Objective: Currently there are no disease-treatments for Synucleinopathies including Parkinson’s disease dementia (PDD). Our objective is to use Ambroxol to target GBA/Glucocerebrosidase to treat PDD.

Background: One of the largest genetic risk factors for Parkinson’s Disease, Parkinson’s disease Dementia, and Lewy Body Dementia is to carry a mutation in the gene GBA, which encodes the lysosomal enzyme Glucocerebrosidase (GCase). Even patients without mutations have lower levels of this enzyme. Raising the levels of this enzyme lowers the levels of alpha synuclein in cell and animal models.
Ambroxol is an over the counter expectorant that is available across most of the world, but not in Canada or the United States. Ambroxol was identified in a high throughput screen as a pharmacological chaperone of GCase, and has been shown to raise the levels of this enzyme in cells, animals and humans with Gaucher disease and PD.

Method: We will randomize 58 patients to placebo or Ambroxol 1050 mg/day for 1 year, with an optional 6 month open label extension. Inclusion criteria are Age > 50, established PD for > 1 year before onset of cognitive symptoms, Montreal Cognitive Assessment (MoCA) <=24 and MMSE => 16, and no other significant medical illnesses or significant neurological disease. The Primary outcome measures are the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician’s Global Impression of Change (CGIC), and safety and pharmacological outcomes. Secondary outcomes include the UPDRS, an extended set of cognitive and clinical assessments, and plasma/CSF and neuroimaging biomarkers.

Results: To date, we have screened 60 participants, and enrolled 44, 37 of which have been titrated to full dose. 29 have passed 6 months, and 26 have completed a year. 20 participants have agreed to lumbar puncture. We have found that Ambroxol is well tolerated. We have not seen any Severe Adverse Events which we believe are due to Ambroxol. We are achieving Ambroxol blood levels of ~10 micromolar, which is raising the levels of GCase in white blood cells by 1.6-fold.

Conclusion:
If successful, this will be the first disease modifying treatment for PDD. Our plan is to end recruitment this summer (2021), and baseline characteristics will be presented.

Clinical Trial Registration NCT02914366. Funded by the Weston Brain Institute.

« Back to MDS Virtual Congress 2021

MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-randomized-controlled-trial-repurposing-ambroxol-as-a-disease-modifying-treatment-for-parkinsons-disease-dementia/