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Clinical Trial
. 2023 Mar;38(3):386-398.
doi: 10.1002/mds.29297. Epub 2023 Feb 18.

LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease

Danna Jennings  1 , Sarah Huntwork-Rodriguez  1 , Maurits F J M Vissers  2   3 , Vinay M Daryani  1 , Dolores Diaz  1 , Marisa S Goo  1 , John J Chen  1 , Romeo Maciuca  1 , Kyle Fraser  4 , Omar S Mabrouk  4 , Jeroen van de Wetering de Rooij  1   5 , Jules A A C Heuberger  2 , Geert Jan Groeneveld  2   3 , Marie T Borin  1 , Andrés Cruz-Herranz  1 , Danielle Graham  4 , Kimberly Scearce-Levie  1 , Javier De Vicente  1 , Anastasia G Henry  1 , Peter Chin  1 , Carole Ho  1 , Matthew D Troyer  1
Affiliations
Clinical Trial

LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease

Danna Jennings et al. Mov Disord. 2023 Mar.

Abstract

Background: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD).

Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD.

Methods: Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers.

Results: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7-1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%).

Conclusions: At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: LRRK2 inhibitor; Parkinson's disease; clinical trials.

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References

    1. de Rijk MD, Tzourio C, Breteler MM, et al. Prevalence of parkinsonism and Parkinson's disease in Europe: the EUROPARKINSON collaborative study. European Community concerted action on the epidemiology of Parkinson's disease. J Neurol Neurosurg Psych 1997;62(1):10-15. https://doi.org/10.1136/jnnp.62.1.10
    1. Blin P, Dureau-Pournin C, Foubert-Samier A, et al. Parkinson's disease incidence and prevalence assessment in France using the national healthcare insurance database. Eur J Neurol 2015;22(3):464-471. https://doi.org/10.1111/ene.12592
    1. Dorsey E, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2007;68(5):384-386. https://doi.org/10.1212/01.wnl.0000247740.47667.03
    1. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers 2017;3:17013. https://doi.org/10.1038/nrdp.2017.13
    1. Poewe W, Mahlknecht P. The clinical progression of Parkinson's disease. Parkinsonism Relat Disord 2009;15(Suppl 4):S28-S32. https://doi.org/10.1016/S1353-8020(09)70831-4

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