Objective: To characterize the biomarker effects of BIIB122/DNL151 in participants with LRRK2 pathogenic mutations diagnosed with Parkinson’s disease (LRRK2-PD).

Background: BIIB122/DNL151 is a CNS-penetrant small molecule LRRK2 inhibitor co-developed by Biogen Inc. and Denali Therapeutics Inc. as a potential treatment for individuals with Parkinson’s disease (PD). Dose-dependent reductions in whole-blood pS935 LRRK2, urine BMP(22:6/22:6) and CSF total LRRK2 have been observed in healthy participants and individuals with PD [1] treated with BIIB122/DNL151. The BEACON study (NCT06602193), solely funded and conducted by Denali Therapeutics Inc, aims to characterize these target and pathway biomarker effects in addition to lysosomal and disease biomarkers in LRRK2-PD participants treated with BIIB122/DNL151.

Method: This Phase 2a, randomized study will evaluate pharmacodynamic biomarker effects in ~50 LRRK2-PD participants during the 12-week double-blind, placebo-controlled period followed by an open label extension period (up to 96 weeks). Changes from baseline in target (whole-blood pS935 LRRK2) and pathway (urine BMP(22:6/22:6)) engagement biomarkers with BIIB122/DNL151 compared to placebo will be assessed at Week 12.

Results: Based on recent data investigating the lipidome of LRRK2 mutation carriers via samples acquired from the Parkinson’s Progression Markers Initiative (PPMI), exploratory endpoints may include assessment of biomarkers of lysosomal function such as the measurement of lipids in the glycosphingolipid pathway. In addition, we aim to explore measurements of lysosomal enzymes, and biomarkers of neurodegeneration such as Tau and phospho-Tau species in CSF, plasma, PBMCs, and/or urine at baseline and post-dose timepoints. Furthermore, since a substantial portion of individuals with LRRK2-PD do not manifest alpha-synuclein pathology (Kalia et al 2015), assessment of alpha-synuclein aggregation via the seed amplification assay (SAA) will be employed to determine differential treatment responses based on SAA status.

Conclusion: Data generated from this study will enable scientific insights into mechanisms and biomarkers of LRRK2-driven PD, deepen our understanding of the therapeutic mechanism of action of BIIB122/DNL151, and may reveal unique SAA+ versus SAA- LRRK2-PD biomarker signatures.

References: [1] Jennings D, et al. Mov Disord. 2023;38(3):386-398.

[2] Kalia L, et al. JAMA Neurol. 2015;72(1):100-105.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-the-pharmacodynamic-effects-of-biib122-dnl151-in-participants-with-lrrk2-mutation-driven-parkinsons-disease-beacon-study/