Studies Showed Statistically Significant Improvements in Survival in Subjects Treated with Leukine Starting 48 Hours After Acute, High Dose Radiation Exposure without Need for Blood Transfusions or Other Forms of Intensive Supportive Care
Leukine Administration Starting 48, 72, 96 and 120 Hours after Lethal Radiation Exposure:
- Enhanced Recovery of Platelets, Lymphocytes, Neutrophils and Reticulocytes
- Reduced Frequency, Severity and Duration of Infection, Septicemia and Hemorrhage1
Studies Provided the Basis for FDA Approval of Leukine for Treatment of Myelosuppression and Hematopoietic Damage and Dysfunction Resulting from ARS
Lexington, MA – February 18, 2021 — Partner Therapeutics, Inc. (PTx), a commercial biotech company, announces publication of two pivotal studies that provided the basis for approval of Leukine (sargramostim, yeast-derived rhu GM-CSF) to improve survival in patients exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]). The first study, “Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation” (Clayton, et al.) was published February 9, 2021 in Radiation Research. The second study, “Efficacy of Delayed Administration of sargramostim up to 120 hours Post Exposure in a Nonhuman Primate Total Body Radiation Model” (Zhong, et al.), was published in International Journal of Radiation Biology on September 22, 2020.
Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure and H-ARS with resultant infection, bleeding, anemia, and increased risk of death. Leukine is the only FDA approved drug to treat H-ARS that has demonstrated a statistically significant improvement in survival when initiated 48 hours after radiation exposure. Leukine is also the only FDA approved drug for H-ARS to show a survival benefit in the absence of blood transfusions and other intensive forms of supportive care. In H-ARS, Leukine was shown to reverse the effects of radiation-induced pancytopenia by accelerating the recovery of immune cells. Leukine has shown broad hematological effects on subjects (females and males) when treatment was administered as late as 120 hours after irradiation, enhancing platelet, lymphocyte, neutrophil and reticulocyte counts, as well as reducing frequency and severity of infections, septicemia and hemorrhage.2
Clayton et al. concluded: “Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61–90%) vs. 42% (26–59%; P=0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 hours postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.” 3
Zhong et al. concluded, “Delayed sargramostim treatment at 48 hours post-irradiation significantly reduced mortality (p=.0032) and improved hematological parameters including neutrophil but also lymphocyte and platelet counts. Additional delays in sargramostim administration at 72, 96, and 120 hours post-irradiation were also similarly effective at enhancing the recovery of lymphocyte, neutrophil, and platelet counts compared to control. Sargramostim treatment also improved the survival of the animals when administered at up to 96 hours post-irradiation. While sargramostim treatment at 48 hours significantly reduced mortality associated with sepsis (p<=.01), the additional prophylactic treatment with azithromycin did not have clinically significant effects.” 2
“In the event of a large nuclear or radiation emergency, prompt dispersal of time-sensitive therapeutics (i.e. treatment within 24 hour of incident) such as G-CSFs may present logistical challenges. As such, Medical Counter Measures (MCM) that are efficacious with delayed administration may be advantageous in such a scenario.” 2
Leukine, which is FDA designated as an Essential Medicine in the Drug Category: Radiologic-Nuclear threat MCMs, was initially approved in the United States in 1991 and has five hematologic oncology indications. Development of the H-ARS indication was supported with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Contract No. HHSO100201300005I. Efficacy studies of Leukine could not be conducted in humans with ARS for ethical and feasibility reasons. FDA approval for this indication was granted under the “Animal Rule”.
Clinical studies of Leukine in patients undergoing autologous or allogeneic bone marrow transplantation showed improvements in recovery of white blood cells, reduced incidence of severe and life-threatening infections, and improved survival. These trials provided supportive data for this indication. In Leukine clinical studies in human subjects, the most commonly reported side effects included fever, nausea, diarrhea, and vomiting. Hypersensitivity reactions and infusion-related reactions have been reported with Leukine injection. Patients, particularly those with pre-existing lung disease, should be closely observed for such events.
ABOUT ACUTE RADIATION SYNDROME (ARS) AND HEMATOPOIETIC ARS
ARS, also known as radiation sickness or radiation toxicity, occurs when individuals are exposed to high doses of whole-body ionizing radiation that causes systemic traumatic injury.8-12 The first signs of injury appear in organ systems including the hematopoietic system, gastro-intestinal tract, lymphatic system, lungs and, at extremely high exposure levels, the central nervous system. Significant causes of death among patients with ARS include sepsis, infections, bleeding and poor oxygenation/removal of carbon dioxide, all of which may lead to multi-organ failure.4,5,8,9 H-ARS is an acute component of radiation sickness. Exposure to high-dose whole-body ionizing radiation damages the bone marrow, spleen, thymus, lymph nodes and blood cells, resulting in pancytopenia: severely low levels of white blood cells, platelets and red blood cells. Low white blood cell counts, including lymphocytes, eosinophils, monocytes and neutrophils culminates in immunosuppression that leads to development of bacterial, viral and fungal infections and ultimately sepsis. Low platelet counts, or thrombocytopenia, leads to hemorrhage, which impairs oxygenation and increases risk of infection. Low red blood cell levels and destruction of reticulocytes and hemoglobin combined with epithelial cell damage and vasodilation in response to inflammation further compromise oxygenation leading to anemia and ultimately tissue hypoxia.3-5,7-9
ABOUT H-ARS TREATMENT
Treatment of ARS focuses primarily on reducing and treating infections, maintaining hydration, and treating injuries and burns, as well as bone marrow restoration. Administration of GM-CSF or G-CSF is recommended by the World Health Organization and US Department of Health and Human Services, Radiation Emergency Medical Management to improve survival in adults and children, shorten duration of severe neutropenia and minimize infection severity.4-7,9
Leukine is the first drug for H-ARS to demonstrate improved survival when initiated 48 hours after radiation exposure. In June 2018 Leukine was FDA approved for treatment of adult and pediatric patients acutely exposed to myelosuppressive doses of radiation (H-ARS). The US Government first purchased Leukine for potential use in a radiation emergency in 2013, then purchased additional incremental supply in 2016 and 2019.
LEUKINE® (sargramostim) is an immune-modulating therapy that orchestrates immune system responses to restore immune homeostasis. It is a yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF). In addition to growth factor activity, endogenous GM-CSF possesses multifaceted immune properties, including differentiation, maturation, and mobilization of cells that contribute to innate and adaptive immune responses. It has been shown to facilitate cellular signaling, epithelial repair, and other processes that augment immune responses and help defend the body against infection and cancer. 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.
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)
- 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 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 careers.partnertx.com
- Final Report for Study 1017-3493/DIV1890 (Zhong) Authier S, Final Report: rhuGM-CSF [Leukine® (sargramostim)]: Blinded Time to Dosing Efficacy Study in Irradiated Rhesus Primates with Minimal Supportive Care, Citoxlab North America Study No. 1017-3493; Partner Therapeutics Ref No. 1017-3493; August 31, 2018.
- Zhong Y, Pouliot M, Downey AM, Mockbee C, Roychowdhury D, Wierzbicki W, Authier S (2020): Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model, International Journal of Radiation Biology. https://doi.org/10.1080/09553002.2019.1673499
- Clayton NP, Khan-Malek RC, Dangler CA, Zhang D, Ascah A, Gains M, Gardner B, Mockbee C, Keutzer JM, McManus J, Authier S, Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation. Radiat Res. 195, 191-199 (2021). https://doi.org/10.1667/RADE-20-00131.1
- Dainiak N, Medical management of acute radiation syndrome and associated infections in a high-casualty incident, Journal of Radiation Research 2018: 1-11. https://doi.org/10.1093/jrr/rry004
- Yeddanapudi N, Clay MA, Durham DP, Hoffman CM, Homer MJ, Appler JM, Informing CONOPS and medical countermeasure deployment strategies after an improvised nuclear device detonation; the importance of delayed treatment efficacy data. Int’l Journal of Radiation Biology 2020: 96-1 4-11. https://doi.org/10.1080/09553002.2018.1532618
- Gale RP, Armitage JO, Use of molecularly-cloned hematopoietic growth factors in persons exposed to acute high-dose, high-dose rate whole-body ionizing radiation. Blood Reviews 2020:45:100690. https://doi.org/10.1016/j.blre.2020.100690
- Myeloid Cytokines for Treatment of Acute Exposure to Myelosuppressive Doses of Radiation: Hematopoietic Subsyndrome of Acute Radiation Syndrome (H-ARS), US Department of Health and Human Services, Radiation Emergency Medical Management. https://remm.nlm.gov/cytokines.htm
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- Ascah A, Clayton NP, Dangler CA, Khan-Malek R, Authier S, Final Report: rhGM-CSF [Leukine® sargramostim]: Blinded Efficacy Study of Leukine in Irradiated Rhesus Primates, CiToxLAb North America Study No. 1014-2323; Sanofi-Aventis Ref No.: TSK0144; June 16, 2017.