LILA Holding AG is a Swiss rare-disease company developing ambroxol hydrochloride as a pharmacological-chaperone therapy for the neurological manifestations of Gaucher disease types 2 and 3.
Our approachThe challenge
Neuronopathic Gaucher disease (types 2 and 3) is caused by mutations in the GBA1 gene, leading to deficient glucocerebrosidase (GCase) activity. This causes toxic accumulation of glucosylceramide in the brain and progressive neurodegeneration.
Type 2 (acute neuronopathic) is the most severe form, with onset in infancy and a median survival of roughly 11–19 months. Type 3 (chronic neuronopathic) causes progressive cognitive decline, seizures, ataxia and loss of motor function through childhood and adulthood.
Current enzyme-replacement and substrate-reduction therapies manage systemic disease but do not cross the blood–brain barrier, leaving the neurological component untreated. No therapy is approved anywhere in the world for the neurological manifestations of Gaucher disease.
Our science
Ambroxol stabilises misfolded GCase through a well-characterised molecular mechanism, and is one of few compounds shown to reach the brain at measurable concentrations.
Ambroxol binds mutant GCase at the neutral pH of the endoplasmic reticulum, stabilising the misfolded protein and enabling correct folding and trafficking to the lysosome.
At the acidic pH of the lysosome, ambroxol dissociates from GCase, leaving the enzyme catalytically active. The net result is more functional GCase where it is needed.
In the first clinical pilot study, ambroxol was detected in the cerebrospinal fluid of all treated patients (Narita et al., 2016), supporting CNS exposure.
Differentiation
Marketed as an over-the-counter mucolytic in 50+ countries since the late 1970s. Published high-dose studies in Gaucher disease have reported no serious treatment-related adverse events; long-term high-dose safety continues to be studied.
Off-patent and manufactured worldwide, making it affordable even at high therapeutic doses — relevant for the low- and middle-income countries where many nGD patients live.
Migalastat (Galafold), approved by the FDA in 2018 for Fabry disease, validates the pharmacological-chaperone mechanism for a lysosomal storage disorder.
Evidence
Ambroxol has been studied in neuronopathic Gaucher disease across independent clinical centres worldwide. The studies below are the most directly relevant to the neurological forms.
Five patients (four GD3, one GD2) received high-dose ambroxol. Ambroxol was detected in the cerebrospinal fluid of all patients, confirming blood–brain barrier penetration, and patients showed reductions in myoclonus and seizure frequency.
Thirteen Polish patients with type 3 Gaucher disease (L444P/L444P homozygous) on stable ERT received ambroxol at 10 mg/kg/day for one year. Neurological improvement was observed on standardised assessment, alongside reductions in selected biomarkers.
Two children with GD2 were treated with high-dose ambroxol from 1 and 4 months of age, in addition to enzyme-replacement therapy. One showed nearly age-appropriate neurocognitive and motor development after three years — in a disease form with a median survival of roughly 11–19 months.
The longest published follow-up of high-dose ambroxol combined with enzyme-replacement therapy in neuropathic Gaucher disease, reporting sustained neurological stability over a full decade of continuous treatment.
Four Korean patients with Gaucher disease and myoclonic epilepsy received high-dose ambroxol with ERT. Improvements in epilepsy and cerebellar tremor were documented in some patients at sustained high doses, with a favourable safety profile.
Contact
We welcome inquiries from researchers, clinicians and patient-advocacy organisations working in Gaucher disease and lysosomal storage disorders.
For general inquiries and partnerships.
A Swiss corporation registered in the Canton of Zurich.