After reviewing pre-clinical laboratory data from Professor Anthony Schapira’s team at UCL, a committee of experts brought together by Cure Parkinson’s, prioritised the simple cough medicine ambroxol for further investigation to understand if it has the potential to slow the progression of Parkinson’s.

This decision was based on evidence from a phase 2 clinical trial that demonstrated that ambroxol could improve the breakdown and clearance of waste proteins that build-up and clump together in brain cells – a characteristic feature of Parkinson’s. The UK-based phase 2 clinical trial of ambroxol in 17 people with Parkinson’s, was funded and supported by Cure Parkinson’s, Van Andel Institute and the John Black Charitable Foundation; and the results of that study, together with additional pre-clinical and clinical findings, support ambroxol and other drugs in this class of so-called GCase-modulators as a promising area of research to slow or stop the progression of Parkinson’s.

The phase 3 trial of ambroxol called ‘ASPro – PD’ is in set-up, funded by Cure Parkinson’s alongside its strategic partners Van Andel Institute and the John Black Charitable Foundation, and by the Parkinson’s Virtual Biotech, the drug discovery and development arm of Parkinson’s UK. The trial, it is hoped, will determine if ambroxol can slow 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, commonly used to relieve mucus production in coughs and inflammation in sore throats.

In 2009, researchers discovered that ambroxol increased the activity of an enzyme called GCase (glucocerebrosidase) in the body, which is believed to have a role in Parkinson’s. Further scientific experiments demonstrated that ambroxol could rescue laboratory models of Parkinson’s. Based on this and other evidence, the International Linked Clinical Trials (iLCT) committee prioritised ambroxol for clinical trial testing in people with Parkinson’s, prompting the UK-based phase 2 clinical trial called AIM-PD. The results of this and other global research provide further support of ambroxol and other GCase-enhancers as promising potential treatments for Parkinson’s.

What is GCase?

GCase (glucocerebrosidase) is an enzyme found inside our cells that is involved in the breakdown and clearance of waste proteins. A build-up of proteins like alpha-synuclein, which becomes mis-folded and clumps together, is a characteristic feature of Parkinson’s and is believed to have a role in the neurodegeneration associated with the condition. People with tiny mutations in the gene responsible for making the enzyme GCase – known as the GBA1 gene – produce less GCase, and are at greater risk of developing Parkinson’s. Less GCase makes the waste disposal system of cells less efficient, resulting in a build-up of waste proteins, and this puts stress on cells.

The GBA1 gene

Genetic testing has now revealed that mutations in the GBA1 gene, which causes problems with GCase production, are found in around 10-15% 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 the GBA1 mutation, also have lower levels of GCase production. This finding suggests that GCase-enhancers like ambroxol might be useful for a wider proportion of the Parkinson’s community than just those people with a mutation in the GBA1 gene.

What is the evidence for ambroxol as a potential treatment for Parkinson’s?

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

Making the case for GCase

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

Read more about this study

The study team’s research showed ambroxol appeared to partially restore GCase activity and combat the toxic effects of clumped forms of the alpha-synuclein protein. Read more here

This evidence, from a cough medicine already approved for use and known to be safe, led the iLCT committee to prioritise and recommend ambroxol for a clinical trial in people with Parkinson’s.

The phase 2 trial of ambroxol – AIM-PD:

Cure Parkinson’s, Van Andel Institute and the John Black Foundation funded and supported the small phase 2 clinical trial of ambroxol in people with Parkinson’s called AIM-PD, which was 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 safety, 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. Tests of cerebrospinal fluid (CSF) were 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 levels of alpha-synuclein and GCase both rose in the CSF of study participants by 35% and 13% respectively; this suggests there was improvement in the waste clearance from the brain.

Participants’ movement symptoms improved based on observations and measurements made by the trial clinicians.

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

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

Further reading: 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 trial 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 progression of Parkinson’s.

Next steps

To get to this stage, a wide range of people from the Parkinson’s community have been involved: through consultation, early laboratory based research and clinical trial work, the trial has already had input from neuroscientists and neurologists, medical regulators and people with Parkinson’s. The phase 3 trial of ambroxol called ‘ASPro – PD’ is in set-up. This trial, it is hoped, will determine if ambroxol can slow or stop the progression of Parkinson’s.

If the ASPro-PD clinical trial proves that ambroxol does indeed slow the progression of Parkinson’s, the urgent focus of everyone involved will be to ensure that the drug reaches people with Parkinson’s as quickly as possible, working with the pharmaceutical industry and regulators to make this happen. Time is of the essence; provisional work on this has already started.

PD Frontline

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 certain genetic risk factors, and treatments are being developed to target these aspects of the condition. Importantly, these new potential treatments are being tested in people with Parkinson’s to see if they have beneficial effects for the wider Parkinson’s community, not just for individuals carrying certain genetic risk factors. Recently, there has been increasing evidence supporting this; some of the biological pathways associated with genetic variations appear to be abnormal in people with Parkinson’s who do not carry genetic mutations.

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.

Crucially, 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 the GBA1 gene and the LRRK2 gene. 

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