Our partners Cure Parkinson’s in the UK recently announced that a large-scale phase 3 trial to assess ambroxol in Parkinson’s patients is going ahead this year. This is fantastic news, as ambroxol is one of the more promising candidate disease-modifying treatments; in other words, it has the potential to stop or slow disease progression. But what is ambroxol and what makes it so interesting?
Ambroxol has been used to treat respiratory symptoms like coughs for about 50 years. In this context (expectorant), it stimulates synthesis and release of surfactants that help loosen and transport mucus. But it also has anti-infection activity, anti-inflammatory activity, and, importantly for us, neuroprotective potential. In 2009, a large-scale screening experiment showed that ambroxol was a potent stabiliser of an enzyme called GCase, and subsequent studies in model organisms showed that ambroxol could increase GCase activity in the brain supporting the clearance of accumulated proteins including α-synuclein, which is implicated in Parkinson’s. This is where things get interesting, with a nice convergence between Parkinson’s pathology and genetics.
The gene that codes for GCase in humans is called GBA1, variants of which have long been linked to Gaucher disease. Individuals with Gaucher disease have a much higher risk of developing Parkinson’s, and it is now known that 10–15% of people with Parkinson’s have specific GBA1 variants that lower GCase activity. This makes GBA1 variants the most common genetic risk factor for Parkinson’s disease. The enzyme GCase is involved in the clearance of waste proteins from cells as part of a pathway (let’s call it “taking out the trash”) that is known to be overwhelmed in Parkinson’s disease. Some of the best-known pathological hallmarks of Parkinson’s (what’s left behind when we look inside the brain) involve a build-up and clumping together of proteins like α-synuclein. And several other genetic causes or risk factors for Parkinson’s are linked to the same cellular clearance pathways.
So, genes and pathology all end up pointing in the same direction. But can something like ambroxol, by stabilizing GCase and supporting trash removal, potentially help the 85% or so of people without the GBA1 variants that increase risk of Parkinson’s as well as those with risk variants? Here’s where things get even more interesting: many people with Parkinson’s without the GBA1 risk variants also show low GCase activity, and most will show a build-up of proteins in neurons clogging up the clearance systems. With all of these findings (and there’s a ton more we don’t have the space to dive into) highlighting the potential for ambroxol to treat Parkinson’s, the international linked clinical trials (iLCT) committee made the decision in 2014 to prioritize ambroxol for clinical evaluation, leading to a phase 2 trial that was conducted in 2017–2018. So, what did the results show?
The study, which was led by Professor Anthony Schapira at University College London, enrolled 17 volunteers with Parkinson’s, eight of whom had GBA1 mutations and nine of whom did not. The volunteers took ambroxol for six months. Researchers assessed the levels of the drug and protein in CSF (cerebrospinal fluid, which could be sampled by spinal tap—after all, it’s a little hard to see what’s going on inside someone’s brain at a sub-cellular level!), showing that ambroxol was able to pass through the blood–brain barrier (i.e., it could get from the bloodstream into the brain). There were increased levels of both α-synuclein and GCase in the CSF, suggesting an improvement in cellular waste clearance. Although the trial wasn’t geared to fully assess clinical symptoms, the participants’ movement symptoms were observed to improve—and these improvements were seen in all participants regardless of whether they had a GBA1 mutation!
This was a fabulous first step toward demonstrating efficacy (for ambroxol) in Parkinson’s, and the findings of the phase 2 study were published in 2020. The real test is what comes next: a large-scale, multi-centre, randomised, placebo-controlled trial (i.e., the gold standard for providing evidence). Professor Schapira’s team is enrolling participants now. To directly quote Will Cook, CEO of Cure Parkinson’s in the UK:
“This trial is a big step forward in the search to find new treatments for Parkinson’s. Once the ambroxol trial is underway, it will be one of only six phase 3 trials on public record of potentially disease-modifying drugs in Parkinson’s, worldwide. We at Cure Parkinson’s are working hard – through our efforts within the iLCT programme and in our fundraising efforts – to increase this number significantly in the next few years, to accelerate our progress towards a cure for Parkinson’s.”
We will strive to work with partner organisations like Cure Parkinson’s to support this hugely ambitious and important goal, and we look forward excitedly to the results of this important trial.
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