Study results suggest that agonist stimulation of PPAR delta may be an effective therapeutic strategy to addressing dysfunctional metabolism in Alzheimer disease.
“That's what this drug is doing, it's getting you back on your game. It's refeeding the brain that is being starved in Alzheimer."
John Didsbury, PhD, Founder and CEO of T3D Therapeutics, Inc., sat with NeurologyLive to speak to the final results of the phase IIa exploratory and feasibility clinical trial of T3D-959 in patients with mild-to-moderate Alzheimer disease. The results were presented by Didsbury at the 2018 Alzheimer’s Association International Conference in Chicago, Illinois.
T3D-959, a dual peroxisome proliferator activated receptor (PPAR) delta/gamma agonist with 15-fold higher PPAR delta potency, was studied in 36 patients with mild-to-moderate Alzheimer disease. Subjects were randomized to 1 of 4 doses of T3D-959 daily for 14 days—3 mg, 10 mg, 30 mg, or 90 mg—assessed for safety and tolerability, and evaluated for changes from baseline in cerebral metabolic rate of glucose (FDG-PET imaging), functional connectivity of the hippocampus (BOLD-fMRI) and cognitive function (ADAS-Cog11 and DSST).
The results show multiple signals of efficacy, Didsbury notes, from changes in the metabolome, changes in glucose metabolism in the brain, and improvements in cognitive testing. FDG-PET results demonstrated changes in brain glucose uptake in a dose-dependent fashion and may increase relative glucose uptake in needed regions of the brain. The cognitive evaluation by ADAS-Cog11 demonstrated that all ApoE4-negative patients improved 4.8—6.1 points at low and mid (3 mg–30 mg) doses, while ApoE3-positive patients improved 1–3.5 points at mid and high (30 mg–90 mg) doses. DSST results revealed an average improvement of 2.4 points in subjects with moderate Alzheimer and 7 points in subjects with mild Alzheimer regardless of the dose or genotype.
Didsbury adds that T3D-959 is essentially treating Alzheimer disease as a chronic anorexia of the brain because the brain is not receiving the energy needed—a result of insulin resistance.
After the completion of the phase IIa trial, a phase IIb will be underway where subjects with mild-to-moderate Alzheimer disease will be dosed with T3D-959 for 6 months. Researchers will assess cognitive performance and look at glucose metabolism in the brain using FDG-PET brain scans.