Complexa, Inc., Berwyn, Pennsylvania, USA.
Projections Research Inc, Phoenixville, Pennsylvania, USA.
Clin Transl Sci. 2019 Nov;12(6):667-676. doi: 10.1111/cts.12672. Epub 2019 Aug 12.
10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA-10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA-10. After single and multiple ascending doses, CXA-10 demonstrated dose-proportional increases in plasma exposure. CXA-10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA-10-202, a consistent decrease from baseline was observed with CXA-10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP-1, and IL-6. In CXA-10-203, after coadministration with CXA-10, geometric mean peak plasma concentration (C ) and area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC ) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA-10. Adverse events (AEs) were dose-related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA-10 was safe and well-tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA-10 75-300 mg once daily.
10-硝基-9(E)-十八碳-9-烯酸（CXA-10）是一种新型的硝基脂肪酸化合物，在多种疾病中具有治疗作用，这些疾病的发病机制涉及氧化应激、炎症、纤维化和/或直接的组织毒性。在健康和肥胖受试者中进行的 I 期研究评估了口服 CXA-10 在进食和禁食状态下单次和多次给药的药代动力学（PK）、药效学（PD）、安全性和耐受性，这些研究结果可确认 CXA-10 的作用机制。单次和多次递增剂量后，CXA-10 表现出剂量比例增加的血浆暴露。CXA-10 降低了来自非临床研究中观察到的与炎症和代谢应激改变相关的生物标志物水平。在 CXA-10-202 中，与基线相比，CXA-10 150mg 剂量可观察到一致的降低，但 CXA-10 25mg 和 450mg 剂量对改变炎症和代谢功能障碍的生物标志物（包括瘦素、甘油三酯、胆固醇、MCP-1 和 IL-6）没有观察到降低。在 CXA-10-203 中，CXA-10 与普伐他汀合用时，普伐他汀的几何平均血浆峰浓度（C ）和从 0 时间点到给药间隔结束的血浆浓度-时间曲线下面积（AUC ）分别降低 20%和 25%，与辛伐他汀合用时，辛伐他汀的 C 和 AUC 分别增加 10%和 25%，与依折麦布合用时，C 和 AUC 分别降低 20%和 5%。这些发现与 CXA-10 的药理学作用一致。不良事件（AE）与剂量相关，报告发生率超过 10%的最常见 AE 为腹泻、腹痛和恶心。CXA-10 安全且耐受良好，体检、生命体征、临床实验室评估或心电图评估均未报告有临床意义的异常。在局灶节段性肾小球硬化症和肺动脉高压患者中开展的 II 期研究正在调查 CXA-10 每日一次 75-300mg 的疗效和耐受性。
