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.

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.