Objective: To evaluate safety and biomarker effects of BIIB122/DNL151 in participants with pathogenic LRRK2 variants diagnosed with Parkinson’s disease (LRRK2-PD).

Background: Increased LRRK2 kinase activity has been linked to lysosomal dysfunction and Parkinson’s disease (PD) pathology in both LRRK2-PD and sporadic PD [1-4]. Inhibiting LRRK2 kinase is expected to improve lysosomal dysfunction and is a promising approach to treat PD.  There is limited data evaluating LRRK2 inhibition in LRRK2-PD [5]. BIIB122/DNL151 is a selective, orally bioavailable, CNS–penetrant, reversible inhibitor of LRRK2 being co-developed by Biogen Inc. and Denali Therapeutics Inc. as a potential treatment for individuals with PD. The ongoing Phase 2b LUMA study is enrolling individuals with early-stage sporadic PD and LRRK2-PD. The Phase 2a study presented here is designed to evaluate safety and biomarker effects of BIIB122/DNL151 in LRRK2-PD across a broad disease spectrum.

Method: The Phase 2a study, conducted and funded by Denali Therapeutics, is designed to evaluate safety and biomarker effects of BIIB122/DNL151 in ~50 LRRK2-PD participants across a broad disease spectrum. The study will be conducted at select clinical sites with access to LRRK2-PD participants.

Key eligibility criteria: Clinical diagnosis of PD with positive DAT imaging, LRRK2 pathogenic mutation, age ≥30 years for homozygous and ≥30 and ≤ 80 years for heterozygous LRRK2 carriers, treatment naïve or on stable dose of PD standard of care therapy, not previously enrolled in LUMA.

Results: Primary endpoint will be the incidence of adverse events in the 12-week DB period. Secondary endpoints include target and pathway engagement biomarkers (pS935 LRRK2 in whole blood, BMP in urine) at 12 weeks. Several pharmacodynamic (lysosomal function and neurodegeneration biomarkers in blood and CSF), clinical efficacy assessments, and pharmacokinetic measures will be evaluated as exploratory endpoints.

Conclusion: LRRK2 inhibition is a promising target with the potential to improve lysosomal dysfunction and slow progression of PD. This study will enroll a broad population of LRRK2-PD participants and aims to complement safety and biomarker data derived from LUMA. Data from this study may inform the design of future studies with BIIB122/DNL151.

References: [1] Bonet-Ponce et al. Sci Adv. 2020;6(46).
[2] Robak et al 2017. Brain. 2017;140(12):3191-3203.
[3] Smolders and Van Broeckhoven Acta Neuropathol Commun. 2020;8(1):63.
[4] Dehay B, et al. Mov Disord. 2013;28:725–732.
[5] Jennings D et al. Sci Transl Med 2022;14(648).

Disclosures:
D.J., S.H-R., J.K., S.O., S.V.D., R.M., C.H., and P.C. are all employees of Denali Therapeutics and may hold stock or stock options.
K.F., B.H. and Z.B. are all employees of Biogen and may hold stock or stock options.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-inhibition-by-biib122-dnl151-in-participants-with-pathogenic-lrrk2-variants-and-parkinsons-disease-study-design-to-evaluate-safety-pharmacodynamics-and-pharmacokinetics/