NYX‐458 Improves Cognitive Performance in a Primate Parkinson's Disease Model

BACKGROUND NYX‐458 is a N‐methyl‐d‐aspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico‐striato‐pallidal‐thalmo‐cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD. OBJECTIVES NYX‐458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)–administration model, was used to assess the effects of NYX‐458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high‐dose MPTP‐administration model, was used to assess potential for NYX‐458 induced change in motor symptoms. METHODS NYX‐458 was evaluated in the chronic low‐dose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX‐458 was also assessed in the high‐dose MPTP model as a monotherapy and in combination with low‐dose or high‐dose levodopa to assess potential impact on motor symptoms. RESULTS NYX‐458 administration resulted in rapid and long‐lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia. CONCLUSIONS NYX‐458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD‐like cognitive impairment. These data support the continued evaluation of NYX‐458 as a potential therapeutic for cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society