Sargramostim (Leukine), a recombinant form of human granulocyte-macrophage colony stimulating factor (GM-CSF) approved for bone marrow stimulation, showed potential as a possible Alzheimer’s disease treatment, a small phase II study suggested.
In a randomized, double‐blind, placebo-controlled trial of 40 people with mild‐to‐moderate Alzheimer’s disease, sargramostim appeared to improve memory, reported Huntington Potter, PhD, of the University of Colorado School of Medicine in Aurora, and colleagues.
After 3 weeks of treatment, Mini‐Mental State Examination (MMSE) scores of the sargramostim group increased compared with baseline (P=0.0074) and with placebo (P=0.0370), they wrote in Alzheimer’s & Dementia: Translational Research and Clinical Interventions. Treatment effects persisted 45 days after treatment ended (P=0.0272).
Sargramostim treatment increased innate immune cell and cytokine measures as expected. No drug‐related serious adverse events or amyloid‐related imaging abnormalities were seen.
The findings suggest “Alzheimer’s can be treated by using a manufactured version of a natural human protein — GM-CSF — to help the body’s own immune system attack the disease,” Potter told MedPage Today.
People with rheumatoid arthritis tend not to get Alzheimer’s disease which is what prompted this trial, Potter said. “We had previously found this protein, 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,” he pointed out. “Naturally increased levels of GM-CSF in people with rheumatoid arthritis may be one reason that they are protected from Alzheimer’s disease.”
The trial included 40 mild-to-moderate Alzheimer’s disease patients randomized to receive subcutaneous injections of either sargramostim (20 participants were treated with 250 mcg/m2/day) or placebo (20 participants had saline) 5 days a week for 3 weeks. Nearly all participants were white; mean ages were 67 for the treatment group and 70 for placebo. On the 30-point MMSE, baseline scores were 17.10 for the sargramostim group and 20.75 for placebo.
The primary outcome was safety. The most common sargramostim-associated adverse events were dermatology-related (16 for sargramostim; five for placebo), gastrointestinal (eight for sargramostim; five for placebo), or headache (eight for sargramostim; two for placebo). Sargramostim treatment led to increases in interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α); a drop in IL-8; and a decrease in albumin/globulin ratio, confirming its expected effect.
At the end of the 3-week treatment period, mean MMSE total score change in the sargramostim group was a statistically significant 1.45 units higher compared with baseline. The difference in mean change from baseline in MMSE total scores between sargramostim and placebo also was significant: 1.80 at the end of treatment and 1.75 at followup 45 days later.
On the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog13), sargramostim showed no statistically significant effect compared with baseline or with placebo at the end of the treatment period. At 45 days, scores on the ADAS-Cog13 were statistically significantly worse in the sargramostim group compared with baseline (P=0.0009) and with placebo (P=0.0147). This returned to non-significance 90 days after treatment ended.
Compared with placebo, plasma markers of amyloid beta changed by 10% (P=0.0105) after sargramostim treatment. Plasma markers of total tau and UCH-L1 decreased 24% (P=0.0174) and 42% (P=0.0019), respectively.
Whether sargramostim’s cognitive benefits were related to glial‐based reductions of Alzheimer’s pathology or other neuronal benefits is unknown, Potter and colleagues noted. “Taken together, the potential broad‐reaching effects of GM‐CSF/sargramostim on the innate immune system and on neuronal function represent a novel approach to Alzheimer’s disease therapy,” they wrote.
“These encouraging results appear to challenge the conventional view that innate immune activation is always harmful in Alzheimer’s disease,” observed John Breitner, MD, MPH, of McGill University in Montreal, who wasn’t involved with the study.
“The findings align with our earlier reports that several inflammatory markers are diminished in the cerebrospinal fluid of cognitively unimpaired elderly with reduced Abeta42, thus probable cerebral amyloid accretion,” Breitner told MedPage Today. “The same does not hold for those with apparent tau along with amyloid pathology. Activation of innate immune activity could therefore be a useful strategy for persons, including asymptomatic persons, who remain in the early stages of Alzheimer’s pathogenesis.”
Findings were limited by the study’s short treatment period and small sample size. “We have FDA approval and funding from the NIH and the Alzheimer’s Association to carry out a longer phase II trial to determine if patients continue to improve with GM-CSF treatment,” Potter said.
The research was supported by the states of Colorado and Florida, the University of Colorado School of Medicine, the University of Colorado Hospital, the Global Down Syndrome Foundation, the Linda Crnic Institute for Down Syndrome, an Alzheimer’s Association Part the Cloud Grant, the Dana Foundation, Don and Sue Fisher, the Hewit Family Foundation, the Sprout Foundation, Marcy and Bruce Benson, Les Mendelson, other philanthropists, and NIH/NCATS Colorado CTSA.
Two co-authors disclosed being inventors on U.S. patents owned by the University of South Florida but not licensed. One co-author disclosed employment with Partner Therapeutics, the manufacturer of sargramostim (Leukine), as of February 2021.