LRRK2-targeting antisense oligonucleotide in Parkinson's disease: a phase 1 randomized controlled trial
Omar S Mabrouk1, Ben Tichler2, H Moore Arnold3
1Biogen Inc, Cambridge, MA, USA. omar.mabrouk@biogen.com.
Nature Medicine
|March 25, 2026
Summary
Intrathecal BIIB094, an antisense oligonucleotide, safely reduced LRRK2 levels in Parkinson's disease patients. This novel Parkinson's disease therapy showed promising biomarker changes, suggesting potential to impact disease pathology.
Area of Science:
- Neurology
- Genetics
- Pharmacology
Background:
- Leucine-rich repeat kinase 2 (LRRK2) variants are a leading genetic cause of Parkinson's disease (PD).
- Targeting LRRK2 may offer a therapeutic strategy for PD.
- BIIB094 is an antisense oligonucleotide designed to degrade LRRK2 mRNA.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intrathecal BIIB094 in Parkinson's disease patients.
- To assess the effect of BIIB094 on LRRK2 levels and downstream biomarkers.
Main Methods:
- REASON study: a first-in-human, randomized, placebo-controlled phase 1 trial.
- Part A: Single doses of BIIB094 (10-150 mg) or placebo.
- Part B: Multiple doses of BIIB094 (40-120 mg) or placebo every 4 weeks, stratified by LRRK2 variant status.
Main Results:
- BIIB094 was generally safe and well-tolerated, with mild to moderate adverse events.
- No serious adverse events related to BIIB094 were reported.
- BIIB094 dose-dependently reduced cerebrospinal fluid (CSF) LRRK2 by up to 59% and phosphorylated Rab10 by up to 50%.
Conclusions:
- Intrathecal BIIB094 demonstrated a favorable safety profile in Parkinson's disease patients.
- BIIB094 effectively lowered LRRK2 and phosphorylated Rab10 levels in CSF.
- Observed reductions in CSF lysosomal proteins suggest a potential mechanism for LRRK2-targeted PD therapeutics.
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