Objective: Evaluate the effects of BIIB122/DNL151 treatment on CSF levels of pRab10, a biomarker of CNS LRRK2 modulation, in a Phase 1 study in healthy volunteers (NCT04557800) and a Phase 1b study in individuals with PD (NCT04056689).

Background: Lysosomal dysfunction is a key contributor to PD pathogenesis, with many PD-associated genes, including LRRK2, encoding lysosomal-related proteins [1, 2]. In sporadic PD, LRRK2 may be hyperactivated through environmental factors, noncoding genetic variants, and gene-environment interactions [1, 2]. LRRK2 phosphorylates Rab10 at the T73 residue (pRab10), impacting endolysosomal function [3]. Rab proteins regulate intracellular trafficking, and hyperphosphorylation of certain Rabs results in lysosomal stress and α-synuclein accumulation [2, 4-8]. LRRK2 inhibition may have therapeutic potential in PD by restoring lysosomal function. BIIB122 is an oral, selective, highly CNS-penetrant LRRK2 kinase inhibitor that reduces LRRK2’s activity; it is hypothesized to rescue lysosomal deficits, potentially slowing PD progression [9, 10]. In Phase 1/1b studies, BIIB122 treatment resulted in LRRK2 inhibition, lysosomal pathway modulation in the periphery, and a dose-dependent reduction from baseline in total CSF LRRK2 levels [9].

Method: A novel IP-LC-MS assay was used to evaluate CSF levels of pRab10, a LRRK2 substrate.

Results: In the Phase 1 MAD study (n=4-11 per arm), median reductions in pRab10 at Day 9/10 were 4%, 14%, 3%, 5%, 30%, 33%, and 28% (placebo and 30-, 45-, 70-, 150-, 225-, and 300-mg dose arms, respectively). In the Phase 1b MAD study (n=7-10 per arm), at Day 28, a median increase in pRab10 of 19% in the placebo arm and median reductions in pRab10 of 16%, 32%, and 39% (80-, 130-, and 300-mg dose arms, respectively) were seen. Reductions in CSF pRab10 had modest correlations with changes in select CSF lysosomal proteins (e.g., CTSS).

Conclusion: Despite the limited sample sizes, these data provide evidence that BIIB122 modulates LRRK2 pathways in the CNS at therapeutically relevant doses. Further analyses will evaluate the relationship of pRab10 alterations and other changes in lysosomal proteins. LUMA (NCT05348785), a Phase 2b trial evaluating LRRK2 inhibition in individuals with PD, will measure clinical progression and biomarker assessments to understand the overall impact of chronic LRRK2 inhibition in PD.

References: [1] Kluss JH, et al. Biochem Soc Trans. 2019;47(2):651-661.
[2] Rocha EM, et al. Trends Neurosci. 2022;45(3):224-236.
[3] Di Maio R, et al. Sci Transl Med. 2018;10(451):eaar5429.
[4] Bonet-Ponce L, Cookson MR. FEBS J. 2021;289(22):6781-6890.
[5] Hutagalung AH, Novick PJ. Physiol Rev. 2011;91(1):119-149.
[6] Steger M, et al. Elife. 2016;5:e12813.
[7] Pfeffer SR. FEBS Lett. 2023;597(6):811-818.
[8] Erb ML, Moore DJ. J Parkinsons Dis. 2020;10(4):1271-1291.
[9] Jennings D, et al. Mov Disord. 2023;38(3):386-398.
[10] Thakur G, et al. Genes (Basel). 2022;13(8):1426.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phase-1-and-1b-pharmacodynamic-data-support-central-modulation-of-lysosomal-pathways-with-biib122-dnl151-a-lrrk2-kinase-inhibitor-insights-for-the-luma-trial/