Sargramostim, Immune System Activator, May Aid Cognition, Small Trial Finds

People with mild-to-moderate Alzheimer’s disease  treated for three weeks with sargramostim, a medication that activates the immune system, showed improvements in cognition in a small clinical trial.

These results support further investigation of sargramostim — and, more generally, the strategy of targeted immune activation — in treating Alzheimer’s, its researchers said.

Findings were published in Alzheimer’s & Dementia: Translational Research and Clinical Interventions, in the study, “Safety and efficacy of sargramostim (GM‐CSF) in the treatment of Alzheimer’s disease.”

The immune system helps to protect the body from disease-causing invaders by inducing inflammation. Alzheimer’s is generally believed to be characterized by increased inflammation, particularly within the brain, which is thought to drive the disease. Emerging research, however, suggests that the role of inflammation in Alzheimer’s is more nuanced.

This study builds on previous findings that people with rheumatoid arthritis (RA) — an autoimmune disease where the immune system attacks healthy tissue in joints — are at a lower risk of Alzheimer’s. Although this was originally thought to result from RA patients taking certain kinds of anti-inflammatory medications, newer findings suggest this could be because certain pro-inflammatory molecules are present at higher levels in people with RA.

Specifically, prior work has suggested that a pro-inflammatory signaling molecule called granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) could protect against Alzheimer’s.

A team led by researchers at the University of Colorado reported the results of a Phase 2 clinical trial (NCT01409915) that evaluated the safety and efficacy of sargramostim given Alzheimer’s patients.

Sargramostim contains a recombinant (lab-made) version of GM-CSF. It is currently approved, under the brand name Leukine, as a treatment to boost the activity of the immune system in conditions where the immune system is impaired (e.g., some kinds of cancer). Leukine is marketed by Partner Therapeutics, which acquired the medication from its initial developer Sanofi.

In the trial, which was sponsored by the University of Colorado, 40 mild-to-moderate Alzheimer’s patients were randomized to either sargramostim (at a standard dosage of 250 micrograms/square meter/day for five days each week) or to a placebo, for a total of three weeks. Participants underwent follow-up assessments after 45 and 90 days.

About half of these patients were female, their average age was about 70, and all but one were white.

The study’s main goal was to assess the safety of sargramostim in people with Alzheimer’s. Results were positive: no serious adverse events related to the treatment were reported. The most common treatment-related side effects — including headache, skin-related reactions, and digestive issues — were in line with the medication’s known safety profile.

Analyses indicated that the treatment activated the immune system as expected, evidenced by higher numbers of immune cells and by increased levels of pro-inflammatory signaling molecules called cytokines.

The researchers stressed that this trial was not designed to thoroughly assess efficacy; there were too few participants to make statistically robust conclusions. Nonetheless, they highlighted some noteworthy results that indicated the treatment could aid cognition.

Specifically, scores on the Mini‐Mental State Examination (MMSE) — a measure of cognitive abilities — improved significantly, by 1.45 points on average, over three weeks in patients given sargramostim. MMSE score changes in this trial group were also significantly higher than those of patients on placebo after three weeks, with similar results at 45 days.

Of note, 70% of sargramostim-treated participants showed an improvement in MMSE scores after three weeks of treatment, as compared to 35% of those given placebo. Similar differences were seen at 45 and 90 days.

Additional cognitive tests generally did not show a statistically significant effect of sargramostim treatment, though the researchers noted a trend toward improvement on some memory-related scores.

Sargramostim’s use also normalized levels of Alzheimer’s-related proteins in participants’ blood. For example, blood levels of amyloid beta 40 — a form of amyloid beta often at low levels in people with Alzheimer’s — rose significantly with sargramostim treatment, and were 10% higher than levels in placebo patients.

Collectively, the findings “show that GM‐CSF/sargramostim treatment was safe and well‐tolerated and provided measurable disease‐modifying and memory‐enhancing benefits to participants with mild‐to‐moderate [Alzheimer’s],” the researchers concluded.

Given the known immune-stimulating function of GM-CSF, these results indicate that immune activation may be beneficial in Alzheimer’s, they wrote. But, they added, “the main conclusion of the study is that additional longer, larger trials of GM‐CSF/sargramostim in [Alzheimer’s] are warranted.”

“This surprising finding that stimulating the innate immune system and modulating inflammation may be a new treatment approach and induced us to start a larger trial of Sargramostim in Alzheimer’s disease with more participants treated over a longer time,” Huntington Potter, PhD, director of the University of Colorado Alzheimer’s and Cognition Center, and a study co-author, said in a press release.

That trial, not yet listed, is being sponsored by the Alzheimer’s Association/Part The Cloud, the University of Colorado, the Global Down Syndrome Foundation, and the National Institute on Aging.