Ambroxol Shows Target Engagement but No Cognitive Benefit in Individuals with Parkinson Disease Dementia

In a phase 2 clinical trial (NCT02914366) published in JAMA Neurology, treatment with ambroxol for people diagnosed with Parkinson disease and dementia (PDD) was shown to be safe and well tolerated but did not improve cognitive outcomes at 52 weeks. Ambroxol is widely used as an over-the-counter medication in Europe but not in the United States to thin excessive or abnormal mucus in people with respiratory illnesses and is known to bind to and chaperone the β-glucocerebrosidase (GCase) enzyme, increasing its activity. PDD is associated with deficiency or dysfunction in GCase activity—related to variants in the GBA1 gene—which may impair a-synuclein clearance. In the results reported from this phase 2 study, ambroxol treatment was associated with increased GCase activity, but no measurable clinical improvement in cognition.

The 52-week, placebo-controlled, double-blind clinical trial included 55 adults with mild-to-moderate PDD who were randomized 1:1:1 to receive high-dose ambroxol (1050 mg/day), low-dose ambroxol (525 mg/day), or placebo. The primary efficacy outcomes were change from baseline in Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog-13) and Clinician’s Global Impression of Change (CGIC). Secondary end points included neuropsychiatric, motor, and functional measures, as well as pharmacokinetics, pharmacodynamics, and exploratory cerebrospinal fluid (CSF) biomarkers. Safety and tolerability were monitored throughout the study, and optional lumbar punctures were performed in a subset of participants at baseline, week 26, and week 52. Only the high-dose ambroxol (n=22) and placebo (n=24) groups were included in statistical analyses of the primary and secondary outcomes.

• The study did not meet its primary efficacy outcomes; ADAS-Cog-13 and CGIC scores did not significantly differ between the high-dose ambroxol and placebo groups.
• Treatment with ambroxol did demonstrate target engagement:
  • Mean plasma ambroxol levels reached 7.48 μM (standard deviation [SD], 3.17 μM; 95% CI, 6.08 μM  to 8.87 μM) at week 8 and 5.21 μM (SD, 2.66 μM; 95% CI, 3.82 μM  to 6.61 μM) at week 52.

• Mean CSF concentrations of ambroxol were 0.73 μM (SD, 0.07 μM; 95% CI, 0.64 μM to 0.81 μM) at week 12 and 0.51 μM (SD, 0.04 μM; 95% CI, 0.64 μM to 0.55 μM) at week 52.

• • At week 26, mean white blood cell GCase activity was higher in the ambroxol group at 12.45 nmol/h/mg (SD, 1.97 nmol/h/mg; 95% CI, 11.54 nmol/h/mg to 13.36 nmol/h/mg) vs 8.50 nmol/h/mg (SD, 1.96 nmol/h/mg; 95% CI, 7.65 nmol/h/mg to 9.34 nmol/h/mg) in the placebo group (P=.05).
• Gastrointestinal symptoms were the most common adverse events; ambroxol was otherwise well tolerated.

In terms of exploratory findings, participants in the ambroxol group had a smaller increase in plasma glial fibrillary acidic protein (GFAP) levels, a marker of neurodegeneration. Additionally, participants with GBA1 gene variants treated with ambroxol showed potential cognitive and neuropsychiatric symptom stabilization. The authors note that further studies are needed to investigate the potential of ambroxol treatment to improve cognitive outcomes.