Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial

Abstract

A potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson’s disease patients. Both Parkinson’s disease patients and controls were monitored for 2 months for baseline profiling. Parkinson’s disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson’s disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson’s disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson’s disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

“…These results provide support for the proposed mechanism of action of AZD3241 on microglia and encourage further studies evaluating its potential to modify the disease course of PD as well as other neurodegenerative disorders. A small double‐blind trial of sargramostim, a recombinant granulocyte macrophage colony stimulating factor, demonstrated modest improvements in clinical, magnetoencephalography (MEG)‐recorded cortical activities and regulatory T cell number and function compared to placebo or pretreatment states . A review of http://clinicaltrials.gov shows a number of other terminated or completed but unreported studies of treatments directed at neuroinflammation.…”

“…A small double-blind trial of sargramostim, a recombinant granulocyte macrophage colony stimulating factor, demonstrated modest improvements in clinical, magnetoencephalography (MEG)-recorded cortical activities and regulatory T cell number and function compared to placebo or pretreatment states. 67 A review of clinicaltrials.gov shows a number of other terminated or completed but unreported studies of treatments directed at neuroinflammation. ViNeuro, a compound said to have a variety of immunomodulating functions (increases the activities of T cells, B cells, and natural killer (NK) cells and enhances mitochondrial antioxidant status) in various tissues including brain, was studied in a triple-blind randomized controlled clinical trial for safety and efficacy (NCT00517842, completed in September 2008).…”

Progress of Pharmacological Approaches in Parkinson's Disease

“…It improves the function of neuroprotective, regulatory T cells. In two placebo‐controlled double‐blind phase I trials, granulocyte‐macrophage colony‐stimulating factors served as a neuroprotective agent in PD by increasing the numbers and improving the function of regulatory T cells …”

“…In two placebo-controlled doubleblind phase I trials, granulocyte-macrophage colony-stimulating factors served as a neuroprotective agent in PD by increasing the numbers and improving the function of regulatory T cells. 71,72 Epidemiological evidence suggests a slightly protective effect of the ß2-agonist salbutamol on the risk to develop PD 73 especially for long-acting formulations, although this is not without controversy. The ß2-agonists may exert an inhibitory effect on inflammatory processes and may, thus, be capable of modulating inflammatory conditions.…”

Data processing, multi-omic pathway mapping, and metabolite activity analysis using XCMS Online

“…The XCMS systems biology results implicated tumor progression with biofilm development via polyamine biosynthesis 9 . This platform has also been used on a phase I clinical trial drug for a Parkinson’s disease immunotherapy that was found to target the tryptophan pathway and later validated with targeted metabolomics 20 . More recently, cellular responses to chemical exposure of a xenoestrogen on breast cancer cells have been studied and found to alter tRNA charging and ribonucleoside salvage pathways 21 .…”