Objective: To provide novel fluid biomarker results from REASON – a Phase 1 clinical trial testing a LRRK2 antisense oligonucleotide in both LRRK2-Parkinson’s disease and idiopathic Parkinson’s disease.

Background: REASON was a 2-part first-in-human randomized phase 1 study designed to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of BIIB094, a LRRK2 antisense oligonucleotide (ASO) in Parkinson’s disease patients.  In part A, 40 participants received single doses of BIIB094 10–150 mg or placebo. In part B, 42 participants received four doses of BIIB094 40–120 mg or placebo every 4 weeks (stratified by LRRK2 variant status). Novel methodology was developed to assess pharmacodynamic markers in cerebrospinal fluid (CSF) of patients treated with BIIB094.  Specifically, a total LRRK2 + phosphorylated Rab10 (pRab10) 2-plex was deployed to monitor indirect target engagement, and downstream LRRK2 kinase activity, respectively.  A novel 12-plex assay was also designed to assess how LRRK2 modulation in CNS could impact lysosomal proteins in CSF.

Method: To assess the impact of BIIB094 on pharmacodynamic changes in patient CSF, LRRK2 and pRab10 were monitored using a novel anti-peptide immunocapture – nanoflow LC – high resolution mass spectrometry (IP-LC-MS) assay developed and validated in house at Biogen.  

Furthermore, to determine if BIIB094 had an impact on lysosomal biology in PD CSF, a 12-plex LC-MS assay was developed and validated at Biogen. CSF proteins monitored in the 12-plex include ubiquitin, LAMP1, LAMP2, Cathepsin B, D, F, S, L, GM2A, GPNMB, GCase, and LC3.

Results: In part B of the REASON, data demonstrated that CSF LRRK2 and pRab10 levels were lowered by up to 59% and 50%, respectively, independent of LRRK2 variants.

In part B of the REASON study, BIIB094 reduced cathepsin lysosomal proteins in CSF, including Cathepsin B, L, S, up to 25% with a return towards baseline when treatment was stopped,  suggestive of modulation of the LRRK2-endolysosomal network.

Conclusion: These data are the first demonstration of LRRK2-ASO modulatory effects on cerebrospinal fluid-based biomarkers in human Parkinson’s disease.  Presentation will include details on novel assays including description of performance and biomarker study results.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-antisense-oligonucleotide-biib094-ion859-impact-on-cerebrospinal-fluid-biomarkers-in-parkinsons-disease-patients/