.21,22 Therefore, GM-CSF treatment may exert a local effect on restoration of lung health and function and a systemic effect by resuming immune homeostasis.3,23
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.
ABOUT THE JPEO-CBRND The Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) protects the Joint Force by providing medical countermeasures and defense equipment against chemical, biological, radiological and nuclear (CBRN) threats. JPEO-CBRND's goal is to enable the Joint Force to fight and win unencumbered by a CBRN environment. JPEO-CBRND facilitates the rapid response, advanced development, manufacturing and acquisition of medical solutions, such as vaccines, therapeutics, and diagnostics, to combat CBRN and emerging threats such as COVID-19. To learn more about JPEO-CBRND's COVID-19 response, visit https://www.jpeocbrnd.osd.mil/coronavirus or follow JPEO-CBRND on social media at @JPEOCBRND.
1Haslett 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
2Knapp 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
3Rösler 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
4Blumenthal 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
5Xu 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
6Zou 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
7 Zhao 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.
8Ackermann 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
9Liao 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
10Branchett WJ, Lloyd CM. Regulatory cytokine function in the respiratory tract. Mucosal Immunol. 2019;12(3):589–600. doi: 10.1038/s41385-019-0158-0
11Tazawa 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
12Unkel 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
13Huang 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
14Blanco-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.
15Chu 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.
16 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
17Zheng 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
18Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420(6917):885-891. doi: 10.1038/nature01326
19Fowler 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.
20Munford 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
21Herold 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
22Hall 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
23Hall 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.