Partner Therapeutics Announces Initiation of Clinical Trial to Evaluate Leukine® in Patients with COVID-19 Associated Respiratory Illness

LEXINGTON, Mass., March 24, 2020 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx) announced that Leukine^® (sargramostim, rhu-GM-CSF) is being assessed in the SARPAC trial (sargramostim in patients with acute hypoxic respiratory failure due to COVID-19 – EudraCT #2020-001254-22) at University Hospital Ghent to treat patients with respiratory illness associated with COVID-19.  Major medical centers in Germany, Italy and Spain are considering joining the study.  The study will evaluate the effect of Leukine on lung function and patient outcomes.

"Patients with COVID-19 who progress to acute hypoxic respiratory failure due to COVID-19 have very limited treatment options and a high mortality rate," said Prof. Bart Lambrecht, Principal Investigator for the trial at University Hospital Ghent and the Flanders Institute of Biotechnology (VIB). "We rapidly initiated this study with Leukine, because GM-CSF has profound effects on antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung, and can promote lung repair mechanisms."

Granulocyte macrophage colony stimulating factor (GM-CSF) is essential for the health of the lungs. Alveolar macrophages, a cell type found in the lungs, are dependent on GM-CSF for differentiation and normal functioning. GM-CSF is an immunomodulator that plays a critical role in host defense against pathogens and maintaining proper functioning  of the immune system.¹  GM-CSF confers resistance to influenza by enhancing innate immune mechanisms.² In animal studies, GM-CSF reduced morbidity and mortality due to acute respiratory distress syndrome (ARDS) from viral pneumonia.³ In clinical studies, use of Leukine showed beneficial effects in patients with viral pneumonia.^4,5 Recent data highlight the importance of understanding the immune status of patients and role of immunomodulating agents like GM-CSF to activate the immune system to help clear virus and reduce the risk of secondary infections.⁶

"Partner Therapeutics is committed to investigating Leukine in patients with COVID-19 and we are working with academic and government agencies here in the US and in Europe in this effort," said Dr. Debasish Roychowdhury, Chief Medical Officer at Partner Therapeutics. "We believe, like many investigators and scientists, that GM-CSF has multiple ways by which it may help these patients, including playing a role in clearing the infection, boosting the immune system and repairing damaged tissues."

"In pre-clinical studies, GM-CSF protects the lungs from viral pneumonia and the influenza A virus", stated E. Scott Halstead, MD, PhD, Associate Professor, Penn State University College of Medicine, Department of Pediatrics, Division of Pediatric Critical Care Medicine. "Preliminary data indicate an apparent benefit of inhaled Leukine therapy for autoimmune pulmonary alveolar proteinosis ("aPAP") and suggest it has reduced the need for whole lung lavage therapy for patients receiving treatment. Collectively, the data suggest that aerosolized Leukine may prove to be a meaningful therapy to decrease mortality and increase ventilator-free days in patients with respiratory disorders associated with viruses such as COVID-19 and Influenza A."

For the treatment of COVID-19 associated acute hypoxic respiratory failure and ARDS, Leukine will be used in nebulized form for direct inhalation or through intravenous administration for patients already on a respirator. Nebulized Leukine has been studied in phase 2 and phase 3 randomized trials in pulmonary conditions that affect alveolar macrophages, such as aPAP.  IV administration of Leukine has been studied extensively in other conditions and in phase 2 randomized trials in ARDS.

Leukine was initially approved in the United States in 1991 and has been approved for use in five clinical indications.  Its safety and tolerability profile are well understood.  In 2018, Leukine was approved for use as a medical countermeasure to treat Acute Radiation Syndrome (ARS) and has been procured for use by the U.S. Strategic National Stockpile. Leukine is distributed outside the U.S. on a named-patient basis through PTx's designated program manager, Tanner Pharma Group.  The use of Leukine to treat respiratory disorders associated with COVID-19 is investigational and has not been fully evaluated by any regulatory authority. 

Please see full Prescribing Information for LEUKINE^® at www.leukine.com

About Leukine^â (sargramostim)
Leukine^® is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating factor (rhuGM-CSF) and the only FDA approved GM-CSF.  GM-CSF is an important leukocyte growth factor known to play a key role in hematopoiesis, epithelial repair, and augmentation of innate host defense by effecting the growth and maturation of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell mediated immunity. 

Important Safety Information for LEUKINE^® (sargramostim)

Contraindications

• LEUKINE^® is contraindicated in patients with known hypersensitivity to human granulocyte-macrophage colony stimulating factor such as sargramostim (GM-CSF), yeast-derived products, or any component of LEUKINE^®.

Warnings and Precautions

• Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE^®. If any serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE^® therapy and institute medical management. Permanently discontinue LEUKINE^® in patients with serious allergic reactions.
• LEUKINE^® can cause infusion-related reactions, including respiratory distress, hypoxia, flushing, hypotension, syncope and/or tachycardia. Observe closely during infusion, particularly in patients with preexisting lung disease, as dose adjustment or discontinuation may be required.
• Do not administer LEUKINE^® simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy.
• Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE^® administration. LEUKINE^® should be used with caution and monitored in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure.
• Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE^® administration, particularly in patients with a previous history of cardiac arrhythmia. Use LEUKINE^® with caution in patients with preexisting cardiac disease.
• If ANC > 20,000 cells/mm³ or if WBC counts > 50,000/mm³, LEUKINE^® administration should be interrupted or the dose reduced by half. Twice weekly monitoring of CBC with differential should be performed.
• LEUKINE^® therapy should be discontinued if disease progression is detected during treatment.
• Treatment with LEUKINE^® may induce neutralizing anti-drug antibodies. Use LEUKINE^® for the shortest duration required.
• Liquid solutions containing benzyl alcohol (including LEUKINE^® Injection) or LEUKINE^® for Injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates and low birth weight infants.
• Concomitant use of drugs that can potentiate the myeloproliferative effects of LEUKINE^® should be avoided.

Adverse Reactions

Adverse events occurring in >10% of patients receiving LEUKINE^® in controlled clinical trials and reported in a higher frequency than placebo are:

• In Autologous bone marrow transplantation (BMT) patients–asthenia, malaise, diarrhea, rash, peripheral edema, urinary tract disorder
• In Allogeneic BMT patients–abdominal pain, chills, chest pain, diarrhea, nausea, vomiting, hematemesis, dysphagia, GI hemorrhage, pruritus, bone pain, arthralgia, eye hemorrhage, hypertension, tachycardia, bilirubinemia, hyperglycemia, increase creatinine, hypomagnesemia, edema, pharyngitis, epistaxis, dyspnea, insomnia, anxiety, high glucose, low albumin
• In AML patients–fever, weight loss, nausea, vomiting, anorexia, skin reactions, metabolic laboratory abnormalities, edema

Please see full Prescribing Information for LEUKINE^® at www.leukine.com

Indications and Usage

LEUKINE^® (sargramostim) is a leukocyte growth factor indicated for the following uses:

• LEUKINE^® is indicated to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).
• LEUKINE^® is indicated in adult patients with cancer undergoing autologous hematopoietic stem cell transplantation for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.
• LEUKINE^® is indicated for the acceleration of myeloid reconstitution following autologous peripheral blood progenitor cell (PBPC) or bone marrow transplantation in adult and pediatric patients 2 years of age and older with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL).
• LEUKINE^® is indicated for the acceleration of myeloid reconstitution in adult and pediatric patients 2 years of age and older undergoing allogeneic bone marrow transplantation from HLA-matched related donors.
• LEUKINE^® is indicated for the treatment of adult and pediatric patients 2 years and older who have undergone allogeneic or autologous bone marrow transplantation in whom neutrophil recovery is delayed or failed.
• LEUKINE^® is indicated to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).

About Partner Therapeutics, Inc.:
PTx is an U.S.-based commercial-stage biotech company focused on the development and commercialization of therapeutics that improve health outcomes in the treatment of cancer. PTx's development focus spans the entire range of cancer therapy from primary treatments to supportive care. The company believes in delivering great products with the purpose of creating the best possible outcomes for patients and their families. 

References

Cited References

1. Trapnell BC et al. GM-CSF Regulates Pulmonary Surfactant Homeostasis and Alveolar Macrophage-Mediated Innate Host Defense. Annual Review of Physiology 2002 64:1, 775-802.
2. Halstead ES, et al. GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization. Respir Res. 2018; 19(1):3. doi:10.1186/s12931-017-0708-5
3. 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
4. Herold S, et al. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Resp Crit Care Med doi.org/10.1164/rccm.201311-2041LE
5. Paine R, et al. A randomized trial of recombinant human GM-CSF for patients with acute lung injury. Crit Care Med. 2012 Jan; 40(1): 90–97. doi:10.1097/CCM.0b013e31822d7bf0
6. Hall MW. Immune Modulation in Pediatric Sepsis. J Pediatr Intensive Care. 2019;8(1):42–50. doi:10.1055/s-0038-1676607

Other Relevant References

• Campo I, et al. Inhaled sargramostim and whole lung lavage as therapy of autoimmune pulmonary alveolar proteinosis (aPAP). Eur Respir J. 2016; 46(60). Presented at European Respiratory Society meeting 2016. DOI: 10.1183/13993003.congress-2016.PA3870
• 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
• Luisetti M, et al. Physical properties, lung deposition modeling, and bioactivity of recombinant GMCSF aerosolized with a highly efficient nebulizer. Pulm Pharmacol Ther. 2011; 24(1):123-7. doi:10.1016/j.pupt.2010.08.004
• Presneill JJ, et al. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med. 2002; 166(2):138-43. DOI:10.1164/rccm.2009005
• 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. DOI 10.1186/s40348-016-0055-5
• Subramaniam R, et al. Protecting against post-influenza bacterial pneumonia by increasing phagocyte recruitment and ROS production. J Infect Dis. 2014; 209(11):1827-36. doi:10.1093/infdis/jit830
• Tazawa R, et al. Inhaled GM-CSF for pulmonary alveolar proteinosis. N Engl J Med. 2019; 381(10):923-932. doi: 10.1056/NEJMoa1816216
• Tazawa R, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2010; 181(12):1345-54. doi: 10.1164/rccm.200906-0978OC
• Umstead TM, et al. Lower respiratory tract delivery, airway clearance, and preclinical efficacy of inhaled GM-CSF in a post-influenza pneumococcal pneumonia model. Am J Physiol Lung Cell Mol Physiol. 2020. doi: 10.1152/ajplung.00296.2019
• Weber GF, et al. Pleural innate response activator B cells protect against pneumonia via a GM-CSFIgM axis. J Exp Med. 2014; 211(6):1243-56. doi: 10.1084/jem.20131471
• Xu Z, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020. doi.org/10.1016/S2213-2600(20)30076-X

SOURCE Partner Therapeutics, Inc.

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