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

Autor:	Jennings D; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Huntwork-Rodriguez S; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Vissers MFJM; Centre for Human Drug Research, Leiden, the Netherlands.; Department of Clinical Neuropharmacology, Leiden University Medical Center, Leiden, the Netherlands., Daryani VM; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Diaz D; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Goo MS; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Chen JJ; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Maciuca R; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Fraser K; Biogen Inc, Cambridge, Massachusetts, USA., Mabrouk OS; Biogen Inc, Cambridge, Massachusetts, USA., van de Wetering de Rooij J; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA.; PRA Health Sciences, Groningen, the Netherlands., Heuberger JAAC; Centre for Human Drug Research, Leiden, the Netherlands., Groeneveld GJ; Centre for Human Drug Research, Leiden, the Netherlands.; Department of Clinical Neuropharmacology, Leiden University Medical Center, Leiden, the Netherlands., Borin MT; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Cruz-Herranz A; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Graham D; Biogen Inc, Cambridge, Massachusetts, USA., Scearce-Levie K; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., De Vicente J; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Henry AG; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Chin P; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Ho C; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA., Troyer MD; SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA.
Jazyk:	angličtina
Zdroj:	Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2023 Mar; Vol. 38 (3), pp. 386-398. Date of Electronic Publication: 2023 Feb 18.
DOI:	10.1002/mds.29297
Abstrakt:	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. (© 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Plný text