Ambroxol was found to be safe and well tolerated in a randomized clinical trial investigating its use in Parkinson disease dementia. Still, the treatment did not result in statistically significant cognitive improvements over 52 weeks.
The phase 2, double-blind, placebo-controlled trial enrolled 55 patients aged older than 50 years with mild to moderate Parkinson disease dementia (PDD). All participants had received a diagnosis of Parkinson disease at least 1 year before the onset of cognitive symptoms. Participants were randomly assigned to receive either high-dose ambroxol (1050 mg daily) or placebo for 52 weeks. An initial low-dose group (525 mg daily) was included but removed from final analysis due to recruitment and statistical limitations.
Ambroxol, an over-the-counter expectorant, functions as a pharmacological chaperone that enhances β-glucocerebrosidase (GCase) activity. Reduced GCase activity is associated with α-synuclein accumulation, a key pathological hallmark in Parkinson disease. Increasing GCase levels is considered a potential disease-modifying approach.
Pharmacodynamic analysis confirmed target engagement. At week 26, mean (SD) GCase activity was higher in the ambroxol group compared with placebo: 12.45 (1.97) nmol/h/mg vs 8.50 (1.96) nmol/h/mg (91% CI, 11.54–13.36 vs 7.65–9.34; P = .05). Plasma ambroxol concentrations peaked at 7.48 μM at week 8 and remained at 5.21 μM at week 52.
Despite this biological effect, no differences were observed between groups on primary efficacy measures. Alzheimer’s Disease Assessment Scale–Cognitive Subscale, version 13 (ADAS-Cog-13), and Clinician’s Global Impression of Change (CGIC) scores did not differ at weeks 26 or 52. For example, at week 52, the mean (SD) ADAS-Cog-13 score was 20.90 (13.19) in the placebo group and 23.18 (11.15) in the ambroxol group (P = .73). No statistically significant differences were seen across secondary measures, including the Parkinson’s Disease Cognitive Rating Scale, Montreal Cognitive Assessment (MoCA), and Neuropsychiatric Inventory (NPI).
Safety outcomes were favorable. A total of 365 adverse events (AEs) were reported—193 in the ambroxol group and 172 in the placebo group. Most were mild or moderate. Serious AEs (all requiring hospitalization) occurred in 7 participants receiving ambroxol and 3 receiving placebo, but none were attributed to the study drug. Gastrointestinal disorders were more frequent with ambroxol (12% vs 5% of AEs). Psychiatric AEs and falls were less common in the ambroxol group, although these findings were not statistically significant.
A subgroup analysis of GBA1 variant carriers (n = 8) suggested a potential treatment signal. Among four carriers who received high-dose ambroxol and had follow-up data, three demonstrated cognitive improvement on the ADAS-Cog-13 that exceeded the minimal clinically important difference (−11, −6, −11), while two carriers in the placebo group did not meet this threshold (−1, +2). However, sample size was too small for definitive conclusions.
Exploratory biomarker analysis found that plasma levels of glial fibrillary acidic protein (GFAP), a marker of neuroinflammation, increased from baseline in the placebo group (135.07 pg/mL to 167.90 pg/mL) but remained stable in the ambroxol group (127.95 pg/mL to 118.05 pg/mL), with a statistically significant group-by-time interaction (P = .008). This post hoc result suggests a potential anti-inflammatory effect and supports future biomarker investigation.
The authors concluded that ambroxol was safe, demonstrated biological activity, and may benefit subgroups of patients—particularly GBA1 variant carriers—but did not produce cognitive improvement in the overall PDD population. They recommended larger and longer-duration trials to further explore ambroxol’s therapeutic potential and to validate plasma GFAP as a biomarker.
Disclosures can be found in the published study.
Source: JAMA Neurology
