Alterations in MDS-UPDRS part III scores were associated with increased expression of Treg phenotypes and immunosuppressive function, suggesting a potential role of Treg function in diminution of disease progression.
Recently published results from a small phase 1b study (NCT01882010) showed that treatment with low-dose sargramostim (Leukine; Partner Therapeutics), the only FDA-approved recombinant human granulocyte-macrophage colony stimulating factor (rHuGM-CSF), is safe and well-tolerated among patients with Parkinson disease, warranting a larger study.1,2
Senior author Howard E. Gendelman, MD, chair, Department of Pharmacology and Experimental Neurology, University of Nebraska Medical Center, and colleagues evaluated 125 microgram/mm2 of sargramostim in 5 patients on a 5-day-on, 2-day-off regimen over a 12-month treatment period that was later extended at patient and investigator request to 24 months (n = 10).
All 5 patients completed the original 12-month treatment period. The drug was safe and well-tolerated; however, all subjects reported at least 1 adverse event (AE) over the course of the study, with all participants reporting elevated white blood cell (WBC) counts, injection site reactions (4 of 5, 80%), fall with injury (3 of 5, 60%) and gastrointestinal tract problems/nausea (3 of 5, 60%).2 Each of the AEs observed were mild to moderate in nature, with no severe or serious AEs reported or associated with treatment. Viral infection and leg cramping, 2 serious AEs, were reported over the 12-month period but were deemed unrelated to the study drug.
"The clinical paper studied Leukine, where disease progression was altered and the drug was safely administered for 1 year,” Gendelman said in a statement.1 “Additional research is required in a larger clinical study before definitive conclusions can be made for drug effectiveness.”
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III scores were monitored over 3 months prior to initiating treatment to establish baseline. Four of the 5 patients showed improved MDS-UPDRS part III scores over 12 months, with the fifth patient showing no change. These scores were improved on average by 4 points, whereas those treated with standard therapy typically experience a 2.4-point average deterioration.
Treatment with sargramostim also significantly increased the level of demethylation by 20% at 2 months and maintained demethylation levels at 6 months, which authors said was “indicative of stable FOXP3 expression and suppressive Treg phenotype during treatment.” Further analysis examining the treatment on Treg suppressive activities showed that Treg function was significantly enhanced compared to baseline, with the potentiation of Treg function maintained over the 12-month study.
Gendelman and colleagues also assessed the effect of sargramostim on treatment biomarker expression with Treg-mediated immunosuppressive function and found it to be positively associated with increased co-expression of ItgB7, FOXP3, FAS, CD27, and CD45RA. Negative correlations were observed between increasing MDS-UPDRS part III scores and diminished frequencies of FAS+CD4+ T cells and Treg subsets that co-express ItgB7, CD45RA, and CD27 with the lack of CCR7, suggesting that motor function is improved with increased Treg subset levels and greater suppressive activity.
"Importantly, Leukine's effects on Tregs and neuro-inflammation translated into improvement in motor function in these patients. Our next step is to submit an IND for Parkinson disease and then initiate a phase 2, randomized, double-blind, placebo-controlled, multi-site study to confirm these results in a larger population of patients,” John McManus, chief business officer, Partner Therapeutics, said in a statement.1 “Patients with Parkinson have no treatment options that halt or reverse disease progression and we consider it a matter of urgency to accelerate Leukine's clinical development to provide a potential solution."
Associations of motor function improvements with increased Treg subset levels and greater suppressive activity was confirmed by positive correlation of increased Treg function as measured by lower number of Tregs required to yield 50% suppression and diminished MDS-UPDRS part III scores.
The study authors concluded that the study supports the hypothesis that use of immunomodulators to induce and/or expand Tregs, shift Teff phenotype, and enhance immunosuppression in neurodegenerative disease affects neuroimmune interactions and has the potential to slow disease outcome.