Objective: To study the potential disease-modifying properties of ambroxol in PD patients with a GBA1 mutation

Background: The most common genetic risk factor for Parkinson’s disease (PD) is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). Homozygous GBA mutations lead to development of Gaucher’s disease (GD). Heterozygous mutations have shown to increase the risk of developing PD. GCase activity in GD patients typically lies around 10% compared to controls, whereas in carriers this approximates 50%. About 300 different mutations in the GBA-gene have been identified, including risk, mild and severe variants.

The repurposed mucolytic ambroxol has shown the property to upregulate GCase activity and therefore has the potency to become a disease modifying therapy in PD.

Method: This is a single-center, double-blind, randomized, placebo-controlled trial with 80 PD patients carrying a GBA mutation, receiving ambroxol 1800mg/day or placebo for 48 weeks. Primary outcome is the comparison of Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III motor subscore in the practically defined OFF-medication state at 60 weeks. Secondary outcomes include intracellular GCase activity using 5-(Pentafluorobenzoylamino) Fluorescein Di-beta-D-Glucopyranoside (PFB-FDGlu), sphingolipid profiles, a dopaminergic PET-scan ([18F]FDOPA PET) of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson’s Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaires.

Results: To date, 21 patients have been included in the study. The mean (SD) disease duration of PD at time of inclusion was 79.9 (33.2) months. The most common included GBA variants so far are E326K (33.3%), T369M (14.3%) and L444P (9.5%). Baseline GCase activity has been analyzed and correlations with GBA variants will be shown.

Until now, 20 subjects could be titrated up to 1800 mg or placebo per day. One patient did not tolerate the highest dose due to gastro-intestinal problems. No serious adverse events have been reported so far, with the longest follow-up being 39 weeks.

Conclusion: 1. Ambroxol up to 1800 mg per day is well tolerated

2. The included GBA mutations are mainly risk variants

References: Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson’s Disease. N Engl J Med. 2009;361(17):1651–61.

Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet. 2008;372(9645):1263–71.

Migdalska-Richards A, Schapira AH. The relationship between glucocerebrosidase mutations and Parkinson disease. J Neurochem. 2016 Oct;139 Suppl 1(Suppl Suppl 1):77-90

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MDS Abstracts - https://www.mdsabstracts.org/abstract/groningen-early-pd-ambroxol-treatment-great-trial-a-randomized-double-blind-placebo-controlled-single-center-trial-with-ambroxol-in-parkinson-patients-with-a-gba-mutation/