Based on the 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 for clinical evaluation in Parkinson’s.

This resulted in a UK-based clinical trial, co-funded by Cure Parkinson’s. The results – together with international efforts – support ambroxol and other GCase-enhancers as a promising avenue in our search for treatments to halt the progression of Parkinson’s.

Dr Mullin presents at our Research Update Meeting 2019

When we get a cold, many of us think nothing of reaching for over-the-counter medicines to help control our symptoms. So it comes as quite a surprise that a shop-bought cold remedy – found in households across Europe – is now under the spotlight as a potential treatment for Parkinson’s. Ambroxol is an expectorant, used commonly on the continent as a medicine for coughs and sore throats, as well as in the treatment of lung diseases. However, in 2009, researchers discovered that ambroxol increases the activity of an enzyme – known as GCase – which is believed to have a role in Parkinson’s. Based on this and other evidence, the iLCT committee prioritised ambroxol for clinical evaluation in 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 a promising avenue in our search for treatments to halt the progression of Parkinson’s.

The evidence for ambroxol

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

What is GCase?

GCase is an enzyme found inside our cells. It’s involved in the breakdown and clearance of waste proteins. Researchers first suspected that GCase had a role in Parkinson’s when they discovered that people with tiny mutations in the gene responsible for the production of GCase – known as the GBA gene – are at greater risk of developing the disease.

The GBA-1 gene

Genetic testing has now revealed that mutations in the GBA1 gene – which cause faults in GCase production – are found in approximately 5%–8% of people with Parkinson’s. It’s the most common genetic risk factor for Parkinson’s.

Professor Anthony Schapira at University College London and the Royal Free Hospital instigated further research. He and his colleagues found that treatment with ambroxol increased the GCase activity in samples of skin cells from people with Parkinson’s.

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They 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 levels of alpha-synuclein  in cells that had too much of it.

So, ambroxol appeared to partially restore GCase activity and combat the accumulation of alpha-synuclein. 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.

Research steps

The Phase 2 Trial of Ambroxol – AIM-PD:

In 2016, Cure Parkinson’s together with Van Andel Institute and the John Black Charitable Foundation, agreed to fund a small phase 2 clinical trial of ambroxol for Parkinson’s (called AIM-PD) led by Professor Schapira. This ran from January 2017 to April 2018. It aimed to lay the foundations for larger trials by answering fundamental questions about the suitability and effectiveness of ambroxol as a potential treatment.

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17 volunteers with Parkinson’s took ambroxol for six months. The researchers assessed how well the medicine was reaching the brain and how much it increased GCase activity. They monitored side effects, and carried out some basic measures of disease symptoms.

The results published in January 2020 showed that ambroxol was able to reach the brain after being taken in tablet form, it was safe and had few side effects. In addition to showing increased levels of GCase, there were indications that more alpha-synuclein was being expelled from the brain. There was evidence of movement symptoms also improving but as this was an unblinded study, this outcome must be treated with caution.

Read the study paper here.

The findings from the trial are by no means definitive because they come from a small ‘proof-of-concept’ study – testing simple biochemical changes in 17 participants. Nevertheless, they add to the evidence that GCase-enhancement is a really promising research theme in our quest to find treatments that slow, stop or reverse the course of Parkinson’s.

Cure Parkinson’s is now working hard with researchers to explore this further and robustly assess the potential of this cough medicine 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.

If the evidence in favour of ambroxol and GCase enhancers continues to build, Cure Parkinson’s will be at the forefront of driving this into clinical practice for the treatment of patients.

Read more about the AIM-PD trial

The phase 2 clinical trial involved 17 people with Parkinson’s. Eight had GBA1 mutations, nine did not. Each participant took an increasing dose of daily ambroxol tablets up to 1.26g of the drug per day – 10 times the normal dose – for six months.

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 the molecules being delivered to or released from the brain.

Movement symptoms, such as speech, walking and tremor, were assessed and scored using a standard scale.

After six months, ambroxol was present in the CSF. This is important because it proves that it can pass from the bloodstream into the brain, to reach its intended target. The level of the toxic protein prevalent in Parkinson’s called alpha-synuclein, and the level of GCase rose in the CSF, by 35% and 13%, respectively. This suggests improvement in 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 clinicians. Read more about this trial. However, this element of the results should be treated with caution at this stage. The trial design was such that it didn’t robustly test the physical impact of ambroxol. There was no placebo control – everyone knew that all participants had been taking ambroxol, rather than sugar pills – and this can have an impact on perceived improvements.

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