Use of Ambroxol as Therapy for Gaucher Disease

Abstract

ImportanceAmbroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009.ObjectivesTo assess hematologic and visceral outcomes, biomarker changes, and safety of ambroxol therapy for patients with Gaucher disease (GD) without disease-specific treatment.Design, Setting, and ParticipantsPatients with GD who could not afford enzyme replacement therapy were enrolled and received oral ambroxol from May 6, 2015, to November 9, 2022, at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Thirty-two patients with GD (29 with GD type 1, 2 with GD type 3, and 1 with GD intermediate types 2-3) were enrolled. Of those, 28 patients were followed up for longer than 6 months; 4 were excluded due to loss of follow-up. Data analyses were performed from May 2015 to November 2022.InterventionAn escalating dose of oral ambroxol (mean [SD] dose, 12.7 [3.9] mg/kg/d).Main Outcomes and MeasuresPatients with GD receiving ambroxol were followed up in a genetic metabolism center. Biomarkers of chitotriosidase activity and glucosylsphingosine level, liver and spleen volumes, and hematologic parameters were measured at baseline and various time points throughout the ambroxol treatment.ResultsA total of 28 patients (mean [SD] age, 16.9 [15.3] years; 15 male patients [53.6%]) received ambroxol for a mean (SD) duration of 2.6 (1.7) years. Two patients with severe symptoms at baseline experienced deterioration of hematologic parameters and biomarkers and were deemed nonresponders; clinical response was observed in the other 26 patients. After 2.6 years of ambroxol treatment, the mean (SD) hemoglobin concentration improved from 10.4 (1.7) to 11.9 (1.7) g/dL (mean [SD], 1.6 [1.7] g/dL; 95% CI, 0.8-2.3 g/dL; P < .001), and the mean (SD) platelet count improved from 69 (25) to 78 (30) × 103/µL (mean [SD], 9 [22] × 103/µL; 95% CI, −2 to 19 × 103/µL; P = .09). The mean (SD) spleen volume decreased from 17.47 (7.18) to 12.31 (4.71) multiples of normal (MN) (mean [SD], −5.16 [5.44] MN; 95% CI, −10.19 to −0.13; P = .04), and the mean (SD) liver volume decreased from 1.90 (0.44) to 1.50 (0.53) MN (mean [SD], −0.39 [0.42] MN; 95% CI, −0.75 to −0.04; P = .03). Biomarker median percentage changes from baseline were −43.1% for chitotriosidase activity (from 14 598 [range, 3849-29 628] to 8312 [range, 1831-16 842] nmol/mL/h; z = −3.413; P = .001) and −34.1% for glucosylsphingosine level (from 251.3 [range, 73.6-944.2] to 165.7 [range, 21.3-764.8] ng/mL; z = −2.756; P = .006). Patients were divided into subgroups according to age when initiating treatment; those who received treatment at a younger age (mean [SD] age, 6.3 [2.7] years) experienced more rapid improvements: hemoglobin concentration increased by 16.5% (from 10.3 [1.5] to 12.0 [1.5] g/dL; mean [SD] change, 1.6 [1.6] g/dL; 95% CI, 0.7-2.5 g/dL; P = .002), and platelet count increased by 12.0% (from 75 [24] to 84 [33] × 103/µL; mean [SD] change, 9 [26] × 103/µL; 95% CI, −5 to 24 × 103/µL; P = .17); whereas chitotriosidase activity decreased by 64.0% (from 15 710 [range, 4092-28 422] to 5658 [range, 1146-16 843] nmol/mL/h; z = −2.803; P = .005), and glucosylsphingosine level decreased by 47.3% (from 248.5 [range, 122.8-674.9] to 131.0 [range, 41.1-448.5] ng/mL; z = −2.385; P = .02). Three of the 28 patients experienced mild and transient adverse events.Conclusions and RelevanceIn this case series of ambroxol repurposing among patients with GD, long-term treatment with ambroxol was safe and associated with patient improvement. Improvements in hematologic parameters, visceral volumes, and plasma biomarkers were larger among patients with relatively mild symptoms of GD and patients who received initial treatment at younger ages.

Exploring the efficacy and safety of Ambroxol in Gaucher disease: an overview of clinical studies

“…Studies have shown that the enzyme chitotriosidase (CHT) and the chemokine CCL1811 are produced by Gaucher cells and released into the patient’s circulation ( Hollak et al, 1994 ). These two proteins are potential biomarkers because their plasma levels are significantly elevated in GD patients, and change as the disease progresses as well as after a treatment intervention like ABX ( Zhan et al, 2023 ).…”

“…However, understanding the reported adverse effects in detail is key to minimizing their impact and preventing future occurrences. Among the 14 reported trials, 4 extensive primary studies explored ABX’s impact on a large cohort of GD patients ( Zimran et al, 2013 ; Istaiti et al, 2021 ; Istaiti et al, 2023 ; Zhan et al, 2023 ). Notably, 3 of these studies took place in Israel, reflecting its higher GD prevalence compared to other populations ( Zimran et al, 2013 ; Istaiti et al, 2021 ; Istaiti et al, 2023 ).…”

“…In an observational data involving a cohort of 28 GD patients representing the three clinical forms who completed the proposed treatment, ABX (administrated over 2.6 ± 1.7 years) successfully improved the overall clinical status in most of the enrolled patients including reduced fatigue, more energy, fewer nosebleeds, and disappearance of petechia on the skin ( Zhan et al, 2023 ). Patients with nGD experienced stable or improved neurological manifestations during the treatment.…”

“…Modulation and structural analysis showed that ABX interacts with both the enzyme active and allosteric site residues. Based on this discovery, several clinical and pilot studies have been conducted to evaluate the efficacy and safety of ABX as an alternative and/or adjunct therapy in GD patients of different forms ( Istaiti et al, 2021 ; Zhan et al, 2023 ). Although ABX is well tolerated in most patients, the findings obtained from these studies showed a wide response variability even in cases with similar genotypes ( Table 1 ).…”

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

“…At 186 of follow-up, only improvements in cerebrospinal fluid GCase activity, α-Synuclein, GCase protein level and blood Tau were statistically significant. Zhan et al[30] reported statistically significant improvements in haemoglobin concentration, spleen and liver volume, Chitotriosidase activity and Glucosylsphingosine level were noted in 28 patients following a mean of 2.6 years of treatment with Ambroxol. Changes in laboratory values were not reported…”