Phase 1 Data Link ARV-102 LRRK2 Degradation to Oculomotor and CSF Biomarker Changes in Parkinson Disease

New phase 1 data suggest that treatment with ARV-102 (Arvinas), a proteolysis-targeting chimera (PROTAC) designed to degrade leucine-rich repeat kinase 2 (LRRK2), was associated with improvements in oculomotor function and changes in cerebrospinal fluid (CSF) biomarkers in participants with Parkinson disease (PD).¹

The findings, presented at the International Parkinson and Movement Disorders Society Congress (MDS), held October 4-8in Seoul, Korea, came from the multidose portion of a single-center, double-blind phase 1 study (EUCT 2024-516888-84-00). Investigators reported that ARV-102-induced reductions in CSF LRRK2 were correlated with changes in measures of endolysosomal function and oculomotor performance, providing early evidence of biological pathway engagement with LRRK2 degradation.

The multidose portion of the study enrolled participants with PD who did not have major motor fluctuations or dyskinesia and had a Hoehn and Yahr score of 3 or less. Participants were randomly assigned in a 1:1:1:1 ratio to once-daily ARV-102 at doses of 20 mg, 40 mg, or 80 mg, or placebo for 28 days.¹

Study author Kyle Fraser, PhD, translational sciences director at Arvinas Therapeutics, and colleagues assessed oculomotor function using Neuralight, a software-based platform, alongside changes in Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) scores and CSF proteomic measures using SomaScan. A total of 24 participants completed the 28-day treatment period, with a median age of 62 years (range, 51-77) and 83% being male.

Investigators reported an improvement from baseline to day 28 in the amplitude of saccadic hypometria (ASH) with ARV-102 compared with placebo, without an observed effect on vigilance. Saccadic hypometria, characterized by eye movements that fall short of a visual target because of reduced saccade amplitude, has been associated with basal ganglia dysfunction and can worsen with PD progression.¹

Changes in MDS-UPDRS Part III scores were also assessed. The least-squares mean change from baseline to day 28 was 4.8 (95% CI, 0.6-8.9) for placebo, compared with 2.2 (95% CI, -2.3 to 6.7), 1.6 (95% CI, -2.5 to 5.7), and 0.8 (95% CI, -3.6 to 5.2) for the 20-, 40-, and 80-mg ARV-102 groups, respectively.

CSF proteomic analyses demonstrated reductions in proteins associated with endolysosomal function and neuroinflammation, including CD68 and GPNMB. Treatment was also associated with increases in measures related to synaptic integrity and axonal guidance, including NPTX2 and CBLN4.

Notably, baseline CSF LRRK2 concentrations did not correlate with the percentage change from baseline in CSF LRRK2. However, the percentage change in CSF LRRK2 correlated with changes in CSF pathway measures, including CD68 (R=0.72; P <.0001), as well as changes in ASH (R=-0.58; P <.01).¹

Prior phase 1 evaluations in healthy participants and those with PD found that single and multiple doses of ARV-102 were generally well tolerated and produced dose-dependent increases in drug exposure, LRRK2 degradation, and downstream pathway engagement in plasma and CSF.

LRRK2 variants have been associated with both autosomal-dominant and idiopathic forms of PD, making the kinase a target of interest in disease-modifying research. Rather than inhibiting LRRK2 activity, ARV-102 uses the ubiquitin-proteasome system to promote degradation of the protein.

According to the investigators, these findings indicate that ARV-102-mediated LRRK2 degradation in CSF was accompanied by changes in oculomotor function and CSF measures associated with synaptic biology, endolysosomal function, and neuroinflammation.The investigators concluded that the findings support further evaluation of LRRK2 degradation as a potential therapeutic strategy in PD.

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REFERENCE
1. Fraser K, van de Bult L, Smits L, et al. Phase 1 Study of ARV-102, a PROTAC LRRK2 Degrader, in Parkinson’s Disease: Oculomotor and Biomarker Data. Presented at: International Parkinson and Movement Disorder Society; October 4-11, 2026; Seoul, Korea.