A Clinician’s Perspective on First-in-Human Data for LRRK2 Degrader ARV-102

Philip Kremer, MD

Leucine-rich repeat kinase (LRRK2) is a multifunctional enzyme implicated in the pathogenesis of Parkinson disease (PD) and, to a lesser extent, in other neurodegenerative and inflammatory disorders. Mutations in the LRRK2 gene, particularly G2019S, are the most common known genetic cause of autosomal dominant familial PD and are also found in sporadic cases. In PD, LRRK2-associated pathology is somewhat unique: while some patients with LRRK2 mutations exhibit classic α-synuclein pathology, others show tau inclusions or minimal Lewy pathology, highlighting phenotypic and pathological variability.

At the recently concluded 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, Arvinas presented new first-in-human data from a phase 1 study testing ARV-102, an LRRK2 degrader. The data, while still early-stage, comprised single-ascending dose (SAD) and multiple-ascending dose (MAD) cohorts, testing several different dosing ranges of ARV-102 in healthy volunteers. Between the cohorts, those in the SAD group were followed up until day 10 whereas those in the MAD cohort were followed-up until day 28.

The findings were considered positive, with the therapy showing a safe profile and resulting in LRRK2 reductions greater than 50% at single doses of at least 60 mg and repeated doses of at least 20 mg. To gain greater insights on the therapeutic potential of this agent, and its early supportive data, NeurologyLive® reached out to Philip Kremer, MD, Research Director Neurology, Center for Human Drug Research (CHDR), The Netherlands. In the discussion, Kremer provided insights on the pharmacokinetic profile of the drug, the difficulties in conducting trials testing novel approaches like ARV-102, and the next steps in the drug’s development.

NeurologyLive: What about ARV-102’s mechanism makes it an attractive treatment? How does it function?

Philip Kremer, MD: ARV-102 is a novel investigational oral PROTAC designed to cross the blood-brain barrier and selectively degrade LRRK2 (leucine-rich repeat kinase 2), a kinase implicated in the pathogenesis of neurological disorders such as Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Unlike traditional small molecule inhibitors that block enzyme activity, PROTACs facilitate the degradation of the target protein, eliminating rather than inhibiting disease-causing proteins.

Within the phase 1 healthy volunteer cohort, what stands out from the findings? From a clinical perspective

In healthy volunteers, the orally bioavailable PROTAC LRRK2 degrader ARV-102demonstrated the ability to cross the blood-brain barrier, with substantial reductions in peripheral and central LRRK2 protein levels, indicating that ARV-102 induces LRRK2 degradation. LRRK2 degradation and downstream pathway engagement was observed after single doses of ARV-102. Pharmacokinetic data support dose-dependent exposure and oral once-daily dosing. Additionally, ARV-102 was well tolerated, with no serious adverse events or discontinuations reported after single or multiple doses. These compelling data with a novel therapeutic modality in healthy volunteers support the evaluation of ARV-102 in neurodegenerative diseases associated with LRRK2 dysfunction.

What are the next steps in this drug’s development? Have you had any discussions about studies in PD or PSP?

This study provided the first-in-human data for ARV-102, supporting the continuation of the clinical program and building upon Arvinas' body of evidence for ARV-102 in its neuroscience pipeline. Following the completion of the Phase 1 trial in healthy volunteers, a Phase 1 trial of ARV-102 has been initiated in patients with Parkinson’s disease and is now enrolling (EUCT 2024-516888-84-00).

What are some of the difficulties with conducting trials of novel approaches for neurodegenerative disorders?

The absence of validated measurable biomarkers that correlate with phenotype and clinical course of neurodegenerative diseases together with the heterogeneity of patient populations and the extended time to clinical progression represent critical challenges in developing novel agents in this space.

Designing a clinical study to evaluate a novel therapeutic modality involves exploring and implementing innovative approaches to clinical trial design to maximize the probability of success, and to minimize study duration and risk to participants. Including biomarkers in healthy volunteer phase 1 studies enables assessment of target and pathway engagement, providing an early proof-of-mechanism before progressing to patient populations and supports rational dose selection for future patient studies.

The identification and validation of prognostic and predictive measurable biomarkers to monitor disease progression and efficacy of therapeutic interventions in advance of clinical changes, and the ability to select and enroll homogeneous patient populations become, therefore, essential elements in the design early clinical studies that can provide reliable treatment effect data over a short period of time in a relatively limited number of patients.