A 10-year follow-up of high-dose ambroxol treatment combined with enzyme replacement therapy for neuropathic Gaucher disease

Gaucher


C O R R E S P O N D E N C E
A 10-year follow-up of high-dose ambroxol treatment combined with enzyme replacement therapy for neuropathic Gaucher disease To the Editor: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency in glucocerebrosidase (GCase), leading to the lysosomal accumulation of glucosylceramide (Gb1).The prevalence varies among ethnic groups, ranging from 0.45 to 25.0 per 100 000 live births. 1,2Neuropathic forms of GD (nGD) are severe and characterized by cognitive decline, seizures, gaze palsy, and ataxia.
Notably, in Asian populations, about half of GD patients exhibit the neuropathic form, often experiencing a more severe progression. 3e genotype-phenotype relationship involves over 400 GBA gene variants; N409S is common in Ashkenazi Jews and linked to the nonneuropathic form, while N483P is prevalent in Asians and associated with neuropathic forms. 1 Enzyme replacement therapy (ERT) is conventional but less effective for neurological symptoms due to the blood-brain barrier.Consequently, alternative therapies such as substrate reduction therapy and chaperone therapy are being explored for nGD.Ambroxol, initially developed as a mucolytic agent with antiinflammatory and antioxidant properties, has garnered attention as a small molecule capable of crossing the blood-brain barrier.High-dose ambroxol has shown promise in partially restoring GCase activity and is now employed in chaperone therapy for nGD. 4 Here, we conducted a 10-year longitudinal study involving the high-dose administration of ambroxol combined with ERT in six patients with nGD.This study aimed to assess the treatment efficacy of ambroxol and compare the outcomes of patients with nGD according to disease severity.A total of six patients with nGD were enrolled at Asan Medical Center (Seoul, Korea) since August 19, 2013.This study, approved by the Institutional Review Board (approval no.2014-1113) and the Ministry of Food and Drug Safety, obtained written informed consent from all participants.The patients received biweekly ERT with imiglucerase (Abcertin ® , ISU ABXIS, Seongnam, Korea) at a dosage of 60 IU/kg.Ambroxol was started at 1.5 mg/kg/day and increased by 3 mg/kg/day monthly, up to a maximum of 35 mg/kg/day.The trough plasma concentration of ambroxol remained below 10 μmol/L.The severity of the disease was assessed using mSST scores and functional independence, categorizing patients into mild and severe groups.Primary outcomes measured changes in disease severity, with additional assessments on neurological outcomes, systemic parameters, biomarkers, and safety.Pharmacokinetics of ambroxol and GCase activity were also analyzed.
Six female patients with genotypes associated with neuropathic forms and responsiveness to ambroxol treatment (N227S, F252I, L483P, R296Q) were categorized into mild and severe groups based on mSST scores and functional independence (Figure 1A,B).The median ages at diagnosis and neurological onset were 10.5 years (range, 1-31) and 12 years (range, 10-24), respectively.Median ages at the start of ERT and ambroxol treatment were 12 years (range, 3-32) and 18.0 years (range, 16-33).The median follow-up period is 9.8 years (range, 2.8-10).At the initiation of ambroxol treatment, four patients classified in the mild group with low mSST scores (median, 7.5) exhibited minimal dependency on assistance and increased independence in daily living, as indicated by the Korean version of the modified Barthel index (K-MBI) scores (median, 100).In contrast, the severe group consisted of two sisters who presented severe neurological symptoms, including myoclonus, seizures, severe intellectual disability, and psychosis.They had high mSST scores (median, 17) and required support for walking, demonstrating severe dependency (K-MBI scores median, 35).Notably, the mild group was diagnosed at a younger age (median, 6.5 vs. 13 years) and started ambroxol earlier (median, 18.5 vs. 21 years) but had a shorter follow-up period (median, 7.9 vs. 10 years).However, no statistically significant differences were found between the two groups.
The primary outcome of the study was disease progression, as measured by the mSST score, in patients with nGD undergoing highdose ambroxol treatment.Individual mSST scores are depicted in Annual brain MR spectroscopy indicated stable or no significant increase in N-acetyl-aspartate/creatine (NAA/Cr) and choline/creatine (Cho/Cr) ratios throughout the treatment (Table S2).
Systemic assessments of visceral symptoms were conducted (Figure S2).Hemoglobin levels remained stable in both groups.ERT significantly improved thrombocytopenia.Notably, following the addition of ambroxol treatment, median platelet counts increased from 172 000/μL at baseline to 256 000/μL after 10 years in the mild group but decreased from 127 000/μL to 99 000/μL in the severe group.The median liver volume showed a slight decrease in the mild group, decreasing from 962 to 828 mL, while it remained stable in the severe group (942-938 mL).The median spleen volumes decreased in both groups, with the mild group decreasing from 177 to 116 mL and the severe group decreasing from 229 to 144 mL.No significant differences were observed between the two groups.As indicated by Z-scores in the lumbar spine, bone mineral density ranged from 0.2 to 0.9 in the mild group and from À1.7 to À1.6 in the severe group.
Despite ERT improving visceral symptoms, high-dose ambroxol treatment suggests potential additional efficacy, especially in the mild group with early intervention, for alleviating specific visceral symptoms such as thrombocytopenia and osteopenia, compared to the severe group.
Patients who received up to 35 mg/kg/day of ambroxol for at least 2 years exhibited peak concentrations in plasma (1.74-9.9μmol/L) and cerebrospinal fluid (0.4-2.7 μmol/L) (Figure S3).The median duration of ambroxol therapy at the maximal dose is 7.9 years (range 2.1-9.3).Peripheral leukocyte GCase activity significantly increased for all patients (4.7%-15.2% of normal activity), with no significant difference between groups (Figure S4).Biomarkers such as acid phosphatase, angiotensin-converting enzyme, and lyso-Gb1 were measured.Acid phosphatase levels tended to decrease in both groups while angiotensin-converting enzyme and lyso-Gb1 levels showed no significant changes (Figure S5).
Regarding the safety assessment, all patients tolerated ambroxol doses up to a maximum of 35 mg/kg/day.The study identified 11 mild to moderate drug-related adverse events in five patients, such as hypouricemia, productive cough, increased sputum, transient proteinuria, vomiting, and erythema at the gastrostomy site (Table S3).All patients fully recovered, and no serious adverse drug events were reported.
This study represents a relatively long-term investigation into ambroxol treatment for nGD.Ambroxol has shown positive responses in GCase mutations associated with nGD, including p.N227S, p.F252I, p.G232W, p.R159W, p.G241R, and p.N409S.Previous studies also revealed increased GCase activity in mutants such as R296Q and L483P, 5 which were present in the current study patients.Specifically, Patient 3 had the N227S mutation in compound heterozygosity with a frameshift mutation (P210fsX21), and she also exhibited increased GCase activity when treated with ambroxol, both in vitro and in vivo. 5rsonalized testing for genotypes associated with a positive response to ambroxol is crucial for further investigation.myeloma and lymphoma.Understanding the pathophysiology of GD is crucial for developing targeted therapies, especially considering the limitations of ERT.As the accumulation of Gb1 and lyso-Gb1 triggers inflammation in various organs, ambroxol shows promise in this regard considering its anti-inflammatory effect.Previous studies have revealed that atypical cells in patients with GD activate the classical pathway of complement, and ambroxol helps prevent endothelial-to-mesenchymal transition by stabilizing TGF-β signaling. 6Ongoing real-world trials with high-dose ambroxol in GD, considering different types and treatment states, show no severe adverse events.Patients, even those with poor response to ERT, show improved symptoms and halted neurological decline with ambroxol treatment.Additionally, starting treatment at a younger age is associated with better outcomes. 7e 10-year follow-up study on ambroxol treatment in combination with ERT for nGD compares neurological outcomes between the mild and severe groups.The mild group consistently exhibited superior performance in daily activities, maintaining this functional level with early ambroxol treatment.Notably, the mild group achieved a seizure-free state without the need for additional anti-epileptic drugs.
While ERT improved visceral symptoms, the mild group showed additional improvement with ambroxol in thrombocytopenia and osteopenia compared to the severe group.The relatively reduced effectiveness in the severe group may be attributed to prolonged tissue inflammation and organ damage.In conclusion, initiating ambroxol early before disease progression in nGD is crucial for a favorable prognosis, particularly in cases of mild disease status.
Administering high-dose ambroxol presents challenges in real-life scenarios as patients need to take multiple tablets, and its bitter taste may adversely impact patient compliance.Developing concentrated formulations is crucial for improving patient care.Additionally, studying rare diseases like GD has inherent limitations, making large, randomized trials for statistical significance unfeasible.Despite the small sample size of only 6 patients, reflecting the low prevalence of GD in Asia, 2 this study offers valuable insights into the efficacy of ambroxol over an extended period of 10 years.However, caution is needed in interpretation due to the broad spectrum of the study period, which ranged from 2.8 to 10 years.

Figure 1C .
Figure 1C.The overall neurological assessments, including mSST score, K-MBI score, Korean Wechsler Adult Intelligence Scale-IV (K-WAIS), and seizure frequencies, are summarized in Table S1.The mild group maintained a stable mSST score (6.0-9.3), with K-MBI scores consistently around 100, indicating independence in daily living.The severe group showed an initial increase in the median mSST score from 17.0 to 19.5 after 3 years, gradually decreasing to 11.0 after 10 years.The seizure frequency decreased from 5.5 to 1.0 per 2 weeks in the total patient population, with the mild group achieving seizure absence.All patients maintained or reduced their anti-epileptic drugs during ambroxol treatment (Figure S1).Cognitive function, as Some patients with GD, despite undergoing ERT, experience neurological deterioration and atypical progression such as multiple F I G U R E 1 High-dose ambroxol therapy combined with Enzyme replacement therapy (ERT) in patients with Neuropathic forms of GD (nGD) (n = 6).(A) Clinical characteristics of patients.(B) Study design.(C) Neurological assessments (individual mSST score).