Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data

Abstract

Ambroxol hydrochloride is an oral mucolytic drug available over‐the‐counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several‐fold higher dose. Unfortunately, there have been no pharma‐driven clinical trials to establish its use. Thus, real‐world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA‐Parkinson disease (GBA‐PD). Clinicians treating patients with ambroxol for GD and GBA‐PD were approached to collaborate in an investigator‐initiated registry. Anonymized data were collected, including demographics, GD type, GD‐specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5–74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1–76) months and 435 (75‐1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease‐modification for GBA‐PD, these preliminary data may be encouraging to physicians and patients who consider an off‐label use of ambroxol.

Involvement of Ceramide Metabolism in Cerebral Ischemia

“…Post-stroke pneumonia is a common complication in patients that suffered cerebrovascular ischemia ( Li et al, 2019 ). Interestingly, patients treated with ambroxol obtained a better recovery after ischemic stroke or intracerebral hemorrhage ( Jiang et al, 2020 ; Istaiti et al, 2021 ). Recently, ambroxol was described to upregulate acid β-glucosidase and promote neural stem cells differentiation through activation of Wnt/β-Catenin pathway ( Ge et al, 2021 ).…”

“…Therefore, most of the studies have been directed to Gaucher’s disease. However, ambroxol a mucolytic drug used to treat Gaucher’s and Parkinson’s disease in a clinical trial ( Istaiti et al, 2021 ), showed encouraging data for the treatment of ischemia. Post-stroke pneumonia is a common complication in patients that suffered cerebrovascular ischemia ( Li et al, 2019 ).…”

Promising Effect of High Dose Ambroxol Treatment on Neurocognition and Motor Development in a Patient With Neuropathic Gaucher Disease 2

“…Furthermore, by crossing the BBB it might have an impact on central nervous system manifestations ( 20 ). Due to the encouraging results of the above mentioned pilot study, ambroxol has become a common off label therapy for neuropathic GD ( 26 ). In a recently published analysis of 23 GD 2 patients receiving different approved and experimental treatment regimen (symptomatic, ERT, SRT, HSCT, N-acetylcysteine and ambroxol) the mean age of death was 19.2 months (3–55 month) ( 6 ).…”

Targeting Macroautophagy as a Therapeutic Opportunity to Treat Parkinson’s Disease

“…The compound ML-SA1 reduces SNCA accumulation in DA neurons from PD patients by increasing lysosomal biogenesis and function ( Tedeschi et al, 2019 ; Tsunemi et al, 2019 ). Targeting lysosomal function currently has an ample clinical pipeline: the drug Ambroxol is currently approved for the treatment of respiratory diseases, but preclinical and clinical data support a therapeutic potential for PD patients ( Silveira et al, 2019 ; Mullin et al, 2020 ; Istaiti et al, 2021 ). These findings strongly support the hypothesis that dysfunction of the lysosome has a pivotal role in the etiology of PD.…”