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Phase 1 Study Supports Further Development of LRRK2 Inhibitor ARV-102
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Key Takeaways
- ARV-102 significantly reduces LRRK2, a protein implicated in PD and PSP, with dose-dependent efficacy observed in phase 1 trials.
- The agent crosses the blood-brain barrier, offering a novel therapeutic approach for neurodegenerative diseases.
Noah Berkowitz, MD, PhD
New data from a first-in-human, phase 1 study of healthy males showcased the early therapeutic potential of ARV-102 (Arvinas), an oral, brain-penetrant agent designed to degrade leucine-rich repeat kinase 2 (LRRK2). Overall, treatment with the therapy resulted in substantial reduction of LRRK2, a multifunctional protein that has been implicated in Parkinson disease (PD) and progressive supranuclear palsy (PSP).1
The findings, presented at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, comprised data from the single-ascending dose (SAD) portion of the study, as well as initial results from the multiple-ascending dose (MAD) cohort. In the SAD cohort, healthy volunteers were randomly assigned 3:1 to either placebo or a single dose of ARV-102 (10 mg, 30 mg, 60 mg, 90 mg, 150 mg, or 200 mg) on day 1 with follow-up until day 10. In the MAD cohort, volunteers were randomly assigned to either placebo or a once daily dose of ARV-102 (10 mg, 20 mg, 40 mg, or 80 mg) for 14 days with follow-up until day 28.
At the time of the data cutoff, March 13, 2025, the therapy was shown to be well tolerated across both single- and multiple-ascending doses. Through observations of cerebrospinal fluid, investigators found a LRRK2 reductions greater than 50% at single doses of at least 60 mg and repeated doses of greater than or equal to 20 mg. Notably, attenuation of LRRK2 was dose-dependent with ARV-102.
"The ability of ARV-102 to cross the blood-brain barrier and degrade the LRRK2 protein offers a potentially transformative therapeutic approach in the treatment of devastating neurodegenerative diseases," Noah Berkowitz, MD, PhD, chief medical officer at Arvinas, said in statement.1 "We believe these results support continuing our ARV-102 clinical program and building upon our body of evidence for this lead PROTAC degrader candidate in our neuroscience pipeline."
LRRK2 is a key player in PD pathogenesis, particularly in its genetic and molecular mechanisms. Mutations in the LRRK2 gene are among the most common genetic contributors to familial and sporadic PD, with the most notable mutation being G2019S, which leads to increased kinase activity. Considered a small molecule agent, ARV-102 has been shown to cross the blood-brain barrier and degrade LRRK2 in previous preclinical studies.
Treatment with ARV-102, an investigational PROteolysis TArgeting Chimera (PROTAC) LRRK2 degrader, did not result in any serious adverse events (AEs) in either cohort. Overall, the most common treatment-related AEs observed in the SAD cohort (n = 47) were headache and fatigue, with headache occurring more frequently in actively treated patients than those on placebo (headache: 17.1% [6 of 35] vs 0% [0 of 12]; fatigue: 8.6% [3 of 35] vs 25% [3 of 12]). Procedural pain associated with the lumbar puncture was more frequent in placebo controls (41.7% [5 of 12] vs 28.6% [10 of 35]); however, post lumbar puncture syndrome was only observed in the treated cohort, at a rate of 17.1% (6 of 35).
In the study, ARV-102 demonstrated a medium maximum concentration (Tmax) 6 hours after oral administration. Both the area under the concentration-time curve in the first 24 hours post-dosing and the maximum plasma concentration (Cmax) increased dose-dependently, with a median terminal plasma half-life of 73 hours. Additionally, ARV-102 levels in CSF showed a dose-dependent increase in both SAD and MAD cohorts.
At single doses of 60 mg or higher and repeated doses of 20 mg or higher, ARV-102 achieved over 90% reduction of LRRK2 in peripheral blood mononuclear cells (PBMCs), highlighting its potent target engagement. Single doses of 30 mg or more induced a significant decrease (over 50%) in peripheral phospho-Rab10T73, a biomarker of downstream LRRK2 activity, though data from the MAD cohort is forthcoming. Additionally, single doses of 30 mg or more resulted in over 90% reduction of BMP in urine, a marker of lysosomal function, with further insights from the MAD cohort still pending. Overall, these findings underline the promising pharmacodynamic profile of ARV-102 in modulating key disease pathways.
In late 2024, Arvinas initiating dosing in the SAD cohort of a phase 1 trial assessing ARV-102 in patients with PD. The study, which is planned to have MAD doses initiated in 2025, will test the safety, absorption, and effects of the agent in this patient population, for which there are no treatments approved that specifically target LRRK2. In its release, Arvinas noted that it expects to complete enrollment and present initial data from the ongoing SAD cohort in 2025.
LRRK2 is a key player in PD pathogenesis, particularly in its genetic and molecular mechanisms. Mutations in the LRRK2 gene are among the most common genetic contributors to familial and sporadic PD, with the most notable mutation being G2019S, which leads to increased kinase activity. Considered a small molecule agent, ARV-102 has been shown to cross the blood-brain barrier and degrade LRRK2 in previous preclinical studies.
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