To evaluate the preclinical effects of chronic dosing of the clinical-stage small molecule α-synuclein misfolding inhibitor UCB0599 in α-synuclein transgenic mice.

Intraneuronal accumulation of aggregated α-synuclein is a key pathological hallmark of Parkinson’s disease. The α-synuclein aggregation cascade is a pathological process that drives neurodegeneration, neuroinflammation, and disease progression. UCB0599 is an orally available small molecule that was designed to disrupt the first step in the aggregation cascade by preventing α-synuclein misfolding and the formation of α-synuclein aggregates on lipid membranes. A Phase 2 proof-of-concept study is currently underway to assess UCB0599 as a disease-modifying therapy in patients with Parkinson’s disease (PD0053; NCT04658186).

The pharmacokinetic profile of UCB0599, an enantiomer of NPT200-11, was assessed in wildtype mice at 1 and 5 mg/kg followed by a 3-month chronic dosing study in Line 61 α-synuclein transgenic mice. Neuropathological and behavioral endpoints were measured to assess the disease-modifying potential of UCB0599.

Following intraperitoneal administration in wildtype mice, UCB0599 was rapidly absorbed and demonstrated good CNS distribution. Line 61 transgenic mice treated for 3 months with UCB0599 displayed dose-dependent decreases in total and aggregated α-synuclein levels, as well as the neuroinflammatory marker, glial fibrillary acidic protein (GFAP). In addition to improvements in these key neuropathological markers, reductions in dopamine transporter (DAT) staining observed in the dorsal striatum of Line 61 transgenic mice were not seen following treatment with UCB0599. Rescue of hallmark neuropathological markers in mice treated with UCB0599 was accompanied by significant improvement of functional gait abnormalities compared to control animals.

Chronic in vivo dosing with UCB0599 in α-synuclein transgenic mice corrected key neuropathological markers and functional motor endpoints closely linked to Parkinson’s disease suggesting potential as a disease-modifying therapy.