Preclinical safety and toxicokinetic evaluation of TJ0113, a first-in-class mitophagy inducer for Parkinson's disease

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-09-13 DOI:10.1016/j.taap.2025.117565

Yanan Tian , Fengqi Wang , Jikai Shen , Ruiqi Zhang , Qianwen Chen , Le Xu , Dong Liu , Mengyang Fan , Zhen Tian , Xufeng Cen , Xiaoyan Xu , Hongguang Xia

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引用次数: 0

Abstract

Mitochondrial dysfunction is a key driver of neurodegeneration, highlighting mitophagy as a tractable therapeutic axis. Yet the clinical translation of mitophagy-targeting agents requires robust, GLP-compliant nonclinical safety data to support and de-risk human trials in line with international guidelines. TJ0113, a first-in-class small-molecule inducer of mitophagy, has shown disease-modifying activity in preclinical models and is being evaluated in a registered, randomized, double-blind, placebo-controlled Phase II trial in Parkinson's disease (NCT06596005). We conducted a comprehensive safety assessment of TJ0113 in Sprague–Dawley rats and Beagle dogs under GLP. Single-dose studies (up to 1500 mg/kg, oral) and repeat-dose studies (rats: 15, 30, 100 mg/kg/day for 26 weeks; dogs: 6, 20, 60 mg/kg/day for 39 weeks) evaluated systemic toxicity, toxicokinetics (TK), safety pharmacology endpoints (including ECG), and a standard genotoxicity battery (Ames, chromosomal aberration, micronucleus) consistent with ICH S2(R1). No treatment-related mortality or target-organ toxicity occurred. A modest increase in relative kidney organ coefficient in rats was observed but without biochemical or histopathological correlates and was considered non-adverse. Clinical pathology, ECG, and dog urinalysis remained within physiological limits; all genotoxicity tests were negative. TK showed rapid absorption with linear, dose-proportional exposure and no accumulation at the end of dosing. The NOAELs were 100 mg/kg/day in rats (26 weeks) and 60 mg/kg/day in dogs (39 weeks). These data establish a favorable nonclinical safety profile for TJ0113 and provide GLP evidence supporting further clinical development of this selective mitophagy-targeting agent.

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TJ0113的临床前安全性和毒性动力学评价，一种一流的帕金森病线粒体自噬诱导剂

线粒体功能障碍是神经退行性变的关键驱动因素，突出了线粒体自噬作为一个可处理的治疗轴。然而，线粒体自噬靶向药物的临床转化需要可靠的、符合glp的非临床安全性数据，以支持符合国际准则的人体试验并降低风险。TJ0113是一种同类首个小分子线粒体自噬诱导剂，已在临床前模型中显示出疾病改善活性，并正在帕金森病的注册、随机、双盲、安慰剂对照II期试验（NCT06596005）中进行评估。我们在GLP作用下对Sprague-Dawley大鼠和Beagle犬进行了TJ0113的综合安全性评价。单剂量研究（高达1500 mg/kg，口服）和重复剂量研究（大鼠：15、30、100 mg/kg/天，持续26 周；狗：6、20、60 mg/kg/天，持续39 周）评估了与ICH S2（R1）一致的全身毒性、毒性动力学（TK）、安全药理学终点（包括ECG）和标准遗传毒性电池（Ames、染色体畸变、微核）。无治疗相关死亡或靶器官毒性发生。在大鼠中观察到相对肾脏器官系数的适度增加，但没有生化或组织病理学相关性，被认为是非不良反应。临床病理、心电图、犬尿分析均在生理范围内；所有遗传毒性试验均为阴性。TK呈线性剂量比例暴露，吸收迅速，给药结束时无积累。大鼠（26 周）和狗（39 周）的NOAELs分别为100 mg/kg/d和60 mg/kg/d。这些数据为TJ0113建立了良好的非临床安全性，并为进一步临床开发这种选择性有丝分裂靶向药物提供了GLP证据。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.