Therapeutic Effects of Nizubaglustat in a Mouse Model of <scp>GM2</scp> Gangliosidosis

Nizubaglustat is a novel selective inhibitor of glucosylceramide synthase (GCS) and the non-lysosomal glucocerebrosidase (NLGase, GbA2) with brain penetrant properties. It is currently in clinical development as an oral treatment for rare lysosomal storage diseases with neurological involvement. One such disease group called GM2 gangliosidosis, to date, has no approved therapeutic treatment. To test the potential efficacy of nizubaglustat in a mouse model of GM2 gangliosidoses, we treated Sandhoff disease (SD) mice carrying a homozygous null mutation in the Hexb gene, as well as healthy heterozygous controls, to understand exposure versus effect under disease conditions. Oral doses of nizubaglustat from 0.2 to 6 mg/kg/day showed linear pharmacokinetics with plasma and brain concentrations sufficient to drive pharmacodynamic changes in markers of target engagement and efficacy. In the brain, an approximately 10-fold increase in GlcCer C16:0 and C18:0 was observed, which is consistent with NLGase inhibition. A statistically significant increase in survival (22%) was noted in SD mice treated at doses as low as 0.2 mg/kg/day compared to controls. Behavioral analyses, which included rotarod and open field tests, were also significantly improved. To understand the added potential mechanism of the improved survival, a subset of neuroinflammatory markers was also examined in specific brain regions. Gene expression studies showed an anti-inflammatory pattern with downregulation of Itgax, Trem2, Cxcl10 genes as an example. Brain immunohistochemistry for GFAP was decreased compared to vehicle treated control animals. These results provide proof-of-concept that nizubaglustat can be a promising therapeutic drug to treat patients with GM2 gangliosidoses.