Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial.

Importance Mutations of the glucocerebrosidase gene, GBA1 (OMIM ), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases beta-glucocerebrosidase (GCase) enzyme activity and reduces alpha-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 alpha-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 alpha-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. This single-center open-label nonrandomized, noncontrolled trial assesses the safety, tolerability, cerebrospinal fluid penetration, and biochemical changes associated with ambroxol therapy for the treatment of patients with Parkinson disease with and without mutations in the glucocerebrosidase gene. Question Does ambroxol cross the blood-brain barrier, and what are the biochemical changes associated with ambroxol therapy in patients with Parkinson disease with and without glucocerebrosidase gene mutations? Findings In this open-label clinical trial of 17 patients with Parkinson disease, ambroxol crossed the blood-brain barrier and bound to the beta-glucocerebrosidase enzyme, and it increased beta-glucocerebrosidase enzyme protein levels and cerebrospinal fluid alpha-synuclein levels in patients both with and without glucocerebrosidase gene mutations. Meaning Ambroxol therapy has potential for study as a neuroprotective compound for the treatment of patients with Parkinson disease both with and without glucocerebrosidase gene mutations.