CONy 2024 | Launch of the Phase III ASPro-PD study of ambroxol in Parkinson’s disease

So the idea of using ambroxol came from our investigations, and those of others, on glucocerebrosidase in Parkinson’s disease and how this increases the risk for Parkinson’s disease. For instance, in the UK, about 12% of all Parkinson’s patients have a so-called GBA1 mutation. So it’s the commonest risk factor for Parkinson’s disease. And obviously people were interested in trying to understand why does it confer this risk and how? The other interesting thing is that not everybody who carries a mutation gets Parkinson’s disease, in fact only a minority, so that’s another important question to answer. And as part of all of those studies, we were looking at molecules that might increase the activity of glucocerebrosidase to balance the effects of the mutation. Work in other laboratories, many years ago, in the context of Gaucher disease, identified ambroxol as a chaperone for glucocerebrosidase. So we had a look at this molecule and found that it did increase glucocerebrosidase activity in all tissues, including in our rodent and nonhuman primate model brains. So that was really very encouraging. Ambroxol also has some other interesting actions that are identified as improving the function of the lysosome. So all together, we thought this was a very interesting candidate to try in Parkinson’s disease.

So the small Phase II study was a proof of principle study, it was called AiM-PD. It involved only about 20 or so patients with Parkinson’s disease. And the questions that we wanted to ask with that small study, was, is ambroxol well tolerated over a six-month period? Does it enter the nervous system as judged by concentrations in the CSF? And can we see an effect of the drug on the glucocerebrosidase pathway as determined by levels of protein in the CSF? So the results of the study clearly showed that the drug does enter the CNS at quite good concentrations, about 11% of the blood, and it does significantly increase glucocerebrosidase protein levels in the CSF. The people with Parkinson’s that were taking the drug tolerated it very well and had no significant side effects related to the drug, and there were no complex interactions with their medication. So, it seemed like a good candidate to proceed.

The Phase III study, called ASPro-PD, is looking at the effect of ambroxol in slowing Parkinson’s disease over a two-year period. This study is supported by Cure Parkinson’s and other agencies, including Parkinson’s UK in the UK and the John Black Foundation, and also from the United States. So we’re indebted to all of those people for supporting this study. And we will base the study in the UK, at about 15 or so sites around the UK. We’ll be recruiting 330 people with Parkinson’s disease for the study, half of whom will have a GBA mutant and half will not. So we’ll be able to look at the effect of the drug over a two year period in these people and also determine at the end of it, a) whether the ambroxol is effective in slowing Parkinson’s disease down, and also whether it works in those with and without a GBA mutation. Our endpoint is the total UPDRS, it’s a fairly standard endpoint. It involves motor, but importantly, quality of life issues too, so patient reported outcomes, which I think are an important endpoint for studies now.

So they can either contact us at UCL through me, or they can encourage their patients to enrol on what’s called PD Frontline. PD Frontline is a UK wide web-based recruitment for people with Parkinson’s disease. And they can, through that, obtain their GBA genotype, their GBA result, find out whether they’re positive or negative. And also, to learn about joining the study.