Study findings published in Alzheimer’s & Dementia: Translational Research and Clinical Interventions suggest Leukine® leads to significant reversal of cognitive impairment and normalizes blood-based biomarkers of dementia in patients with mild-to-moderate Alzheimer’s disease.
Study findings published in Alzheimer’s & Dementia: Translational Research and Clinical Interventions suggest Leukine® (sargramostim), a yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF), leads to significant reversal of cognitive impairment and normalizes blood-based biomarkers of dementia in patients with mild-to-moderate Alzheimer’s disease (AD).
Leukine comes from Partner Therapeutics (PTx), who received Orphan Drug Designation for the drug in September 2019 for the potential treatment of Stage IIb through IV melanoma.
Currently, Leukine is indicated to shorten time to neutrophil recovery following induction chemotherapy in patients 55 years and older with acute myeloid leukemia and to increase survival in both adults and children up to 17 years of age who are exposed to myelosuppressive doses of radiation, among other indications.
In mid-2020, PTx also initiated a U.S. clinical trial and a trial in Singapore to evaluate Leukine as a potential management option for coronavirus disease 2019 (COVID-19).
The rationale for the trial, according to a statement made by study investigator Huntington Potter, Ph.D., was based on the observation that patients with rheumatoid arthritis have a low rate of AD.
“We had previously found GM-CSF, which is increased in the blood of people with rheumatoid arthritis, reduced amyloid deposition in Alzheimer’s mice and returned their poor memory to normal after a few weeks of treatment,” Potter said. “Thus, naturally increased levels of GM-CSF in people with rheumatoid arthritis may be one reason that they are protected from AD. Human GM-CSF is the active compound in the known human drug Leukine, and we are the first to study its effect on people with AD.”
In the randomized, double-blind, placebo-controlled Phase II trial, Dr. Potter and colleagues randomized participants with mild-moderate AD to injections of Leukine (n=20) at 250 mcg/m2/day for five days/week for a total of three weeks or placebo (n=20) for five days/week for three weeks.
Treatment with Leukine was considered safe and well-tolerated by patients in the study. The most common adverse events (AEs) associated with Leukine were dermatologic, gastrointestinal and headaches, all of which were expected for the drug. There were no serious AEs associated with Leukine in this study.
Cognitive measures of memory, as assessed using the Mini-Mental State Exam (MMSE), significantly improved by nearly two points in the Leukine group at follow up compared with baseline (p=0.0074). In addition, patients treated with Leukine also fared significantly better after three weeks compared with the placebo arm (p=0.0370). Improvements lasted for up to 45 days following treatment (p=0.0272).
Also, treatment with Leukine was associated with a 10% increase in plasma amyloid marker Abeta40, which is typically decreased in patients with AD (p=0.0105). There were also decreases in plasma markers of neurodegeneration, including a 24% decrease in total Tau (p=0.0174) and a 42% decrease in UCH-L1 (p=0.0019), compared with placebo.
“These results suggest that short-term Leukine treatment leads to innate immune system activation, cognition and memory improvement, and partial normalization of blood measures of amyloid and tau pathology and neuronal damage in participants with mild-to-moderate Alzheimer’s disease,” Potter said.
Leukine also led to increases in innate and other immune cells and modulated cytokine measures. Potter noted that this “surprising finding that stimulating the innate immune system may be a new treatment approach induced us to start a larger trial of Leukine in Alzheimer’s disease with more participants treated over a longer time.”
The new trial will be backed by the Alzheimer’s Association/Part The Cloud, the Global Down Syndrome Foundation, the University of Colorado and another large grant from the National Institute on Aging.
“Leukine has unique immunomodulatory properties, and we commend Professor Potter and his team for taking their observations in rheumatoid arthritis and “chemo-brain” and applying them to Alzheimer’s disease,” said Chief Technology Officer of PTx Debasish Roychowdhury. “The study was rigorously conducted with numerous measures aimed at studying the effect on the clinical and pathological parameters while also discerning the basic mechanism. We are excited to see that Leukine, even in the short term, can potentially be disease modifying. This study adds to a growing body of research indicating the potential benefits of Leukine’s effects on tissue resident macrophages, such as microglial cells in AD or alveolar macrophages in aPAP or severe COVID-19.”
