Background

GM-CSF leukine, aka sargramostim, is a synthetic form of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor. It is a 127-amino-acid glycoprotein produced by recombinant DNA technology in yeast. Sargramostim stimulates the innate immune system. It is FDA-approved for regenerating neutrophils, monocytes, and macrophages after bone marrow transplants, radiation therapy, and in conjunction with treatment for several types of leukemia. Sargramostim is also used for treating neutropenia, a condition of dangerously low white-blood-cell counts. Sargramostim is not to be confused with filgrastim, a recombinant form of the related granulocyte colony-stimulating factor (G-CSF). 

The rationale for evaluating this immune modulator in Alzheimer's disease is that it might increase phagocytosis of pathogenic protein deposits by bone-marrow-derived macrophages or brain-resident microglia, and that it might also stimulate other neuroprotective innate immunity processes (see review by Ahmed et al., 2021). GM-CSF was reported to activate microglia in response to amyloid pathology without also augmenting microglial release of pro-inflammatory cytokines, as is seen in response to other, closely related neurotrophic factors (Murphy et al., 1998). 

In transgenic mouse models of Alzheimer's disease, GM-CSF was reported to reduce amyloid pathology, improve cognition, and increase the number of microglia (Boyd et al., 2010; Kiyota et al., 2018). However, contradictory findings exist, as well (Manczak et al, 2009). GM-CSF was also tested in Dp16 Down syndrome mice, a model that does not accumulate amyloid but does develop cognitive deficits due to neuroinflammation. Treatment reduced inflammation in the mice, and improved learning and memory in both DP16 and wild-type mice (Ahmed et al., 2022).

Both GM-CSF and its receptor appear to be expressed in aging human brains, both in controls and in people with Alzheimer's (Ridwan et al., 2012). Analysis of archived neuropsychology data from 19 patients who had received sargramostim as part of their supportive care for bone-marrow transplantation reported a cognitive benefit (Jim et al., 2012). 

Sargramostim is also of interest in Parkinson’s disease, where T cell immune responses have been linked to dopaminergic neuron loss and motor dysfunction (Reynolds et al., 2010; Saunders et al., 2012; Benner et al., 2008). In mouse models, sargramostim increased the production of anti-inflammatory regulatory T cells, and was neuroprotective (Mangano et al., 2011; Kosloski et al., 2013).

Findings

In 2011, a Phase 2 randomized study at the University of Colorado, Denver, and the Byrd Alzheimer's Institute of the University of Southern Florida, Tampa, started enrolling 40 patients with mild to moderate Alzheimer's disease to evaluate a three-week course of GM-CSF Leukine (250 microg/m² per day) or placebo injected under the skin for five days each week. Tolerability was the primary outcome, to be monitored for six months. Various cognitive tests were to be performed for up to six months after treatment as a secondary outcome. This study was set to complete in December 2017. 

At the 2017 AAIC, investigators presented interim data on 32 participants, 13 on drug and 19 on placebo (Aug 2017 conference news). Patients were examined at baseline, at the end of the trial, and 45 and 90 days later, for safety and with cognitive and functional tests. Those in the treatment arm had an average MMSE score of 16.46 at baseline, versus 20.63 for those on placebo, a significant difference; ADL scores were also lower—54.61 for the treatment group and 63.16 for placebo. GM-CSF Leukine seemed well-tolerated, with no serious adverse events reported and no signs of ARIA. Patients on drug scored about 1.5 points higher in MMSE than at baseline; placebo scores stayed unchanged. ADL score rose about 1.5 points in the treatment group at three weeks, but then fell similarly in treatment and placebo arms, respectively. No differences were reported between the two groups at later time points. No significant difference emerged at any time between treatment and placebo arms on the ADAS-Cog, CDR-SB, or MOHS tests.

The trial ended in December 2019, with 40 patients completing treatment and both follow-up visits. According to results presented at the November 2020 CTAD conference, there were no serious adverse events attributed to drug, and no amyloid-related imaging abnormalities. At the end of treatment, the sargramostim group improved on the MMSE compared to baseline or placebo. The benefit over placebo was maintained at the 45-day follow-up, but disappeared by 90 days. The ADAS-Cog13 did not differ at end of treatment, but was worse in the treated group at day 45. Increases in blood immune cells and proinflammatory cytokines were confirmed, consistent with GM-CSF’s immune modulatory activity. Plasma Aβ, tau, and the neurodegeneration marker UCHL1 significantly moved toward normal during treatment, then returned to baseline in the follow-up. Trial results were published after peer review (Potter et al., 2021).

In May 2022, a trial comparing a six-month course of the same dose given five days/week to placebo began enrolling 42 participants whose mild to moderate Alzheimer's dementia is confirmed by brain amyloid pathology. The primary outcome is safety; secondary, the MMSE. The trial, at the University of Colorado, is set to run until July 2024.

In 2013, the National Institute on Aging awarded funding for a Phase 2 trial to be conducted by Sanofi Aventis to evaluate sargramostim for its ability to clear amyloid deposits and affect cognition in patients with mild cognitive impairment (Feb 2014 news). This study started in November 2016 and anticipated enrolling 30 people 40 or older who met NIA-AA criteria for MCI due to AD and had a positive amyloid PET scan. This study was to evaluate a six-month course of subcutaneous injection of sargramostim or placebo for reduction of brain amyloid as measured by change in florbetapir retention. Secondary outcome measures were to include safety, CSF analysis, MRI to look for ARIA, and measurement of antibodies against sargramostim. This study was to be conducted in Houston but was withdrawn prior to enrollment due to slow recruitment.

In September 2013, a Phase 1 study began in Parkinson’s disease. The single-center study at the University of Nebraska enrolled 20 Parkinson’s patients who were randomized to self-administer saline placebo or 6 micrograms/kg/day sargramostim for eight weeks. The primary outcome was adverse events; other outcomes included measures of motor function, immune profiling and magnetoencephalography (MEG). Adverse events were mild and included well-established responses to GM-CSF such as injection-site reactions, increased total white cell counts, and bone pain. Treatment led to an increase in numbers of functional regulatory T cells and other markers of immune modulation. There was a modest improvement on the Unified Parkinson’s Disease Rating Scale Part III scores by three points at six and eight weeks that reversed after treatment stopped. MEG markers of motor cortex activation also improved in people on sargramostim (Gendelman et al., 2017).

In January 2019, the same investigators began a two-year pilot study treating 10 people with PD with a reduced dose of 3 micrograms/kg/day sargramostim five days a week. The study assesses safety and tolerability, and includes motor assessment by the UPDRS Part III as a primary outcome. Secondary outcomes are changes in immune cell number, phenotype, and function. The study will run through September 2022. Results of one-year treatment in five male patients were published, showing a reduction in the number and severity of adverse events with 3 micrograms compared to the 6 microgram study (Olson et al., 2021). There was a transient increase in effector T cells in blood, and a sustained increase in regulatory T cells with immunosuppressive function. Participants’ motor function did not decline, and they improved UPDRS part III scores from baseline by about 5 points, although there was no placebo group for comparison.

For details of Alzheimer's disease trials, see clinicaltrials.gov. 

Clinical Trial Timeline