2026 American Academy of Neurology Abstract Website

Objective:

To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BT-267 in healthy adults (HA).

Background:

Leucine rich repeat kinase 2 (LRRK2) mutations are a well-known genetic cause of Parkinson’s disease (PD). Brains of individuals with idiopathic PD have increased LRRK2 kinase activity, which contributes to endolysosomal dysfunction and accumulation of ⍺-synuclein.Activation of LRRK2 kinase activity contributes to the pathogenesis of PD, suggesting inhibition of LRRK2 kinase activity may be useful for the treatment of PD. BT-267 is a selective, brain-penetrant, oral small molecule inhibitor of LRRK2.

Design/Methods:

Randomized, double-blind, placebo-controlled Phase 1 evaluating single and multiple ascending doses of BT-267 for up to 10 days in HA. Safety and tolerability include laboratory assessments and physical examinations were evaluated. BT-267 pharmacokinetics was assessed in plasma and CSF at selected timepoints. Pharmacodynamic measures include phosphorylated (p) and total (t) for LRRK2 and Rab10 in peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF), and bis-monoacylglycerol phosphate in urine.

Results:

As of Oct 10, 2025, 40 participants were enrolled and completed dosing. BT-267 was well tolerated; no serious adverse events (AEs), withdrawals, or discontinuations were observed. Most treatment emergent AEs were mild; only headache occurred in >2 participants. No clinically meaningful changes in vitals, labs, or electrocardiograms were observed. BT-267 exposure increased with dose and supports once-daily dosing. BT-267 CSF/plasma concentration ratio was > 1.6. Dose-dependent median reductions from baseline were observed in p/tLRRK2 ratio and p/tRab10 ratio.

Conclusions:

BT-267 has preferential distribution in the central nervous system, with potential to maximize central exposures while minimizing peripheral exposures. These results suggest that BT-267 may provide a differentiated safety profile and support continued investigation of BT-267 in HA and individuals with PD.