- Ambroxol showed target engagement in Parkinson's dementia but no significant cognitive improvement over placebo.
- The drug, a common cough medicine in Europe, was safe and well-tolerated.
- Ambroxol chaperones GCase and led to increased GCase levels.
Ambroxol, a common cough medicine used in Europe, demonstrated target engagement in people with Parkinson's disease dementia but did not show an effect on cognition compared with placebo, a year-long phase II trial showed.
Looking at the primary efficacy outcomes, there was no evidence to suggest differences in Alzheimer Disease Assessment Scale-cognitive subscale, version 13 (ADAS-Cog-13) and Clinician's Global Impression of Change scores between the groups at week 26 or week 52, reported Stephen Pasternak, MD, PhD, of the Cognitive Neurology and Alzheimer's Disease Research Centre at the Parkwood Institute in London, Ontario, and colleagues.
Ambroxol was safe and well-tolerated, the researchers noted in JAMA Neurology. Parkinson's patients who carried the beta-glucocerebrosidase (GCase) gene GBA1 appeared to have better scores on the ADAS-Cog-13 and the Neuropsychiatric Inventory (NPI).
Post-hoc analyses suggested that plasma glial fibrillary acidic protein (GFAP), a marker of astrogliosis, increased in the placebo group but remained stable in the ambroxol group at week 52.
"Primary outcome measures did not support therapeutic effects of ambroxol on cognition in Parkinson's disease dementia, although there may have been stabilization of neuropsychiatric symptoms," Pasternak and colleagues wrote.
Mutations in GBA cause Gaucher's disease and are an important risk factor for Parkinson's disease. These mutations lower GCase production, causing alpha-synuclein levels to rise.
Ambroxol chaperones GCase; in a previous study of people with Parkinson's disease, the drug led to increased GCase levels. It is approved for treating respiratory conditions in Europe, but not for any indication in the U.S. or Canada.
Three ongoing clinical trials are testing the effects of ambroxol in neurodegenerative diseases: the ASPro-PD trial in Parkinson's disease, the ANeED study in dementia with Lewy bodies, and the AMBITIOUS study in GBA-associated Parkinson's.
In their referral-based, single-center trial, Pasternak and co-authors studied people who had Parkinson's disease for at least 1 year before cognitive impairment. All participants had mild to moderate dementia, were taking stable medications, and had a study partner.
Participants were randomized to low-dose ambroxol (525 mg/day), high-dose ambroxol (1,050 mg/day), or placebo. A total of 30 Parkinson's patients received ambroxol: eight patients (mean age 79) in the low-dose group, and 22 patients (mean age 71) in the high-dose group. The placebo group included 24 people with a mean age of 73.
More than 80% of study participants were male. Eight participants carried variants in GBA1.
Over 52 weeks, the ambroxol groups had more gastrointestinal adverse events than the placebo group (12% vs 5%).
Only people taking high-dose ambroxol were compared with placebo in efficacy measures. Mean high-dose ambroxol concentrations were 7.48 μM in plasma and 0.73 μM in cerebrospinal fluid at the end of titration. At week 26, mean GCase levels were higher in the high-dose ambroxol group compared with the placebo group (12.45 vs 8.50 nmol/h/mg, P=0.05).
Three of five GBA1 carriers treated with ambroxol showed a change greater than the minimal clinically important difference of 3 points in ADAS-Cog scores from baseline to the end of study (-11 points, -6 points, and -11 points). "Although this sample is too small to support any conclusion, these findings are highlighted given the proposed action mechanism of ambroxol in GCase activity that is particularly lower in carriers of the GBA1 gene variant," Pasternak and colleagues noted.
Among GBA1 carriers treated with ambroxol, three of four showed a clinically meaningful improvement on the NPI and one remained stable.
Cognitive symptoms did not worsen over time in the placebo group and a 52-week trial may not have been long enough to assess ambroxol, Pasternak and co-authors said. Future trials also should focus on recruiting more GBA1 carriers and assess GFAP as a potential biomarker, they suggested.
Disclosures
This trial was funded by a grant from the Weston Brain Institute.
Pasternak reported receiving grants from the Weston Brain Institute, the Canadian Institute for Health Research, and Zywie Bio; having a patent for Zywie Bio pending; and being a shareholder in Zywie Bio.
Co-authors reported relationships with pharmaceutical companies and other organizations.
Primary Source
JAMA Neurology
Source Reference: Silveira CRA, et al "Ambroxol as a treatment for Parkinson disease dementia: a randomized clinical trial" JAMA Neurol 2025; DOI: 10.1001/jamaneurol.2025.1687.
https://www.medpagetoday.com/neurology/parkinsonsdisease/116352
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