Ambroxol - the next big hope

But why does it take so long to test a Parkinson's drug?

Ambroxol’s long road to human trials

For someone like me who gave up biology at 14 and did a humanities degree, the Cure Parkinson’s twice yearly research update is an amazing but intense experience. First you get to meet lots of lovely people from the Parkinson’s community who share your interest in research into our condition. Then you spend an afternoon concentrating very hard as world-leading scientists explain the work they are doing in pursuit of the simple aim of the charity which helps fund them - curing Parkinson’s.

This week the Spring update, held in the spacious surroundings of BMA House, was mainly focused on a drug called ambroxol, which is just going into a phase 3 trial. If it comes through this with positive results then it could be the first disease modifying drug - in other words the first not simply to mask the symptoms but to slow, stop or reverse Parkinson’s. But, as we saw with the failure of the exenatide phase 3 trial last autumn, that is a big if.

We heard about ambroxol from every angle with a cast of speakers giving us a crash course in biology, genetics and chemistry which had my unscientific brain spinning. First of all we heard some history, learning that, like exenatide, a diabetes treatment, this was an existing drug, a widely used cough medicine. Dr Marco Toffel of University College London took us back 2,000 years when healers would give a patient with a cough a herbal tea with an ingredient that seemed to cure them.

Leaping forward to the 1970s, we heard that German doctors travelled to India to study the very same herbal tea and isolated a molecule called ambroxol which became a popular cough medicine across Europe (though not prescribed in the UK.)

We then dived into our first genetics lesson, with Dr Toffel explaining that the risk of developing Parkinson’s was higher in people with a mutated version of a gene called GBA. This gene plays an important role in keeping brain cells healthy and the mutation appears to allow the buildup of proteins like alpha-synuclein, which accumulates in the neurons of people with Parkinson's disease. The ambroxol breakthrough came in 2009 when researchers found that it improved the function of neurons damaged by the mutated GBA gene.

While only around 10% of people with Parkinson’s have the GBA mutation, the aim is that they will make up 50% of the participants in the ambroxol trial. It was stressed that this did not mean that the drug, if successful at the trial, would only work for those with the GBA mutation, merely that researchers would have a better understanding of how it functioned in those cases.

We heard also from PD Frontline, an organisation which carries out genetic testing and helps in the recruitment of participants in clinical trials - like ASPro-PD as the ambroxol trial is known. I was surprised to hear that it can take up to a year for people to receive the results of their genetic tests - which must put a brake on the speed at which participants in a clinical trial can be recruited.

Which brings us to what I found the most striking presentation of the afternoon, from Mairead Cullen who is in charge of the day-to-day operations of the ASPro-PD trial. First, she stressed its size and complexity - 330 patients to be recruited at 15 NHS sites across the UK. Recruitment will end in February 2027 - or earlier if they can hit the target sooner. Participants will spend 34 months in the trial, two years when neither they nor the doctors will know whether they are on the drug or a placebo, six months when everyone gets ambroxol, followed by a period of obervation once they are off the drug.

But then Mairead went through the series of regulatory hurdles that the trial had been obliged to clear. We had heard earlier from the trial leader Professor Anthony Schapira about the decade of tests in the lab, starting with skin cells taken from people with Parkinson’s and moving up through flies, fish and mice to a monkey. These tests indicated that ambroxol was safe - hardly surprising since it had been soothing coughs for many years - and was reaching the brain and doing good things there.

The phase 2 clinical trial involving 23 human participants finished in 2018 with the successful results published in 2020. Much of the last five years has been spent writing a series of documents needed before the phase 3 trial could get the green light. First, the protocol, the mission statement for the whole trial. Mairead Cullen described this mammoth undertaking: “There are lots of people who are involved in writing this protocol. It goes through several review committees, and it takes a long time to get it right and get it into that finalised state.”

But there are a host of other documents to be written - manuals for each test site setting out every detail of how the participants are treated and the drug or placebo is dispensed, safety management documents, quality assurance, supplier contracts.

”Once we have all of the documents, we have all of the sites that we think we're going to have in the trial, and we have contracts with all of our vendors, we can then initiate the ethics review and trial approval process.”

It made me tired just thinking about it. No wonder then that a process which began in 2009 with the discovery that ambroxol looked as though it might be beneficial for people with Parkinson’s will probably not conclude before 2030. My suspicion is that at a time when we are told that AI is going to accelerate drug discovery, ever greater levels of bureaucracy are actually slowing it down.

I put that to Mairead Cullen during the Q&A at the end of the event. “It's a lot to do, and it's quite frustrating,” she admitted. “We think by now we would have a quicker pathway.” But she was diplomatic, saying that in the UK trials were at least very safe.

I went home stimulated by my glimpse into the exciting world of drug research but impatient for some sign that it can move faster .

But as I was writing this a message arrived in the inbox of Movers and Shakers, our podcast about Parkinson’s, from a man who had been at the same meeting. Dave Butterworth wasn’t just impatient, he was furious:

“My take on it as a 60 year old man who has been diagnosed for 14 years is the way this compound has been treated is nothing short of .. a disgrace. As I’m sure everyone knows this has been used as an over the counter cough and sore throat treatment since before I was a kid.”

While I am sympathetic to the scientists, Dave was angry, believing that they were preventing him from benefiting from ambroxol:

“They should be asking themselves was it really necessary to allow at least a whole generation to have missed out on its benefits. Surely the process they followed could have been shortened. The drug is known to be safe after its widespread use over decades, if not at the concentrations they are using.”

I can quite understand Dave’s frustration at the long wait for a miracle drug that always seems to be five years away. But there is something we all can do - try to join the ambroxol trial. You can find information about it here and here.