P1‐067: AMBROXOL AS PHARMACOLOGICAL CHAPERONE TARGETING GBA1 AS A DISEASE MODIFYING TREATMENT FOR PARKINSON'S DISEASE DEMENTIA: A PHASE 2 RANDOMIZED, DOUBLE‐BLIND, PLACEBO‐CONTROLLED TRIAL

Currently there are no disease-modifying treatments for cognitive impairment in synucleinopathies including Parkinson's disease dementia (PDD). Being a carrier of a mutation in beta-Glucocerebrosidase (GCase; gene name GBA) is a leading genetic risk factor for synucleinopathies, and even patients without mutations have lower levels of this enzyme. Notably, several groups have demonstrated that the levels of alpha-synuclein (which deposits in the brains of patients with synucleinopathies) and GCase are linked, and raising GCase levels decreases alpha-synuclein in cell and animal models. Ambroxol is an over the counter expectorant with an excellent safety record. It is available in most of the world, but not in Canada or the United States. Ambroxol was identified in a high throughput screen as a pharmacological chaperone for GCAse, a small molecule that is able to bind, stabilize and increase the levels and activity of the enzyme. Here we propose a phase 2 study to determine whether high dose Ambroxol is safe in PDD patients and to acquire preliminary pharmacological and clinical data. We will randomize 75 patients with PDD to receive Ambroxol at 1050mg/day, 525mg/day, or placebo for 1 year, with an optional open label extension. Inclusion criteria are: age > 50 years, PDD defined as Parkinson's disease for at least 1 year prior to developing cognitive impairment, MoCA score <=24, but MMSE >16. 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). Secondary measures will examine Parkinson's disease cognitive and motor scales. We will also examine MRI and CSF-based biomarkers. The pharmacokinetics of GCase will be examined during titration of the medication. So far we have enrolled 25 patients, with 10 completing 1 year. Ambroxol appears to be well tolerated. Ambroxol blood levels are sufficient to see the increases in GCase enzyme activity in patient peripheral leukocytes. Dosing parameters appear to be sufficient to achieve the biochemical goals of the study. If successful, Ambroxol will be the first disease-modifying treatment for cognitive impairment in a synucleinopathy as PDD. Clinical Trial ID NCT02914366. Funded by the Weston Brain Institute.