Dataset Information

An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease.

ABSTRACT: BACKGROUND: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. OBJECTIVE: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. METHODS: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). RESULTS: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. CONCLUSIONS:Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study.

SUBMITTER: Chamberlain S

PROVIDER: S-EPMC7081093 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease.

Chamberlain Stanley S Gabriel Hoda H Strittmatter Warren W Didsbury John J

Journal of Alzheimer's disease : JAD 20200101 3

<h4>Background</h4>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.<h4>Objective</h4>To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug phar ...[more]

PMID: 31884472

Similar Datasets

Project description:BackgroundThe Wnt/β-catenin pathway regulates liver growth, repair, and regeneration. Chronic ethanol (EtOH) exposure blunts normal liver regenerative responses, in part by inhibiting insulin/IGF signaling, and correspondingly, previous studies showed that EtOH-impaired liver regeneration could be restored by insulin sensitizer (proliferator-activated receptor [PPAR]-δ agonist) treatment. As Wnt/β-catenin functions overlap and cross talk with insulin/IGF pathways, we investigated the effects of EtOH exposure and PPAR-δ agonist treatment on Wnt pathway gene expression in relation to liver regeneration.MethodsAdult male Long Evans rats were fed with isocaloric liquid diets containing 0 or 37% EtOH for 8 weeks and also treated with vehicle or a PPAR-δ agonist during the last 3 weeks of the feeding regimen. The rats were then subjected to 70% partial hepatectomy (PH) and livers harvested at various post-PH time points were used to quantitate expression of 19 Wnt pathway genes using Quantigene 2.0 Multiplex Assay.ResultsEtOH broadly inhibited expression of Wnt/β-catenin signaling-related genes, including down-regulation of Wnt1, Fzd3, Lef1, and Bcl9 throughout the post-PH time course (0 to 72 hours), and suppression of Wnt7a, Ccnd1, Fgf4, Wif1, Sfrp2, and Sfrp5 at 18- and 24-hour post-PH time points. PPAR-δ agonist treatments rescued the EtOH-induced suppression of Wnt1, Wnt7a, Fzd3, Lef1, Bcl9, Ccnd1, and Sfrp2 gene expression in liver, corresponding with the improvements in DNA synthesis and restoration of hepatic architecture.ConclusionsChronic high-dose EtOH exposures inhibit Wnt signaling, which likely contributes to the impairments in liver regeneration. Therapeutic effects of PPAR-δ agonists extend beyond restoration of insulin/IGF signaling mechanisms and are mediated in part by enhancement of Wnt pathway signaling. Future studies will determine the degree to which targeted restoration of Wnt signaling is sufficient to improve liver regeneration and remodeling in the context of chronic EtOH exposure.

Project description:BackgroundAlthough obesity has been hypothesized to worsen asthma, data from studies of subjects with well-characterized asthma are lacking.ObjectiveWe sought to evaluate the relationship between body mass index (BMI), asthma impairment, and response to therapy.MethodsBMI (in kilograms per meter squared) and asthma phenotypic and treatment response data were extracted from Asthma Clinical Research Network studies. The cross-sectional relationship between BMI and asthma impairment was analyzed, as was the longitudinal relationship between BMI and response to asthma controller therapies.ResultsOne thousand two hundred sixty-five subjects with mild-to-moderate persistent asthma were evaluated. Analyses of lean versus overweight/obese asthmatic subjects demonstrated small differences in FEV1 (3.05 vs 2.91 L, P = .001), FEV1/forced vital capacity ratio (mean, 83.5% vs 82.4%; P = .01), rescue albuterol use (1.1 vs 1.2 puffs per day, P = .03), and asthma-related quality of life (5.77 vs 5.59, P = .0004). Overweight/obese asthmatic subjects demonstrated a smaller improvement in exhaled nitric oxide levels with inhaled corticosteroid (ICS) treatment than did lean asthmatic subjects (3.6 vs 6.5 ppb, P = .04). With ICS/long-acting beta-agonist treatment, overweight/obese asthmatic subjects demonstrated smaller improvements in lung function than lean asthmatic subjects, with an 80 mL (P = .04) and 1.7% (P = .02) lesser improvement in FEV1 and FEV1/forced vital capacity ratio, respectively. Significant differences in therapeutic response to leukotriene modifiers between BMI categories were not observed.ConclusionsIncreased BMI is not associated with clinically significant worsening of impairment in subjects with mild-to-moderate persistent asthma. There is a modest association between increased BMI and reduced therapeutic effect of ICS-containing regimens in this patient population. Prospective studies evaluating the effect of being overweight or obese on treatment response in asthma are warranted.

Dataset Information

An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease.

Publications

An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets