Price Diana L, Khan Asma, Angers Rachel, Cardenas Alvaro, Prato Maria Key, Bani Massimo, Bonhaus Douglas W, Citron Martin, Biere Anja-Leona
Neuropore Therapies, Inc., San Diego, CA, USA.
UCB Biopharma SPRL, Braine l'Alleud, Belgium.
NPJ Parkinsons Dis. 2023 Jul 17;9(1):114. doi: 10.1038/s41531-023-00552-7.
Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson's disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson's disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson's disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020-003265).
直接靶向α-突触核蛋白（ASYN）已成为治疗帕金森病和其他突触核蛋白病的疾病修饰策略，目前正在通过小分子化合物和靶向ASYN的生物制剂来实现。Minzasolmin（UCB0599）是一种口服生物利用度高且能穿透血脑屏障的小分子ASYN错误折叠抑制剂，正处于临床开发阶段，作为帕金森病的疾病修饰疗法。本文描述了Minzasolmin临床前评估的结果，这些结果为后续的临床开发奠定了基础。对野生型小鼠腹腔注射1和5mg/kg Minzasolmin的药代动力学评估显示，其在脑和血浆中的暴露呈平行且剂量成比例。在PD的61系转基因小鼠模型中进行了为期三个月的给药研究，以测量ASYN病理学和其他与PD相关的终点指标，包括中枢神经系统炎症标志物、纹状体多巴胺转运体（DAT）标记和步态。ASYN病理学的减少与步态和平衡的改善、中枢神经系统炎症标志物丰度的降低以及纹状体DAT水平的正常化相关。这些发现为人体剂量的确定提供了支持，并为正在进行的早期帕金森病患者Minzasolmin临床研究的临床试验设计和生物标志物选择的转化策略提供了依据（ClinicalTrials.gov标识符：NCT04658186；欧盟临床试验编号：2020-003265）。
