Objective: The aim of this work was to evaluate LRRK2 pathway modulation by the potent, selective, CNS-penetrant LRRK2 inhibitor NEU-411 in healthy adults and elderly volunteers.

Background: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapeutic approach for Parkinson’s disease (PD).

Method: A randomized, double-blind, placebo-controlled Phase 1 study was conducted evaluating single and multiple ascending doses of NEU-411 for up to 28 days in healthy participants. The primary endpoints were to investigate the safety, tolerability, and plasma pharmacokinetics of NEU-411. Pharmacodynamic assessment included the assessment of peripheral and central pathway inhibition and target engagement biomarkers of LRRK2.

Results: A total of 150 healthy adults and healthy elderly participants were randomized and treated. NEU-411 was generally well tolerated; no serious adverse events (AE) were reported, and all treatment-emergent adverse events were mild (40% of participants had Grade 1 AE) or moderate (16% of participants had Grade 2 AE) in the 28-Day tolerability study. NEU-411 cerebrospinal fluid (CSF)/unbound plasma concentration ratio was 0.5. Dose-dependent median reductions from baseline were observed in whole-blood LRRK2 (≤60%) and phosphorylated serine 935 LRRK2 (pS935LRRK2; >90%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤ 60%), CSF total LRRK2 (≤ 50%) and pS935LRRK2 (≤ 65%), and urine bis (monoacylglycerol) phosphate (≤ 90%).

Conclusion: NEU-411 achieved substantial and dose-dependent inhibition of peripheral and central LRRK2 kinase and pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. All doses were safe and well-tolerated. These studies warrant continued development of NEU-411 in people with PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-pathway-inhibition-by-neu-411-a-potent-selective-cns-penetrant-lrrk2-inhibitor-in-healthy-participants/