T3D Therapeutics, Inc., Research Triangle Park, NC, USA.
J Alzheimers Dis. 2020;73(3):1085-1103. doi: 10.3233/JAD-190864.
T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer's disease (AD)-like phenotype of PPAR delta null mice motivated this study.
To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments.
Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST).
T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the Tmax showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action.
Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study.
T3D-959 是一种具有独特化学结构的、可穿透血脑屏障的、双重过氧化物酶体增殖物激活受体（PPAR）δ/γ激动剂，对 PPARδ 的选择性比其他药物高 15 倍。PPARδ 在大脑中广泛表达，它在调节葡萄糖和脂质代谢中起着关键作用，并且 PPARδ 基因敲除的小鼠表现出类似阿尔茨海默病（AD）的表型，这促使我们开展了这项研究。
评估 T3D-959 在轻中度 AD 受试者中的安全性和耐受性，考察其全身和中枢药物药理学，并进行探索性认知评估。
34 例轻中度 AD 受试者每日口服 T3D-959 3、10、30 或 90mg，连续 14 天，无安慰剂组。监测安全性和耐受性。通过液相色谱-串联质谱法（LC-MS-MS）分析血浆代谢组学，评估全身药物药理学；通过 18 F-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）测量相对脑代谢率（R CMRgl，AD 效应区域相对于脑参考区域），评估中枢药物药理学；在药物治疗前后和药物治疗完成后一周，通过 ADAS-cog11 和数字符号替代测试（DSST）评估认知功能。
T3D-959 一般安全且耐受良好。Tmax 时单点药代动力学显示剂量依赖性暴露。血浆代谢组学谱变化表明，脂质代谢和与胰岛素敏感性相关的代谢存在剂量依赖性的全身效应。相对 FDG-PET 成像显示，T3D-959 以多种参考区域为基础，对 R CMRgl 具有剂量依赖性的区域性影响。ADAS-cog11 和 DSST 认知评估显示，可能与 ApoE 基因型相关的改善，以及与药物作用机制相关的药效学。
这项 IIa 期临床试验的探索性数据支持进一步开展更大规模安慰剂对照临床试验，以评估 T3D-959 在 AD 患者中的疗效。
