Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease

Background: Neuroinflammation plays a pathogenic role in Parkinson's disease (PD). Immunotherapies that restore brain homeostasis can mitigate neurodegeneration by transforming T cell phenotypes. Sargramostim has gained considerable attention as an immune transformer through laboratory bench to bedside clinical studies. However, its therapeutic use has been offset by dose-dependent adverse events. Therefore, we performed a reduced drug dose regimen to evaluate safety and to uncover novel disease-linked biomarkers during 5 days/week sargramostim treatments for one year. Methods: Five PD subjects were enrolled in a Phase 1b, unblinded, open-label study to assess safety and tolerability of 3 mu g/kg/day sargramostim. Complete blood counts and chemistry profiles, physical examinations, adverse events (AEs), immune profiling, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, T cell phenotypes/function, DNA methylation, and gene and protein patterns were evaluated. Findings: Sargramostim administered at 3 mu g/kg/day significantly reduced numbers and severity of AEs/subject/month compared to 6 mu g/kg/day treatment. While MDS-UPDRS Part III score reductions were recorded, peripheral blood immunoregulatory phenotypes and function were elevated. Hypomethylation of upstream FOXP3 DNA elements was also increased. Interpretation: Long-term sargramostim treatment at 3 mu g/kg/day is well-tolerated and effective in restoring immune homeostasis. There were decreased numbers and severity of AEs and restored peripheral immune function coordinate with increased numbers and function of Treg. MDS-UPDRS Part III scores did not worsen. Larger patient numbers need be evaluated to assess conclusive drug efficacy. Published by Elsevier B.V.

Automated summary

The study showed that long-term treatment with 3 micrograms/kilogram/day of sargramostim significantly reduced the number and severity of adverse events, while improving immune function and alleviating Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale scores. This dosage regimen is effective and well-tolerated for restoring immune homeostasis.