Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2024-10-10 DOI:10.1016/j.taap.2024.117125

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Abstract

Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC₅₀ value of 6.9 μM, the IC₅₀ of SAL0112 on hERG was greater than 100 μM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (P > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies.

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新型 GLP-1 受体偏性激动剂--SAL0112 在非人灵长类动物中的毒理学概况。

口服小分子 GLP-1 受体偏性激动剂对 2 型糖尿病和肥胖症具有良好的治疗效果。SAL0112 是一种新型化合物，已在临床前动物模型中显示出显著疗效。在此，我们进行了体外和体内临床前毒性研究，以探索 SAL0112 的安全性。采用 HTRF 法和 TR-FRET 法检测 cAMP。采用膜片钳法测定 hERG 钾离子通道。在心血管安全性药理学研究和为期 13 周的重复剂量毒性研究中使用了眼镜猴。遥测系统用于检测心电图、心率和血压等心血管指标。在重复剂量毒性研究期间，对体重、进食量、血液学、凝血功能测试、血清生化测试和尿液分析进行了测量。研究结束时进行宏观和微观观察。在第 1 天和第 91 天进行了 TK 研究。SAL0112 在激活猴 GLP-1 受体方面表现出很高的效力，而对啮齿类动物的 GLP-1 受体则没有影响。与对 hERG 具有高效力（IC50 值为 6.9 μM）的达奴利普隆相比，SAL0112 对 hERG 的 IC50 值大于 100 μM。在心血管安全性药理学研究中，与车辆对照组相比，单次服用 SAL0112 达 250 mg/kg 后，心血管指标未见明显变化（P > 0.05）。重复剂量毒性研究显示，SAL0112 有中度的厌食作用和体重下降，但这些作用是可逆的，且与任何病理变化无关。SAL0112 的无观测不良效应水平为 150 毫克/千克，安全系数约为三倍。SAL0112 在猕猴体内表现出良好的安全性，并具有可观的治疗窗口期，支持将该化合物推向临床研究。

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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.