High-Dose Ambroxol Therapy in Type 1 Gaucher Disease Focusing on Patients with Poor Response to Enzyme Replacement Therapy or Substrate Reduction Therapy

Abstract

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103/L, lumbar spine bone density T-score < −2.0, and/or LysoGb1 > 200 ng/mL, and for a group of naïve patients who had abnormal values in two of these three parameters. We enrolled 40 patients: 28 ERT- or SRT-treated, and 12 naïve. There were no severe adverse effects (AEs). There were 24 dropouts, mostly due to AEs (n = 12), all transient, and COVID-19 (n = 7). Among the 16 completers, 5 (31.2%) had a >20% increase in platelet count, 6 (37.5%) had a >0.2 increase in T-score, and 3 (18.7%) had a >20% decrease in Lyso-Gb1. This study expands the number of patients exposed to high-dose ABX, showing good safety and satisfactory efficacy, and provides an additional rationale for adding off-label ABX to the arsenal of therapies that could be offered to patients with GD1 and a suboptimal response or those unable to receive ERT or SRT.

Ambroxol as Therapy for Gaucher Disease—Ambitious but Ambivalent

“…Regarding ambroxol and GD1, although the safety profile seems favorable, clinical responses reported by Zhan et al and Istaiti et al, albeit in very different populations, appear less robust than those reported for ERTs and eliglustat. Perhaps a disconnect exists between the reported good neurological responses and the middling systemic responses, as hinted at in a recent case report in which an infant with type 2 GD who started ambroxol shortly after birth had no neurological progression after 4 years yet had rapid systemic progression requiring institution of ERT.…”

“…However, because ambroxol's effects also include inhibition of pH-neutral, nonlysosomal glucocerebrosidase (GBA2), sodium channel blockade, upregulation of intracellular antioxidant and antiapoptotic signaling pathways, and antiinflammatory and immunomodulatory effects, it is uncertain to what extent reported improvements in neurological manifestations in children with GD3 are solely a function of lysosomal GCase activity enhancement. 4 Regarding ambroxol and GD1, although the safety profile seems favorable, clinical responses reported by Zhan et al 1 and Istaiti et al, 7 albeit in very different populations, appear less robust than those reported for ERTs and eliglustat. Perhaps a disconnect exists between the reported good neurological responses and the middling systemic responses, as hinted at in a recent case report 8 in which an infant with type 2 GD who started ambroxol shortly after birth had no neurological progression after 4 years yet had rapid systemic progression requiring institution of ERT.…”

“…Without pharmacokinetic data for ambroxol administered to patients with GD in different formulations (tablets, syrup, and caplets of different strengths), how can optimal dosing be determined? How does this affect patient adherence, which was problematic in the study by Istaiti et al 7 and doselimiting in the study by Zhan et al? 1 Overall, there is no plan for randomized prospective studies to assess the efficacy of ambroxol in large, varied populations of patients with GD.…”

The use of Ambroxol for the treatment of Gaucher disease: A systematic review

“…These found 36% [39] and 55% [28] of patients reported symptomatic relief. The remaining study reported on changes in laboratory values rather than clinical parameters and did not state whether these were statistically significant.…”

“…A single type of GD comprised the entire cohort in seven case series, with the remaining two reporting multiple types (with only one reporting outcomes for these separately [28]). Three case series reported on type 1 GD [28,35,39]. However, only two reported clinical outcomes.…”