Close
Alexander disease (AxD) is a rare, autosomal dominant leukodystrophy that causes progressive neurological dysfunction.
It is a primary disorder of astrocytes caused by mutations in the glial fibrillary acidic protein (GFAP) gene. Clinical manifestations of AxD, including age of onset, signs/symptoms, MRI features and survival, are highly variable but the typical symptoms include motor symptoms (developmental delay, weakness, spasticity), ataxia, cognitive dysfunction, bulbar dysfunction and sphincter involvement. Diagnosis of AxD is based on the presence of clinical manifestations and suggestive MRI abnormalities. Definitive diagnosis is made through identification of a mutation in the GFAP gene.
There are no disease-modifying treatments currently available for AxD and symptomatic treatment, if effective, can be used to manage only limited manifestations of the disease. For these reasons, there is a substantial unmet medical need to delay or prevent further progression of this devastating disease.
ION373 is a second-generation antisense oligonucleotide (ASO) therapy targeted to GFAP, preventing its production. ION373 has not been evaluated in any clinical setting but preclinical proof-of-concept studies with ASOs targeting GFAP have been conducted in rodent models of AxD, showing phenotypic benefit (Messing et al. 1998, Habberman et al. 2018). Further animal studies have also suggested safe pharmacokinetic and toxicity profiles.
The ION373-CS1 trial is a Phase 1-3, multi-center, double-blind, placebo-controlled, multiple-ascending dose (MAD) study in patients with Alexander Disease. The trial is sponsored by Ionis Pharmaceuticals and is taking place at 14 sites in 8 countries. Participants will be randomized in a 2:1 ratio to receive ION373 or matching placebo for a 60-week double-blind treatment period. After this, all participants will receive ION373 for a 60-week open-label treatment period. Multiple dose cohorts will be evaluated in the study. The primary endpoint of the study is to evaluate the efficacy of ION373 in improving or stabilizing gross motor function in patients with Alexander disease and the secondary endpoint is to see if ION373 impacts the other symptoms of the disease.To be eligible for the study, patients must be between 2 and 65 years of age at screening. Eligible patients must be ambulatory (or, for patients < 5 years of age who may be pre- ambulatory, must be able to sit with minimal support) to exclude patients in whom the disease has advanced to a stage highly unlikely to benefit from a GFAP-lowering therapy.
At UCL, we have recruited, screened, randomised, and given the first dose to one patient already and we will be looking to recruit more patients to this trial from mid-2023 onwards.
Updated 11-01-2023.