Second Randomized Trial of Leukine® (sargramostim) in COVID-19 Demonstrates Improvement in Lung Function

LEXINGTON, Mass., June 28, 2021 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx) announced top-line results of the U.S.-based iLeukPulm clinical trial of inhaled Leukine (sargramostim, yeast-derived recombinant human granulocyte macrophage colony stimulating factor (GM-CSF)) in hospitalized COVID-19 patients (NCT04411680).¹ This prospective, randomized, controlled, open-label study was conducted at 11 U.S. hospitals. The study evaluated 122 patients with polymerase chain reaction (PCR) test-confirmed SARS-CoV-2 infection who had acute hypoxemia requiring supplemental oxygen. The study was supported by the U.S. Department of Defense's Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in collaboration with the Office of the Deputy Assistant Secretary of Defense for Chemical and Biological Defense's (DASD(CBD)) Chemical and Biological Defense Program (CBDP).

Analysis of 28-day study data demonstrated improved oxygenation as measured by alveolar-arterial oxygen gradient, or P(A-a)O₂, after treatment with inhaled Leukine in combination with standard of care (SOC), compared with SOC alone. Patients on Leukine plus SOC showed an average improvement in oxygenation from baseline, as measured by P(A-a)O₂, of 100 mm Hg (31%) compared to 35 mm Hg (5%) on SOC alone (p = 0.033). 84% of Leukine treated patients had improvement in oxygenation, compared to 64% on the control arm (p = 0.023). Inhaled Leukine was well tolerated and adverse events were generally similar across both arms. Publication of the full results of the study is planned once the analysis of the entire data set is completed.

Study results support the findings of the 81-patient randomized, controlled SARPAC clinical trial in Belgium that demonstrated treatment with inhaled Leukine was safe, well tolerated, and achieved a statistically significant improvement in lung function (NCT04326920).² Improvement in oxygenation (P(A-a)O₂) of at least 33 percent from baseline was seen in 54 percent of patients on the Leukine plus SOC arm versus 26 percent of patients on SOC (p=0.0147). Data from SARPAC also showed that Leukine stimulated expansion of T-cells targeting the SARS-CoV-2 virus, indicating a COVID-19 specific immune response. This immune response, if proven, would be expected to address any variant of the SARS-CoV-2 virus.

"The rationale for the use of inhaled Leukine in COVID-19 hypoxemia is based on the role of GM-CSF as a naturally occurring protein found in the normal lung with important roles for defense against infection. SARS-CoV-2 causes respiratory failure due to destruction of alveolar macrophages and alveolar epithelial cells, driven by viral infection and excessive inflammation. This damage causes impaired diffusion of oxygen into the blood and shunting, where oxygen-rich blood mixes with oxygen-poor blood. When diffusion is poor and shunting occurs, the P(A-a)O₂ gradient rises and provides a surrogate measure of abnormal lung function. Leukine has the potential to limit destruction of lung cells and restore normal GM-CSF signaling in the damaged alveoli." stated Robert Paine, MD, chief of the division of pulmonary medicine at University of Utah and co-principal investigator of the study. "In both the SARPAC and iLeukPulm clinical studies, inhaled Leukine significantly improved P(A-a)O₂ gradient indicating improved oxygenation and diffusion."

Lung alveoli are small, sensitive and difficult to defend, with thin walls that allow for gas exchange under normal conditions. Homeostasis in the lung requires preserving oxygen and carbon dioxide exchange and avoiding pathogen entry, while minimizing inflammation. Under physiological conditions, the lungs are protected by alveolar macrophages (AMs).³ AMs are the first line of defense against inhaled pathogens. AMs neutralize pathogens without inducing inflammation. They also clear debris and help preserve surfactant, thereby maintaining lung function. Under normal conditions, GM-CSF secreted by the alveolar epithelial cells maintains healthy AMs and helps mature recruited "inflammatory" monocytes into anti-inflammatory AMs.

In COVID-19 patients with hypoxemia, the SARS-CoV-2 virus causes acute lung injury by infecting and destroying AMs and alveolar epithelial cells. This compromises oxygenation and leads to build up of debris and inflammation. Additionally, production of GM-CSF is decreased, and monocytes do not mature into macrophages.^4-14

"Inhaled Leukine administered to COVID-19 patients suffering from poor oxygenation provides exogenous GM-CSF to their lungs and 'reprograms' inflammatory monocytes turning them into anti-inflammatory, mature AMs. This helps restore homeostasis to the lung alveoli allowing for improved oxygenation which has been seen in both the SARPAC and iLeukPulm clinical studies," stated E. Scott Halstead, MD, PhD, associate professor of pediatrics at Penn State College of Medicine and co-principal investigator of the study. "Further, inhaled Leukine was safe and well-tolerated with few serious adverse events and demonstrated reduced markers of inflammation."

"Both iLeukPulm and SARPAC show a significant improvement in lung function as measured by oxygenation and confirm tolerability of inhaled Leukine. Importantly, Leukine improved oxygenation even for patients receiving remdesevir and steroids," stated Debasish Roychowdhury, MD, Chief Technology Officer for PTx. "The SCOPE study in non-hospitalized high-risk COVID-19 patients continues to enroll well and we look forward to seeing whether Leukine will improve outcomes for these patients. We are deeply grateful to the patients and investigators for iLeukPulm and SCOPE and to JPEO-CBRND for their support."

Well Tolerated and No Incidences of "Cytokine Storm"
As in the SARPAC study, one important aspect of iLeukPulm was to observe whether Leukine was safe in COVID-19 patients who may be prone to severe inflammation and elevated cytokine levels, which some have characterized as a "cytokine storm". Inhaled Leukine was safe and well tolerated in both studies. In iLeukPulm treatment-emergent adverse events (TEAEs) were generally similar across both arms (68 percent Leukine arm vs. 71 percent SOC arm). Serious AEs were lower on the Leukine arm (19 percent vs. 27 percent), as were Grade 3 and 4 treatment emergent AEs (22 percent Leukine arm vs. 27 percent SOC arm). Key markers of inflammation, such as ferritin and c-reactive protein, had mean reductions over time in both arms, which support the SARPAC finding that addition of inhaled Leukine in these patients does not induce a "cytokine storm" and ameliorates inflammation.

Consistent with Past Research on Sargramostim's Effects on the Lungs
The iLeukPulm and SARPAC results are consistent with data from earlier studies of inhaled sargramostim in acute respiratory distress syndrome (ARDS) and autoimmune pulmonary alveolar proteinosis (aPAP) that demonstrated tolerability and positive benefits in the lungs, including improved oxygenation.^15-19 Prior research in patients with ARDS has shown that sargramostim administered intravenously is safe and associated with a trend toward a reduction in mortality. ²⁰

Additional Studies
Based on data from the SARPAC study which demonstrated the potential of Leukine to stimulate immune cells targeting the SARS-CoV-2 virus, irrespective of strain, PTx initiated the SCOPE study to evaluate inhaled Leukine in a trial of 400 COVID-19 patients in an outpatient setting (NCT04707664).²¹ This study is also supported by the DOD's JPEO-CBRND and will be conducted in the U.S., Mexico, Argentina, Brazil and Colombia.

Also, a 60-patient, double-blind, placebo controlled study of Leukine plus SOC versus SOC alone was initiated in Japan earlier in 2021 (NCT04642950).²² The study is expected to complete in October 2021. Another randomized placebo-controlled study of 30 patients is ongoing in Singapore (NCT04400929).²³ This study evaluates intravenous Leukine administration, and is expected to complete in 2022.

ABOUT LEUKINE
LEUKINE® (sargramostim) is a yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF) Leukine is approved by the U.S. Food and Drug Administration (FDA) and is also held by the U.S. government in the Strategic National Stockpile.

Safety and efficacy of inhaled sargramostim for the treatment of COVID-19 has not been established and sargramostim is not approved for treatment of COVID-19. Sargramostim has a different mechanism of action from recombinant G-CSFs products and data should not be extrapolated.

Leukine is indicated:

• To shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).
• For the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients.
• For the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients two years of age and older.
• For the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients two years of age and older.
• For treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients two years of age and older.
• 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]).

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 absolute neutrophil count (ANC) is greater than 20,000 cells/mm³ or if white blood cell (WBC) counts are greater than 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 percent 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 greater than 10 percent 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, gastro intestinal (GI) hemorrhage, pruritus, bone pain, arthralgia, eye hemorrhage, hypertension, tachycardia, bilirubinemia, hyperglycemia, increased 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

ABOUT PARTNER THERAPEUTICS
PTx, an integrated biotechnology company, focuses on development and commercialization of late-stage therapeutics to improve health outcomes in 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

¹ ClinicalTrials.gov. Study of Sargramostim in Patients With COVID-19 (iLeukPulm). Available at: https://www.clinicaltrials.gov/ct2/show/NCT04411680. Updated May 13, 2021. Accessed June 17, 2021.

² ClinicalTrials.gov. Sargramostim in Patients with Acute Hypoxic Respiratory Failure Due to COVID-19 (SARPAC). Available at: https://www.clinicaltrials.gov/ct2/show/NCT04326920. Updated March 2, 2021. Accessed June 17, 2021.

³ Trapnell BC, Whitsett JA. Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol. 2002;64:775-802. doi: 10.1146/annurev.physiol.64.090601.113847

⁴ Rosler 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

⁵ Morales-Nebreda L, Misharin AV, Perlman H, Budinger GR, The heterogeneity of lung macrophages in the susceptibility to disease.  Eur Respir Rev. 2015 Sep;24(137):505-9. doi: 10.1183/16000617.0031-2015

⁶ Mehta A, Guidot D, Pathophysiology Review Series: Alcohol abuse, the alveolar macrophage and pneumonia, American Journal of the Medical Sciences (2012) 343(3):244-247.  doi: 10.1097/MAJ.0b013e31823ede77

⁷ Mu X, Li Y, Fan G, Tissue resident macrophages in the control of infection and resolution of inflammation, Shock (2021) 55(1):14-23.  doi: 10.1097/SHK.0000000000001601

⁸ Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Chen L, Li J, Wang X, Wang F, Liu L, Zhang S, Zhang Z,  The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing, medRxiv (2020).  doi: 10.1101/2020.02.23.20026690.

⁹ Mould K, Barthei L, Mohning M, Thomas S, McCubbrey A, Danhom T, Leach S, Fingerlin T, O'Connor B, Reisz J, D'Allesandro A, Bratton D, Jakubzick C, Janssen W, Cell origin dictates progamming of resident versus recruited macrophages during acute lung injury, Am J Respir Cell Mol Biol (2017) 57(3):294-306.  doi: 10.1165/rcmb.2017-0061OC

¹⁰  Guth A, Janssen W, Bosio C, Crouch E, Henson P, Dow S, Lung environment determines unique phenotype of alveolar macrophages, Am J Physiol Lung Cell Mol Physiol, (2009), 296:936-946.  doi: 10.1152/apjlung.90625.2008

 ¹¹ Alon R, Sportiello M, Kozlovski S, Kumar A, Reilly E, Zarbock A, Garbi N, Topham D, Leukocyte trafficking to the lungs and beyond: lessons from influenza and COVID-19, Nature Review Immunology (2020)Nov 19. doi: 10.1038/s41577-020-00470-2

¹² Wilk A, Rustagi A, Zhao N, Roque J, Martinez-Colon G, McKechnie J, Ivison G, Ranganath T, Vergara R, Hollis T, Simpson L, Grant P, Subramanian A, Rogers A, Blish C, A single-cell atlas of the peripheral immune response to severe COVID-19, medRxiv, (2020).  doi: 10.1101/2020.04.17.20069930

¹³ Benlyamani I, Venet F, Coudereau R, Gossez M, Monneret G, Monocyte HLA-DR measurement by flow cytometry in COVID-19 patients: an interim review, Cytometry Journal of Quantitative Cell Science (2020).  doi: 10.1002/cyto.a.24249

 ¹⁴ Melms, et. al., A molectular single-cell lung atlas of lethal COVID-19, Nature (2020).  doi: 10.1038/s41586-021-03569-1

¹⁵ Tazawa 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;181:1345-1354. doi: 10.1164/rccm.200906-0978OC

¹⁶ Herold S,Hoegner K, Vadáz 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

¹⁷  Tazawa R, Ueda T, Abe M, et al. Inhaled GM-CSF for pulmonary alveolar proteinosis. N Engl J Med. 2019;381(10):923-932. doi: 10.1056/NEJMoa1816216

¹⁸ Campo I, Mariani F, Paracchini E, et al. Whole lung lavage followed by inhaled sargramostim as therapy of autoimmune pulmonary alveolar proteinosis [abstract]. Am J Respir Crit Care Med. 2016;193:A6438.

¹⁹ Campo I, Mariani F, Paracchini E, et al. Inhaled sargramostim and whole lung lavage (WLL) as therapy of autoimmune pulmonary alveolar proteinosis (aPAP) [abstract]. Eur Respir J. 2016;48:PA3870.

²⁰  Paine III R, Standiford TJ, Dechert RE, et al. A randomized trial of recombinant human GM-CSF for patients with acute lung injury. Crit Care Med. 2012;40(1): 90–97. doi: 10.1097/CCM.0b013e31822d7bf0

²¹ ClinicalTrials.gov. Sargramostim Use in COVID-19 to Recover Patient Health (SCOPE). Available at: https://www.clinicaltrials.gov/ct2/show/NCT04707664. Updated May 25, 2021. Accessed June 17, 2021.

²² ClinicalTrials.gov. A Phase II/III Study of Sargramostim. Available at: https://www.clinicaltrials.gov/ct2/show/NCT04707664. Updated May 10, 2021. Accessed June 17, 2021.

²³ ClinicalTrials.gov. Using GM-CSF as a Host Directed Therapeutic Against COVID-19.. Available at: https://www.clinicaltrials.gov/ct2/show/NCT04400929. Updated July 7, 2020. Accessed June 17, 2021.

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