First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers
First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers
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DOI：
10.1002/cpdd.700
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发表时间：
2020-01-01
影响因子：
2
通讯作者：
Sinha, Uma
中科院分区：
文献类型：
--
作者：
Fox, Jonathan C.;Hellawell, Jennifer L.;Sinha, Uma
AG10是一种新型、有效和选择性的口服甲状腺素运载蛋白（TTR）稳定剂，正在开发用于治疗TTR淀粉样变性（ATTR）。该随机、双盲、安慰剂对照研究评价了健康成人志愿者口服施用AG10的安全性、耐受性、药代动力学和药效学（离体稳定化）。突变型和野生型ATTR都是诊断不足的疾病，治疗选择有限。由于TTR淀粉样蛋白生成是通过因遗传突变或衰老而不稳定的TTR四聚体的解离而启动的，因此AG 10旨在从源头上治疗该疾病。口服给予四个单剂量和三个多剂量递增水平的AG10或匹配的安慰剂。通过生命体征、心电图、不良事件和临床实验室检查评估安全性和耐受性。使用经验证的生物分析测定法测量药代动力学。通过三种TTR稳定的药效学试验评估药效学。AG10的耐受性一致良好，未观察到临床问题的安全性信号。药代动力学观察结果包括达到最大浓度的时间，在测试的最高剂量下，在稳态下，在整个给药间隔内观察到TTR稳定90%。血清TTR水平是AG10稳定TTR的体内反映，在给药12天后从基线增加。AG10在健康成人志愿者中似乎是安全的且耐受性良好，并且可以在整个给药间隔内完全稳定TTR，建立了临床概念证明。基于这些数据，AG10有可能成为突变型或野生型ATTR患者的安全有效的治疗方法。
AG10 is a novel, potent, and selective oral transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR). This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics (ex vivo stabilization) of orally administered AG10 in healthy adult volunteers. Both mutant and wild-type ATTR are underdiagnosed diseases with limited therapeutic options. As TTR amyloidogenesis is initiated by dissociation of TTR tetramers destabilized due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Four single and three multiple ascending dose levels of AG10 or matching placebo were orally administered. Safety and tolerability were assessed by vital signs, electrocardiogram, adverse events, and clinical laboratory tests. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics were assessed via three pharmacodynamic assays of TTR stabilization. AG10 was uniformly well tolerated, and no safety signals of clinical concern were observed. Pharmacokinetic observations included time to maximum concentration 90%) stabilization of TTR was observed across the entire dosing interval at steady state on the highest dose tested. Serum TTR levels, an in vivo reflection of TTR stabilization by AG10, increased from baseline following 12 days of dosing. AG10 appears to be safe and well tolerated in healthy adult volunteers and can completely stabilize TTR across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with either mutant or wild-type ATTR.