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Arvinas (Nasdaq: ARVN) announced late‑breaking Phase 1 data for ARV-102, an oral brain‑penetrant PROTAC LRRK2 degrader, presented at MDS 2025 on Oct 5, 2025.
The PR states ARV-102 was generally well tolerated (single doses up to 200 mg; multiple daily doses up to 80 mg) with no discontinuations or SAEs. Plasma and CSF exposure increased dose‑dependently, indicating brain penetration. The PR reports >90% PBMC LRRK2 reductions at ≥20 mg and median PBMC reductions of 86% (50 mg) and 97% (200 mg) in patients. In healthy volunteers, 14 days of 80 mg produced CSF proteomic decreases in lysosomal and microglial pathway markers linked to Parkinson’s disease.
Positive
Well tolerated up to 200 mg; no SAEs or discontinuations
Dose-dependent CSF exposure indicating brain penetration
PBMC LRRK2 reductions >90% with repeated daily doses ≥20 mg
CSF proteomics: reduced lysosomal and microglial markers after 14 days
Negative
Small Parkinson’s trial cohort: 15 treated, 4 placebo
Reported data are interim/single‑dose; multiple‑dose results pending 2026
Insights
Phase 1 data show ARV-102 is brain‑penetrant, well tolerated, and modulates CSF lysosomal and microglial biomarkers linked to Parkinson’s disease.
What it means: The article reports that ARV-102 produced dose‑dependent exposure in plasma and CSF, indicating brain penetration, and achieved >90% LRRK2 reductions in PBMCs at ≥20 mg and median PBMC reductions of 86% and 97% at 50 mg and 200 mg in patients. The trials showed tolerability with no discontinuations for AEs or SAEs and only mild treatment‑related events in the patient cohort.
Why it matters: Direct CSF exposure plus rapid peripheral target degradation and early CSF proteomic changes provide three distinct, disclosed lines of evidence—pharmacokinetics, pharmacodynamics, and pathway biomarker modulation—that together strengthen the chain of biological activity for a brain‑directed LRRK2 degrader. The reported decreases in lysosomal and neuroinflammatory microglial markers in CSF after 14 days link target engagement to downstream pathways previously observed in LRRK2 Parkinson’s disease, supporting further clinical development.
Notes and near‑term milestones: The article states Arvinas will present multiple‑dose patient data in 2026 and, pending those data and IND clearance, intends to start a Phase 1b trial in progressive supranuclear palsy in the first half of 2026.
10/05/2025 – 02:00 PM
– ARV-102 was well tolerated in clinical trials for both healthy volunteers and patients with Parkinson’s disease –
– ARV-102 demonstrated dose-dependent cerebrospinal fluid (CSF) exposure in subjects in both trials –
– After 14 days of treatment in healthy volunteers, ARV-102 decreased lysosomal and neuroinflammatory microglial pathway biomarkers known to be elevated in Parkinson’s disease –
Arvinas Inc. (ARVN) is making headlines after presenting promising Phase 1 data for its investigational drug, ARV-102, at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2025. The data, unveiled on October 5th in Honolulu, showcases ARV-102 as an orally available, brain-penetrant PROTAC (Proteolysis-Targeting Chimera) degrader targeting leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson’s disease.
“We are particularly excited by the CSF proteomics results, which demonstrate modulation of lysosomal and microglial pathways that are known to be associated with neurodegenerative diseases,” said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer of Arvinas, in a press release. “We believe these findings support the intensified development of ARV-102 in ongoing studies of patients with Parkinson’s disease, and in future studies of patients with progressive supranuclear palsy.”
The data stems from two clinical trials: ARV-102-101 in healthy volunteers and ARV-102-103 in Parkinson’s patients. Key findings include:
**Healthy Volunteers (ARV-102-101):**
* **Safety:** ARV-102 demonstrated good tolerability up to 200mg single doses and 80mg multiple daily doses, with no serious adverse events (SAEs) or discontinuations reported.
* **Pharmacokinetics:** ARV-102 displayed dose-dependent exposure in both plasma and cerebrospinal fluid (CSF), confirming brain penetration. This ability to cross the blood-brain barrier is crucial for targeting LRRK2 within the central nervous system.
* **Pharmacodynamics:** Repeated daily doses of ≥20mg resulted in significant LRRK2 protein reduction (>90%) in peripheral blood mononuclear cells (PBMCs) and over 50% reduction in CSF.
* **Biomarker Changes:** The trial observed reduced plasma concentrations of phospho-Rab10T73 and urine concentrations of bis(monoacylglycerol)phosphate (BMP), suggesting modulation of the lysosomal pathway downstream of LRRK2.
**Parkinson’s Disease Patients (ARV-102-103 – Interim Data):**
* **Safety** The trial included 15 patients treated with ARV-102 and 4 patients treated with placebo. Single doses of ARV-102 (50 mg or 200 mg) were well tolerated with only mild treatment-related AEs including headache, diarrhea, and nausea; no SAEs occurred.
* **Pharmacokinetics:** Similar to the healthy volunteer study, ARV-102 showed dose-dependent exposure in plasma and CSF in Parkinson’s patients, again demonstrating brain penetration.
* **Pharmacodynamics:** ARV-102 treatment led to median PBMC LRRK2 protein reductions of 86% (50mg dose) and 97% (200mg dose).
* **CSF Proteomics:** Notably, in healthy volunteers treated with 80mg of ARV-102 daily for 14 days, CSF proteomics revealed significant decreases in both lysosomal and neuroinflammatory microglial markers – pathways previously identified as elevated in Parkinson’s patients with LRRK2 variants. This suggests ARV-102 is impacting the disease-relevant pathways in the brain.
“To our knowledge, this is the first time an investigational LRRK2 therapy has, at 14 days in healthy volunteers, shown effects on distal pathway biomarkers in CSF that are elevated in patients with LRRK2 Parkinson’s disease,” said John Houston, Ph.D., Chairperson, Chief Executive Officer, and President at Arvinas. “These data highlight the potential of PROTAC-mediated LRRK2 degradation, encouraging further development that could benefit patients in the future.”
Arvinas plans to present multiple-dose data from the Phase 1 clinical trial in Parkinson’s patients in 2026. An IND clearance could pave the way for a Phase 1b trial in progressive supranuclear palsy in the first half of 2026.
**The PROTAC Advantage:**
ARV-102 leverages Arvinas’ PROTAC technology which induces the degradation of target proteins, offering a potential advantage over traditional small molecule inhibitors. This approach not only blocks the activity of LRRK2 but also eliminates the protein entirely. LRRK2 is a large, multidomain scaffolding kinase, and its increased activity, scaffolding, and expression are thought to contribute to neurodegenerative diseases. Mutations in the LRRK2 gene are a prevalent cause of familial Parkinson’s disease, and common LRRK2 variants have been linked to both idiopathic Parkinson’s and progressive supranuclear palsy.
**Analyst Take:**
The data is viewed positively by industry analysts, particularly the CSF proteomic data demonstrating the modulation of disease-relevant pathways in the brain. This represents crucial evidence supporting the potential for ARV-102 to not only inhibit LRRK2 but also impact the downstream effects of its activity, potentially leading to disease modification. However, the interim nature of the data from the Parkinson’s disease trial and the small cohort size warrant careful observation of future, multiple-dose data. The planned Phase 1b trial in progressive supranuclear palsy represents a significant expansion of ARV-102’s clinical development program.
**Looking Ahead:**
Arvinas’s progress with ARV-102 signifies an advancement in the development of targeted therapies for neurodegenerative disorders. The ongoing clinical trials will be critical in further evaluating the therapeutic potential and safety profile of ARV-102 in larger patient populations. Investors will be closely watching the data readout from the multiple-dose Parkinson’s cohort expected in 2026.
What Phase 1 ARV-102 safety data did Arvinas report on Oct 5, 2025 for ARVN?
The PR states ARV-102 was generally well tolerated up to 200 mg with no SAEs or discontinuations.
Did Arvinas report brain penetration for ARV-102 (ARVN) at MDS 2025?
According to the PR, plasma and CSF exposure increased dose‑dependently, indicating CSF brain penetration.
What LRRK2 target engagement did Arvinas report for ARV-102 (ARVN)?
The PR reports >90% PBMC LRRK2 reductions at ≥20 mg and median PBMC reductions of 86% (50 mg) and 97% (200 mg) in patients.
What CSF biomarker changes did Arvinas report for ARV-102 at MDS 2025?
The PR states 14 days of 80 mg in healthy volunteers reduced lysosomal and neuroinflammatory microglial CSF markers.
When will Arvinas report additional ARV-102 multiple‑dose data and next trials for ARVN?
The PR says multiple‑dose cohort data will be presented in 2026, and a Phase 1b PSP trial is planned for H1 2026 pending IND clearance.
