Based on laboratory evidence that a simple cough medicine called ambroxol offered potential as a treatment for Parkinson’s, our International Linked Clinical Trials (iLCT) committee of leading Parkinson’s experts prioritised ambroxol to be clinically tested in people with Parkinson’s.

This led to a UK-based clinical trial, co-funded by Cure Parkinson’s; the results, together with international efforts, support ambroxol and other drugs in this class, of so-called GCase-enhancers, as a promising avenue of research to halt the progression of Parkinson’s.

Why is ambroxol an interesting medicine for Parkinson’s?

When we get a cold, many of us think nothing of reaching for over-the-counter medicines to help with our symptoms. So it comes as quite a surprise that a shop-bought cough medicine, found in households across Europe, is under the spotlight as a potential treatment for Parkinson’s. Ambroxol is an expectorant cough medicine, used commonly on the continent to relieve mucous production in coughs and inflammation in sore throats. However, in 2009, researchers discovered that ambroxol increased the activity of an enzyme called GCase in the body, which is believed to have a role in Parkinson’s. Based on this and other evidence, the iLCT committee prioritised ambroxol for clinical trial in people with Parkinson’s. This prompted a UK-based clinical trial, co-funded by Cure Parkinson’s. The results of this trial and other global research further support ambroxol and other GCase-enhancers as promising potential treatments for Parkinson’s.

What is the evidence for ambroxol?

In 2009, researchers were searching for potential ways to treat Gaucher disease, which is caused by a deficiency of the enzyme GCase. They tested a library of over 1,000 already approved drugs to see if any of these drugs could increase GCase activity. The researchers found that, out of all the compounds screened, ambroxol was a potent enhancer of GCase in the body, and this is where the ambroxol and Parkinson’s story began. 

What is GCase?

GCase is an enzyme found inside our cells that is involved in the breakdown and clearance of waste proteins, particularly, the protein alpha-synuclein, which becomes mis-folded and clumps together and is known to have a role in Parkinson’s. Researchers first suspected that GCase had a role in Parkinson’s when they discovered that people with tiny mutations in the gene responsible for making the enzyme GCase – known as the GBA gene – are at greater risk of developing Parkinson’s.

The GBA-1 gene

Genetic testing has now revealed that mutations in the GBA1 gene, which causes problems with GCase production, are found in around 10% of people with Parkinson’s; it is the most common genetic risk factor for Parkinson’s. Interestingly, researchers have found that many people with Parkinson’s who DO NOT have GBA mutations, also have lower levels of GCase production.

Making the case for GCase

Researchers have been looking for drugs that help increase levels of GCase in cells, in the hope that boosting GCase activity will help cells improve their waste clearance, thereby making them healthier; and if cells are healthier, this might then slow down the progression of Parkinson’s.

Professor Anthony Schapira at University College London and the Royal Free Hospital instigated further research into this promising biological pathway. His team found that treating skin cell samples from people with Parkinson’s with ambroxol, increased their GCase level of activity.

Read more about this study

The study team’s research showed the same effect in dopamine neurons (the brain cells that are lost in Parkinson’s), in fruit flies with GBA1 mutations, and in the brains of primates. They also showed that treatment with ambroxol significantly reduced excess levels of the toxic accumulation of the protein alpha-synuclein

So, ambroxol appeared to partially restore GCase activity and combat the toxic effects of accumulated alpha-synuclein protein. This evidence, from a medicine already approved for use and known to be safe, led the iLCT committee to prioritise ambroxol for a clinical trial in people with Parkinson’s.

The research steps

The phase 2 trial of ambroxol – the AIM-PD trial:

Cure Parkinson’s, together with Van Andel Institute and the John Black Charitable Foundation, funded a small phase 2 clinical trial of ambroxol in people with Parkinson’s (called AIM-PD), led by Professor Schapira. This ran from January 2017 to April 2018 and its purpose was to lay the foundations for larger trials of ambroxol by answering fundamental questions about its suitability and effectiveness as a potential treatment for people with Parkinson’s.

Read more about the phase 2 AIM-PD trial

17 volunteers with Parkinson’s took ambroxol for six months – eight had GBA1 mutations, nine did not. A lumbar puncture, to withdraw a sample of cerebrospinal fluid (CSF), was carried out at the start and end of the trial. CSF circulates in the brain and central nervous system, so its analysis can help to reveal if the drug is being delivered to or released from the brain.

The results published in January 2020, showed that after six months, ambroxol was present in the CSF. This is important because it proves that ambroxol can pass from the bloodstream into the brain, to reach its intended target. The level of the toxic protein alpha-synuclein – prevalent in Parkinson’s – and the level of GCase, both rose in the CSF by 35% and 13% respectively. This suggests improvement in the waste clearance from cells in the brain.

Participants’ movement symptoms improved by 6.8 points on a scale, based on observations and measurements made by the trial clinicians.

However, this element of the results should be treated with caution because the trial design was such that it didn’t robustly test the physical impact of ambroxol. There was no placebo control group – everyone knew that all participants had been taking ambroxol, rather than blank pills – and this can have a profound impact on perceived improvements.

Interestingly, the results were observed across all the trial participants, regardless of whether they carried a GBA1 mutation.

Read the full study paper here.

The findings from the trial were by no means conclusive because they came from a small ‘proof-of-concept’ study testing simple biochemical changes in the 17 participants. Nevertheless, the results added to the evidence that GCase enhancement is a really promising research target to find treatments to slow, stop or reverse the course of Parkinson’s.

The next steps

The genetics of Parkinson’s has provided us with insights into the underlying biology of the condition; we now understand more about the biological processes associated with genetic risk factors, and experimental treatments have been developed to target them. These novel treatments are being clinically tested to see if they will have beneficial effects not just for individuals carrying certain genetic risk factors, but also for the wider Parkinson’s community. Recently, there has been increasing evidence supporting this; some of the biological pathways associated with these genetic variations appear to also be abnormal in people with Parkinson’s who do not carry the genetic variation.

PD Frontline

PD Frontline is an online genetic study which aims to put people with Parkinson’s at the forefront of ongoing research. For the first time, drugs that protect against or slow down the progression of Parkinson’s are a real possibility, and many such drugs are targeted at specific genes which we know influence the development of Parkinson’s, such as the GBA-1 gene.

Dr Mullin presents at our Research Update Meeting 2019

To test whether these drugs work, we need to identify people with variations in specific genes who can then take part in clinical trials. PD Frontline tests for two genetic risk factors for Parkinson’s; these are GBA1 and LRRK2. 

Cure Parkinson’s is now working hard with researchers to robustly assess the potential of ambroxol as a future treatment for Parkinson’s. We are also keeping abreast of another clinical trial of ambroxol in Parkinson’s that is underway in Canada, as well as several research programmes investigating other ways to target GCase and its actions.

The evidence for ambroxol and GCase enhancers continues to build and Cure Parkinson’s is at the forefront of driving this into clinical practice for the treatment of people with Parkinson’s.