Summary: Ambroxol, a medication approved to treat coughs, may slow the progression of Parkinson’s disease. The medication is able to effectively cross the blood-brain barrier and increases levels of GCase in patients’ brains. Ambroxol also appears to reduce Parkinson’s-related alpha-synuclein levels.
Ambroxol, a medication originally designed to clear phlegm and ease coughing for people with respiratory diseases such as bronchitis, is being tested to see if it can slow down the progression of Parkinson’s disease by keeping cells healthier for longer.
A research team led by Professor Tony Schapira (UCL Queen Square Institute of Neurology) reported in January that ambroxol was safe and well-tolerated in 17 study participants with Parkinson’s disease.
According to the findings published in JAMA Neurology, the drug also effectively crossed the blood-brain barrier and increased levels of the glucocerebrosidase (GCase) protein in the participants’ brain cells. This protein allows cells to remove waste more effectively, a function which evidence suggests is deficient in some people with Parkinson’s. Increasing levels of the protein may have the potential to keep cells healthier for longer and, therefore, slow Parkinson’s progression.
This week, The Cure Parkinson’s Trust (CPT), the Van Andel Institute (VAI) and the John Black Charitable Foundation announced £522,126 of funding for the next stage of the research, which will seek to determine the optimal dosage of ambroxol. The trial will be run this year at the Leonard Wolfson Experimental Neurology Centre at UCL and led by Professor Schapira, with the aim of leading to a larger clinical trial later on.
“By increasing levels of GCase, ambroxol allows cells to remove waste, which would ideally keep cells healthier for longer and could slow down the progression of Parkinson’s,” explained Professor Schapira.
The announcement comes as part of a USD $4.5 million co-funding agreement with the Van Andel Institute (VAI) to support the International Linked Clinical Trials (iLCT) initiative. iLCT is a thriving global programme that aims to develop new, potentially disease-modifying Parkinson’s therapies, many of which are repurposed medications originally designed or approved to treat other diseases.
Candidate drugs are evaluated and prioritised annually by a committee of world-leading Parkinson’s experts, who select which drugs should enter clinical trials in people with the condition. These drugs have the potential to get to the clinic much faster as they have already passed crucial safety tests.
The iLCT committee had prioritised ambroxol in 2014.
Professor Patrik Brundin, Chair of the Linked Clinical Trials committee and Director of the Center for Neurodegenerative Science at the VAI said: “We are thrilled to continue our long-standing collaboration with The Cure Parkinson’s Trust on the International Linked Clinical Trials initiative and look forward to expanding our program to evaluate additional promising medications in the coming years. We are especially grateful to the trial participants, without whom this critical work would not be possible.”
Will Cook, CEO of CPT said: “This will enable the launch of many more clinical trials of potentially disease-modifying repurposed and novel drugs that have been identified through the diligent iLCT process, and thereby bringing us closer to our goal: a cure for the 10 million people living with Parkinson’s globally.”
About this neuroscience research article
Source: UCL Media Contacts: Chris Lane – UCL Image Source: The image is credited to Vanley.
Importance Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.
Objective To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.
Interventions An escalating dose of oral ambroxol to 1.26 g per day.
Design, Setting, and Participants This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture–related complications). All data analyses were performed from November 1 to December 14, 2018.
Main Outcomes and Measures Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity.
Results Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, –0.115 to –0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, –10.4 to –3.1; P = .001). These changes were observed in patients with and without GBA1 mutations.
Conclusions and Relevance The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD.