Parkinson’s drug shifts key biomarkers, trial results show
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Phase 1 trial results showed an experimental oral therapy was associated with improved eye movement control, lower levels of neuroinflammatory biomarkers, and higher markers of nerve cell health in people with Parkinson’s disease.
The results from the ARV-102-103 trial (EUCT 2024-516888-84-00) build on findings presented earlier this year showing that Arvinas‘ ARV-102 reached the brain and reduced levels of its target protein, LRRK2, in the cerebrospinal fluid (CSF, the fluid that surrounds the brain and spinal cord). ARV-102 was also found to be generally safe and well tolerated.
The findings were shared at the Movement Disorders Society International Congress of Parkinson’s Disease and Movement Disorders, held last week in Seoul, South Korea. The data were presented as late-breaking oral and poster presentations titled “Phase 1 Study of ARV-102, a PROTAC LRRK2 Degrader, in Parkinson’s Disease: Oculomotor and Biomarker Data.”
“Although this study was not designed to assess clinical efficacy, we are encouraged by the exploratory dose-related changes in [abnormal eye movements] and their associations with LRRK2 degradation and changes in pathway biomarkers,” Ilaria Conti, MD, PhD, Arvinas’ vice president of clinical research, said in a company press release. “These findings support further clinical evaluation of ARV-102.”
Mutations in the LRRK2 gene, which encodes a protein of the same name, are one of the most common genetic causes of Parkinson’s. LRRK2 is often overactive in Parkinson’s, which can disrupt waste recycling within cells and exacerbate inflammation, causing damage to nerve cells.
Crossing the blood-brain barrier
ARV-102 is a small-molecule drug known as a proteolysis targeting chimera (PROTAC). Rather than blocking LRRK2 activity, ARV-102 is designed to direct the cell’s natural protein-disposal system toward LRRK2, promoting its breakdown. The treatment is also designed to cross the blood-brain barrier, a protective cell layer that limits which substances can enter the brain.
Arvinas first evaluated ARV-102 in the ARV-102-101 study (EUCT 2023-507910-28-00), which involved 90 healthy volunteers who received once-daily ARV-102 doses for about two weeks. The treatment was found to be safe and well tolerated, and to reach the brain. Once-daily dosing reduced LRRK2 levels in both the blood and CSF, as well as biomarkers of lysosomal damage. Lysosomes are cellular structures that break down waste products.
Building on these findings, the company launched the Phase 1 trial, which enrolled 24 people with Parkinson’s (median age 62, 83% men), who were randomly assigned to receive ARV-102 at 20, 40, or 80 mg doses, or a placebo, once daily for 28 days (about one month).
Researchers found dose-dependent improvements in an objective measure of eye movement called amplitude of saccadic hypometria (ASH). Saccadic hypometria is an eye-movement abnormality characterized by decreased accuracy when moving the eyes toward visual targets that occurs in people with Parkinson’s.
After 28 days, participants receiving ARV-102 showed increases in ASH compared with those receiving a placebo, indicating less severe hypometria. The treatment also decreased biomarkers of lysosomal dysfunction and brain inflammation, and increased biomarkers reflecting improved nerve cell function. The extent of LRRK2 reduction in the CSF directly correlated with these positive changes in both biomarkers and eye movement function.
Maria Tumino
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