SARPAC Clinical Trial of Leukine® (sargramostim, rhu GM-CSF) in Hospitalized COVID-19 Patients Meets Primary Endpoint of Significant Improvement in Lung Function

LEXINGTON, Mass., Feb. 26, 2021 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx) announced top-line results today of the investigator-led SARPAC (Sargramostim in Patients with Acute Hypoxic Respiratory Failure and Acute COVID-19) study of inhaled Leukine^® (sargramostim, yeast-derived recombinant human GM-CSF) in hospitalized COVID-19 patients (NCT04326920).^1,2 This prospective, randomized, open-label study was led by University Hospital Ghent and conducted at five hospitals in Belgium. The study enrolled 81 patients with PCR-confirmed COVID-19 who were suffering from acute hypoxic respiratory failure requiring supplemental oxygen. The full study and translational results are being prepared for publication.

Lung dysfunction resulting in hypoxemia has been a hallmark of severe cases of COVID-19.^3,4,5  SARPAC was launched based on GM-CSF's role in restoring alveolar macrophages that have anti-inflammatory properties and serve to remove pathogens and other debris while maintaining alveolar surfactant.^6,7 This hypothesis has been the basis for prior studies of sargramostim in Acute Respiratory Distress Syndrome (ARDS)^8,9. SARPAC was conducted using inhaled sargramostim to target the lungs. Sargramostim is not approved by U.S. Food and Drug Administration (FDA) for use in COVID-19 or for inhaled administration.

"The results from SARPAC represent a major advance for patients with acute hypoxic respiratory failure due to COVID-19 and validate sargramostim's critical role in the repair and healthy functioning of the lung," said Bart Lambrecht, MD, PhD, Professor of Pulmonary Medicine at The University Hospital Ghent, and Scientific Director of the Center for Inflammation Research at the Flanders Institute of Biotechnology (VIB) in Belgium, and principal investigator of the study. "The study confirms sargramostim's role in restoring the oxygen uptake function of the lung, while at the same time stimulating specific immune cells that fight against the virus."

Top Line Results
The study met the primary endpoint of improved oxygenation after five days of treatment with inhaled sargramostim in combination with standard of care (SOC) compared with SOC alone. Improvement in oxygenation (as measured by alveolar-arterial oxygen gradient) of at least 33% or more from baseline was seen in 54% of patients on the sargramostim plus SOC arm versus 26% of patients on SOC (p=.0147). Improvements in other lung function measures were also noted. 

Well Tolerated and No Incidences of Cytokine Storm
Sargramostim is a cytokine and an important aspect of the study was to observe whether treatment was safe in COVID-19 patients who may be prone to developing a cytokine storm. Inhaled sargramostim was shown to be well tolerated. Adverse events were generally similar across both arms. There were more nose bleeds on the inhaled sargramostim arm (20% vs 5%) that were mostly mild (grade 1 and 2) and transient. Patients receiving sargramostim showed stable or declining levels of key inflammation markers. These findings support that addition of inhaled sargramostim in these patients does not worsen or induce a "cytokine storm," but rather ameliorates it.

Translational Research Points to Other Critical Benefits of Inhaled Sargramostim
Translational research that accompanied SARPAC showed that sargramostim-treated patients had a statistically significant increase in activation of CD8-positive anti-viral T-cells specifically recognizing the COVID-19 virus. "These CD8 cells get activated when they see the virus, and the type of CD8 T-cells we observed are generally seen when you give a vaccination against a virus," Lambrecht said. "On top of that, we also observed virus-specific CD4 helper cells being induced.  The biomarker studies will include the effect of sargramostim in lowering the levels of markers for lung damage and lung fibrosis that has been noted to be elevated in COVID-19 'long haulers'."

Consistent with Past Research on Sargramostim's Effects on the Lungs
SARPAC results are consistent with data from earlier studies of sargramostim in ARDS that demonstrated positive impact on lung health.⁹ "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.⁸ The findings from SARPAC provide strong support for further clinical research to assess the safety and efficacy of inhaled sargramostim in the treatment of COVID-19," stated Dr. Robert Paine, Chief of the Division of Pulmonary Medicine at the University of Utah, adding, "I believe that administering sargramostim by inhalation as soon as patients are being treated in an inpatient or outpatient setting due to COVID-19 could improve time to recovery and facilitate long-term healing."

Additional Studies
In addition to the SARPAC study, inhaled sargramostim is being assessed in the iLeukPulm study, a 120 patient, 2:1 (sargramostim plus standard of care vs. standard of care) randomized study conducted at 11 sites in the United States (NCT04411680).¹⁰ This study is similar in design to SARPAC, assessing the ability of inhaled sargramostim to improve oxygenation in patients hospitalized for COVID-19. Enrollment has concluded in the study and results are expected in Q2 2021. Based on the potential for sargramostim to stimulate immune cells targeting the SARS-CoV-2 virus, irrespective of strain, PTx is also launching the SCOPE trial to evaluate sargramostim in a trial of 400 COVID-19 patients in an outpatient setting (NCT04707664).¹¹ These studies are supported by the U.S. Department of Defense's (DoD) Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND).

"PTx is heartened that this study shows Leukine's potential to help patients in the midst of this pandemic," said Dr. Debasish Roychowdhury, Chief Technology Officer at Partner Therapeutics. "We are deeply grateful for the work being done by the clinical research teams in Belgium and for the patients who have participated in the SARPAC trial. Similarly, we are grateful to the US investigators and patients on the iLeukPulm study.  We look forward to learning the results from that study and to full publication of the data from both SARPAC and iLeukPulm."

ABOUT LEUKINE
LEUKINE^® (sargramostim) is a yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF) Leukine is approved by the FDA and is also held by the U.S. Government in the Strategic National Stockpile.  Leukine is available outside of the United States through a Named Patient Program administered by Tanner Pharma Group.

Safety and efficacy of inhaled sargramostim for the treatment of COVID-19 has not been established and sargramostim is not approved for the 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 2 years of age and older.
• For the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 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 2 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 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, 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  Clinical trials website: Sargramostim in Patients with Acute Hypoxic Respiratory Failure Due to COVID-19 (SARPAC). ClinicalTrials.gov identifier: NCT04326920. Updated December 9, 2020. Accessed February 25, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04326920
² Trial Design Pub of SARPAC: Bosteels C, Maes B, Van Damme K, De Leeuw E, Declercq J, Delporte A, et al. Sargramostim to treat patients with acute hypoxic respiratory failure due to COVID-19 (SARPAC): A structured summary of a study protocol for a randomised controlled trial. Trials (2020) 21(1):491. doi: 10.1186/s13063-020-04451-7.
³Kashani KB. Hypoxia in COVID-19: Sign of Severity or Cause for Poor Outcomes. Mayo Clin Proc. 2020 Jun;95(6):1094-1096. doi: 10.1016/j.mayocp.2020.04.021
⁴ Chandra A, Chakraborty U, Pal J, Karmakar P. Silent hypoxia: a frequently overlooked clinical entity in patients with COVID-19. BMJ Case Rep. 2020 Sep 7;13(9):e237207. doi: 10.1136/bcr-2020-237207
⁵Xie J, Covassin N, Fan Z, et al. Association Between Hypoxemia and Mortality in Patients With COVID-19. Mayo Clin Proc. 2020 Jun;95(6):1138-1147. doi: 10.1016/j.mayocp.2020.04.006
⁶Rosler 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
⁷Luisa Morales-Nebreda et al. Eur Respir Rev. 2015;24:505-509.
⁸Paine 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.
⁹Herold 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.
¹⁰Study of sargramostim in patients with COVID-19 (iLeukPulm). ClinicalTrials.gov identifier: NCT04411680. Updated January 14, 2021. Accessed February 25, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04411680
¹¹ Sargramostim Use in COVID-19 to Recover Patient Health (SCOPE). ClinicalTrials.gov identifier: NCT04707664. Updated January 26, 2021. Accessed February 25, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04707664

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