Category: Parkinson’s Disease: Clinical Trials
Objective: To evaluate the safety and tolerability of repurposing Ambroxol as a disease modifying treatment for Parkinson’s Disease Dementia (PDD).
Background: Carrying a mutation in beta-Glucocerebrosidase (GCase; GBA) is a leading risk factor for synucleinopathies. Increasing GCase lowers alpha-synuclein in cell and animal models. Ambroxol is an over-the-counter expectorant available across most of the world except the USA and Canada. Ambroxol was identified in a high throughput screen as a pharmacological chaperone for GCase, suggesting it may be therapeutic.
Method: Inclusion criteria were PDD (GBA + and GBA-) with mild to moderate dementia (MoCA <=24, MMSE >=16), Hoehn and Yahr 2 – 3.5. Subjects were randomized to Ambroxol 1050 mg/day (high dose), 525 mg/day (low dose) or placebo for 1 year, with an optional 6 month open label. Primary outcome measures are Safety and Tolerability; Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician’s Global Impression of Change (CGIC). Secondary outcomes include battery of PD and cognitive assessments, and plasma/CSF and neuroimaging biomarkers.
Results: 75 candidates were screened, 55 enrolled and 44 completed 1 year. 34 enrolled in the open label extension, and 21 of them have completed this phase (still ongoing). The low dose group was dropped to aid enrollment.
Ambroxol was well tolerated. There were 9 SAE’s in the double blind portion; none judged to be due to Ambroxol). In subjects receiving high dose Ambroxol, blood levels were 8.16 +/- 3.32 mM and 0.73mM +/ 0.08 in CSF levels. GCase levels in white blood cells increased by 1.6 fold.
Interim efficacy data shows that subjects on Placebo worsened on the Neuropsychiatric Inventory (NPI) by 4.9 (+/- 13.7) while those receiving high dose Ambroxol improved by -3.45 +/- 1-.86 (p<0.05). [EF2] Amongst GBA + subjects, pooled Placebo and low dose group worsened by 1.7 +/- 2.5 on the ADAS-Cog, while the high dose group improved by -7.3 +/- 4.8 points (p< 0.05).
Conclusion: Ambroxol appears safe. Plasma and CSF levels reached target ranges.
Preliminary analysis suggests that patients receiving high dose 1050mg/day Ambroxol demonstrated improvements in Neuropsychiatric Inventory, and GBA carriers demonstrated improvement on the ADAS Cog.
ClinicalTrial.gov NCT02914366. Funded by the Weston Brain Institute.
To cite this abstract in AMA style:
S. Pasternak, C. Silveira, K. Coleman, R. Garcia, J. Wells, M. Borrie, P. Macdonald, R. Bartha, M. Jenkins, S. Morrow, D. Mendonca, G. Zou, E. Finger, T. Rupar, R. Tirona, M. Jog. A phase 2 randomized, double-blind, placebo-controlled trial of Ambroxol as a disease-modifying treatment for Parkinson’s disease dementia. [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/a-phase-2-randomized-double-blind-placebo-controlled-trial-of-ambroxol-as-a-disease-modifying-treatment-for-parkinsons-disease-dementia/. Accessed June 15, 2025.« Back to 2023 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-randomized-double-blind-placebo-controlled-trial-of-ambroxol-as-a-disease-modifying-treatment-for-parkinsons-disease-dementia/