Encouraging results from the open label trial of Ambroxol
Original article: Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurology: 2020

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The takeaway

Ambroxol was found to be safe and well tolerated in an open label trial in 18 people with Parkinson’s. It enters the brain and appears to increase levels of its chemical target GCase.

Why is it important?

These issues of safety, tolerability and brain penetrance are essential before a trial of its disease modifying potential can be considered.



  • Novelty 80% 80%
  • Proximity 80% 80%
  • Deliverability 60% 60%

Impact Opinion

The ambroxol clinical trial results are an interesting development in the overall world of Parkinson’s research. It represents an important step in the research exploring the GBA-associated biology of Parkinson’s, but it also provides proof of principle that a clinically available drug can safely be repurposed with the explicit goal of boosting levels of GCase in humans. As exciting as this data may appear, caution must be taken with regards to extracting too much from the study. For example, a larger clinical trial of ambroxol is now required to determine if this increase in GCase levels actually has any clinical benefit and if it can slow or stop progression of the condition.


One potential therapeutic approach being tested in Parkinson’s is the boosting of waste disposal processes (or autophagy). When the cellular mechanisms of waste degradation stop working efficiently, harmful substances (including Parkinson’s-associated proteins such as alpha synuclein) begin to build up inside neurons causing damage. Genetic variations in genes associated with autophagy are some of the most common genetic risk factors associated with Parkinson’s. Mutations in one of these autophagy genes, called GBA1 represent one of the most important genetic risk factors for Parkinson’s. The GBA gene encodes the instructions for making a protein called GCase. GCase is an enzyme, theactivity of which is reduced in people with Parkinson’s and especially in those individuals who are GBA1 mutation carriers. Given the importance of GCase in the waste disposal system, researchers have been searching for and testing drugs that targetthis protein in order to improve waste clearance, in the hope that it could be a promising strategy for neuroprotection in Parkinson’s.

The details

Ambroxol is licensed as a respiratory medication but it has also been shown to have another incidental, valuable effect: it helps restore function to mutant GCase, in this way increasing its activity, and has been shown to reduce levels of harmful alpha synuclein, the main protein whose build up is a marker of Parkinson’s. The current open label trial therefore tested the safety and tolerability of ambroxol in 18 people with mild to moderate Parkinson’s. The average age of the group was 60 yrs, and the vast majority (15) were male. The main questions being addressedby the  study were whether the drug could be safely taken orally 3 times daily at 10 times the licensed dose, whether it would actually reach the brain, and whether a change in GCase activity could be detected after 6 months (186 days). Half of the individuals in the study were GB1A mutation carriers (see our earlier summary on why GBA1 may play an important role in idiopathic Parkinson’s https://www.parkinsonsmovement.com/gba_research/).

All participants underwent 5 clinical visits, at the start of the trial, then at days 11, 98, 186, and then after ambroxol dosing had ended at 279 days to assess wash out. They underwent several neurological tests and completed questionnaires on cognition and non-motor symptoms. In addition to blood samples, participants underwent a lumbar puncture for the collection of cerebrospinal fluid (CSF) which bathes the brain and so offers an array of direct chemical insights into brain metabolism. CSF was collected at baseline and at the end of the study.

Ambroxol was well tolerated and the reported adverse events related to gastrointestinal disturbances and a transient skin condition in one patient. The analyses showed that by day 186, ambroxol had penetrated the brain as indicated by its levels in CSF, and reduced GCase activity – counterintuitively, ambroxol has been shown to reduce free GCase activity in fluid that contains no cells, but increases it when applied to neurons. Levels of alpha synuclein in CSF also increased, potentially indicating enhanced neuronal GCase activity resulting in better clearance, or expulsion, of alpha synuclein into CSF. Some improvements were seen in movement using the Unified Parkinson’s Disease Rating Scale (UPDRS part III), although these did not persist after the drug dosing ended, and are difficult to interpret as no placebo arm was included.

Next steps

As ambroxol was well tolerated, and shown to be brain penetrant, a larger placebo controlled study would be the next step in assessing its potential for disease modification in Parkinson’s.
Mullin, S., Smith, L, Lee, K et al. (2020). Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurology.

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