Category: Parkinson’s Disease: Clinical Trials
Objective: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses (SAD/MAD) of ARV-102, a PROteolysis TArgeting Chimera (PROTAC) leucine-rich repeat kinase 2 (LRRK2) degrader.
Background: LRRK2 has been implicated in the development of neurodegenerative diseases, eg, Parkinson’s disease and progressive supranuclear palsy. ARV-102, a potent, selective, oral, central nervous system (CNS)-penetrant PROTAC, induces degradation of LRRK2 protein.
Method: This was a single-center, randomized, double-blind, placebo-controlled study in healthy male participants. The SAD phase assessed a single oral dose of ARV-102 (range 10–200 mg). The MAD phase assessed oral, once-daily doses of ARV-102 (range 10–80 mg) for 14 days. Safety and tolerability evaluations (primary objective) included laboratory assessments, clinical and neurological exams, and pulmonary function tests. PK was assessed by ARV-102 quantitation in plasma and cerebrospinal fluid (CSF). PD outcomes were effects of ARV-102 on peripheral and central LRRK2 (changes in protein levels in peripheral blood mononuclear cells [PBMCs] and CSF) and on lysosomal pathway biomarkers (changes in PBMC pT73Rab10 protein levels and urine bis[monoacylglycerol] phosphate [BMP]).
Results: In all, 94 participants (n=47 each in SAD and MAD) were included. ARV-102 was generally well tolerated with mostly mild treatment-emergent adverse events (AEs) and no serious AEs. ARV-102 displayed a moderate absorption rate after oral administration and median Tmax of 6 h. AUC0-24 and Cmax increased in a dose-dependent manner with an accumulation ratio of ~5-fold at steady state and median terminal t1/2 of 73 h. ARV-102 exposure in CSF also increased in a dose-dependent manner after single and multiple doses, indicating brain penetration. Dose-dependent median reductions in LRRK2 protein levels from baseline were observed in PBMCs and CSF. Decreases in PBMC pT73Rab10 levels and urine BMP levels were also seen.
Conclusion: At single (10–200 mg) and multiple (10–80 mg) doses, ARV-102 was well tolerated, orally bioavailable, and CNS-penetrant, and achieved substantial peripheral and central LRRK2 degradation and pathway engagement in healthy participants. Based on these findings, a phase 1 SAD/MAD study of ARV-102 was initiated in patients with Parkinson’s disease.
To cite this abstract in AMA style:
L. Smits, Y. Zhang, C. Woodward, S. Aksenov, A. Costa Zaninotto, C. Donnelly, T. Storz, Y. Folami, P. Patel, C. Lubeski, M. Macdougall, K. Kelly, A. Hendricson, S. Korsten, P. Kremer, A. Cacace, I. Conti. First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of ARV-102, a PROTAC LRRK2 Degrader, in Healthy Participants [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/first-in-human-study-to-assess-the-safety-pharmacokinetics-and-pharmacodynamics-of-single-and-multiple-ascending-doses-of-arv-102-a-protac-lrrk2-degrader-in-healthy-participants/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/first-in-human-study-to-assess-the-safety-pharmacokinetics-and-pharmacodynamics-of-single-and-multiple-ascending-doses-of-arv-102-a-protac-lrrk2-degrader-in-healthy-participants/