BIIB122对健康参与者和帕金森病患者中LRRK2的抑制作用。

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

作者信息

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

机构信息

SeniorClinical Scientist - Clinical Development, Denali Therapeutics Inc, South San Francisco, California, USA.

Centre for Human Drug Research, Leiden, the Netherlands.

出版信息

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

DOI:10.1002/mds.29297

PMID:36807624

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.

摘要

背景

富亮氨酸重复激酶2（LRRK2）抑制是治疗帕金森病（PD）的一种有前景的治疗方法。

目的

本研究旨在评估强效、选择性、可穿透中枢神经系统的LRRK2抑制剂BIIB122（DNL151）在健康参与者和PD患者中的安全性、耐受性、药代动力学和药效学。

方法

完成了两项随机、双盲、安慰剂对照研究。1期研究（DNLI-C-0001）在健康参与者中评估了单剂量和多剂量的BIIB122，持续28天。1b期研究（DNLI-C-0003）在轻度至中度PD患者中评估了BIIB122 28天。主要目标是研究BIIB122的安全性、耐受性和血浆药代动力学。药效学结果包括外周和中枢靶点抑制以及溶酶体途径参与生物标志物。

结果

在1期和1b期研究中，分别有186/184名健康参与者（146/145名BIIB122组，40/39名安慰剂组）和36/36名患者（26/26名BIIB122组，10/10名安慰剂组）被随机分组/接受治疗。在两项研究中，BIIB122总体耐受性良好；未报告严重不良事件，大多数治疗中出现的不良事件为轻度。BIIB122脑脊液/非结合血浆浓度比约为1（范围为0.7 - 1.8）。观察到全血磷酸化丝氨酸935 LRRK2（≤98%）、外周血单核细胞磷酸化苏氨酸73 pRab10（≤93%）、脑脊液总LRRK2（≤50%）和尿双（单酰甘油）磷酸酯（≤74%）较基线有剂量依赖性的中位数降低。