The ANeED Study: Ambroxol in New and Early Dementia with Lewy bodies

Abstract

Background: The mechanisms by which GBA and APOE mutations result in PD, DLB and AD are not fully understood; however, there is evidence that it may be connected to reduced levels of GCase enzyme activity. CNS penetration has been confirmed for Ambroxol and has been shown to increase glucocerebrosidase activity and protein levels in animal and human studies. Ambroxol may act by increasing transcription factor EB, the regulator of the CLEAR pathway involved in lysosomal biogenesis and by acting as a chaperone for GCase. Method(s): We will execute a national multicenter phase IIa RCT clinical intervention study with Ambroxol in prodromal and mild DLB in seven Memory Clinics across Norway. We will include persons living with prodromal (DLB-MCI) or mild DLB with MMSE >=15 to Ambroxol or placebo. We will stratify participants based on genotypes for APOE and the CSF biomarker amyloid-beta. Result(s): The ANeED-study has received funding from the national Norwegian health authorities. Formal approvals for ethics, data protection and Medicine Agency are granted and first patients will be included during spring 2021. We are currently building a national platform in Norway to be able to run clinical intervention studies in neurodegenerative disorders like AD and DLB. We are building a PPI program to recruit patients and caregivers to clinical studies. Conclusion(s): We are now starting a phase IIa study with Ambroxol in Norway. APOE, GBA and GCase are central to the disease process in both PD, PDD, DLB and AD. Patients, caregivers and health providers now need to be offered participation in clinical trials also when diagnosed with one of the alpha-synucleinopathies. Preliminary data find Ambroxol to be potentially disease modifying in these disorders, and potential collaborators for a phase III study in DLB in Europe and the US are welcome to contact.