Safety and efficacy of sargramostim (GM‐CSF) in the treatment of Alzheimer's disease

Abstract

Introduction Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non‐steroidal anti‐inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short‐term treatment of transgenic AD mice with the pro‐inflammatory cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM‐CSF/sargramostim to safely ameliorate AD symptoms/pathology. Methods A randomized, double‐blind, placebo‐controlled trial was conducted in mild‐to‐moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow‐up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. Results Sargramostim treatment expectedly changed innate immune system markers, with no drug‐related serious adverse events or amyloid‐related imaging abnormalities. At end of treatment (EOT), the Mini‐Mental State Examination score of the sargramostim group increased compared to baseline ( P = .0074) and compared to placebo ( P = .0370); the treatment effect persisted at FU1 ( P = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% ( P = .0105); plasma markers of neurodegeneration (total tau and UCH‐L1) decreased 24% ( P = .0174) and 42% ( P = .0019), respectively, after sargramostim treatment compared to placebo. Discussion The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long‐term safety and efficacy of GM‐CSF/sargramostim in AD is warranted.

Immunotherapies for Neurodegenerative Diseases

“…Data from clinical trials shows significant cognitive and memory improvement in groups treated with the 127-amino-acid synthetic recombinant form of GM-CSF, Sargamostim (GM-CSF Leukine), when compared to controls. Moreover, phase 2 trials (NCT01409915) involving Sargamostim have deemed it safe and tolerable for all AD patients ( 67 ). Sargamostim's immunomodulatory and neuroprotective roles are also being investigated in PD.…”

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

“…Potter and associates followed their preclinical murine model ( 158) by a randomized, double-blind, placebo-controlled clinical trial in patients with mild-to-moderate Alzheimer disease (AD) (159). Forty patients were given either placebo or sargramostim 250 µg/m 2 /day subcutaneous injection five days/week for 3 weeks; compared to placebo and baseline, sargramostim recipients showed significant improvement in Mini-Mental State Examination (MMSE) scores, along with a decrease in plasma markers of neurodegeneration, tau and plasma ubiquitin C-terminal hydrolase L1 (UCH-L1), and an increase in amyloid beta (Ab40), an amyloid marker that is decreased in AD (159). Clinical studies with sargramostim therapy in neuroinflammatory disease continue.…”

Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

“…In particular, as for G-CSF, it affects synaptogenesis, neurogenesis, and Aβ cerebral phagocytosis by immune cells, thus providing cognitive improvement in AD mice [119]. Accordingly, a recent clinical trial with sargramostim, a recombinant GM-CSF, found an increase in activated microglia, a 50% decrease in amyloid content, a rise in the synaptic area, and an amelioration in spatial memory [120]. Indeed, its blood levels, together with that of other neurotrophic/hematopoietic factors (e.g., BDNF, SCF), have been found to be reduced in early AD [121], resulting in deficient neurotrophic/hematopoietic brain support.…”