Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin dissolved in SBECD solution are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265).
Male C57BL/6 mice (8 weeks of age, 20–27 g), purchased from Charles River Laboratories (Toulouse, France), were dosed intraperitoneally with 1 or 5 mg/kg of minzasolmin (10 mL/kg of 40% w/v Captisol® in water).
Price, D.L., Khan, A., Angers, R. et al. In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease. npj Parkinsons Dis. 9, 114 (2023). https://doi.org/10.1038/s41531-023-00552-7