Long-term sargramostim led to motor gains for 5 patients
Findings from small trial affirm long-term safety of the immune-modulating medication
Long-term treatment with sargramostim, an immune-modulating medication from Partner Therapeutics, was safe and improved motor function for five men with Parkinson’s disease, according to data from a small open-label Phase 1 clinical trial.
Evidence suggested the therapy exerted its benefits by boosting the function of anti-inflammatory regulatory T-cells (Tregs) and increasing autophagy, a cellular waste-removal pathway, in immune cells called monocytes.
While confirmation in a larger Phase 2 trial is needed, the data overall “affirmed long-term safety as well as immune and anti-inflammatory responses reflecting clinical stability in [Parkinson’s] under the sargramostim treatment,” the researchers wrote.
The study, “An open-label multiyear study of sargramostim-treated Parkinson’s disease patients examining drug safety, tolerability, and immune biomarkers from limited case numbers,” was published in Translational Neurodegeneration.
Abnormal immune system activation and subsequent inflammation are thought to be involved in the death of dopamine-producing nerve cells for people with Parkinson’s disease. Treatments that target this aberrant immune activation could be beneficial for patients.
Sargramostim is a lab-made version of granulocyte macrophage colony-stimulating factor (GM-CSF), a signaling molecule in the body that works to coordinate the activity of immune cells.
Particularly, sargramostim is able to shift immune T-cells from having a pro-inflammatory profile toward a more anti-inflammatory profile characteristic of Tregs. By boosting Treg activity in addition to modulating other immune cell populations, sargramostim is expected to promote cell survival under inflammatory conditions.
Brand name Leukine
Partner markets the therapy under the brand name Leukine, which is indicated for a number of situations, including during certain stem cell and bone marrow transplants, but the therapy is not approved for Parkinson’s.
Researchers previously found that a high daily dose of sargramostim — 6 micrograms per kilogram (mcg/kg) — improved motor function in Parkinson’s patients, but was associated with significant side effects.
As such, researchers at the University of Nebraska Medical Center launched a clinical trial (NCT03790670) to evaluate the effects of a lower, 3 mcg/kg daily dose among five Parkinson’s patients. These five men, with a mean age of 64, had been living with Parkinson’s for a mean of eight years.
All participants were treated with under-the-skin sargramostim injections in week-long cycles involving five days of treatment (3 mcg/kg) and two days off treatment.  These cycles were continued for two continuous years, after which treatment was discontinued for three months. Treatment then was reinstated for an additional six months.
Results after a year of treatment indicated that sargramostim was tolerated well, with fewer and less-severe side effects than the previously assessed high dose. Three men also experienced an easing of motor symptoms, as assessed by the Movement Disorder Society — Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3.
In the recent publication, the team now reports long-term trial findings from these five men.
Some side effects
As with the earlier report, sargramostim was found to be safe and tolerated well. All five participants experienced elevated white blood cell counts, a side effect that was expected based on sargramostim’s mechanism, according to the researchers.
Other side effects considered likely to be associated with the therapy included injection site reactions (80%), and pain in the extremities (20%). One severe adverse event that occurred — leg cramping — was considered possibly related to treatment.
Sargramostim treatment led to decreases in MDS-UPDRS Part 3 scores after three months of treatment compared with the three months before study initiation (baseline), reflecting an improvement in motor function that then was sustained stably for two years.
During the three-month intermission without treatment, MDS-UPDRS scores returned to baseline, but declined significantly again when treatment was restarted.
The therapy also was associated with non-significant decreases in MDS-UPDRS Part 2 scores, a part of the MDS-UPDRS that concerns the impacts of motor function on daily living.
A significant increase in Treg numbers and activity levels was observed in patients’ blood over time during treatment, reflecting an increased immunosuppressive capacity that generally correlated with motor function, according to the authors.
Four men developed antibodies against sargramostim in the first months of treatment, but these antibodies did not influence Treg numbers or motor function.
Boosting autophagy in monocytes
Additional blood analyses during the first six months of treatment revealed that sargramostim may exert, in part, its effects by boosting autophagy, a process that helps remove cellular waste, in immune monocytes. Dysfunctional autophagy has been implicated in the toxic buildup of the alpha-synuclein protein that marks Parkinson’s disease.
“We hypothesize that enhanced autophagy recorded during the early treatment stage has the potential to affect neuronal survival and lead to neuroprotective outcomes,” the researchers wrote.
Overall, the findings support the potential anti-inflammatory and neuroprotective properties of sargramostim for Parkinson’s, the researchers noted.
Still, the study was limited by a small sample size and lack of a placebo comparator group. “Larger clinical studies are required to confirm whether sargramostim is associated with improved clinical outcomes,” the team concluded.
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