Long-Term Safety and Efficacy of Combined Therapy with High-Dose Ambroxol and Recombinant Enzyme in Neuronopathic Gaucher Disease

Abstract

Background: Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD. Methods: Four patients with nGD were enrolled. ABX ERT therapy was administered for 4·5 years. Ambroxol was initiated at a dose of 1·5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The changes in glucocerebrosidase (GBA) activity, biochemical, safety, and neurocognitive findings were assessed. Findings: Enhanced residual GBA activity was observed in all patients, as evidenced in both in vitro and in vivo studies. Mean seizure frequencies markedly decreased from the baseline, and the neurocognitive function was maintained. Lyso-Gb1, a biomarker for the severity and progression of GD, gradually decreased in all patients. High-dose ABX was well-tolerated with no severe adverse events. Interpretation: Long-term treatment with high-dose ABX ERT was safe and shows promise for arresting the progression of the neurological manifestations in GD. Clinical Trial Number: The study protocol was registered at the Clinical Research Information Service, Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea) (no. KCT0003218). Funding Statement: This research was supported in part by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF- 2015K1A4A3046807, NRF-2016M3A9B4915706 and NRF-2018M3A9H1078335) and by ISU ABXIS, Gyeonggi-do, Korea. Declaration of Interests: None declared. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board and the Ministry of Food and Drug Safety, Korea (no. 30449).