Preliminary Trial Results Suggest Benefit of Targeting Glucose and Lipid Metabolism for Treatment of Alzheimer’s Disease
Preliminary data have been shared from the PIONEER study (NCT04251182) of a peroxisome proliferator-activated nuclear receptor δ/γ (PPAR δ/γ) agonist (T3D-959; Research Triangle Park, NC), which regulates glucose and lipid metabolism. The trial is at 92% enrollment and participants have mild-to-moderate Alzheimer’s disease (AD) with a Mini-Mental State Examination (MMSE) of 14 to 26. Participants are being randomly assigned to receive daily oral doses 15, 30, or 45 mg/day of the PPAR δ/γ agonist for 24 weeks.
Preliminary results suggest the PPAR δ/γ agonist was safe and well tolerated through over 32,000 treatment days. No treatment-related or possibly treatment-related serious adverse events have occurred to date.
Evidence of a treatment effect was presented at a press conference held by the Alzheimer Association at their International Congress 2022 (AAIC2022) in San Diego, CA and online. Analysis of blinded data from all participants was averaged and showed improvements in cognition and executive function, despite the average including data from people treated with placebo, in whom declines would be expected. Cognition was assessed with the Alzheimer Disease Assessment Scale Cognitive 11 (ADAS-Cog 11), and executive function was assessed by the digit symbol coding test (DCST). Potential improvements in function measured with the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) have also been observed in this averaged data from all participants.
Improvements were demonstrated in comparison to the improvements seen in clinical trials for donezepil. Considering that data are still blinded and the average presented included those treated with placebo, in whom declines would be expected, these data provide a strong signal of potential benefit.
Primary outcomes measures for this study are the Alzheimer Disease Assessment Scale-Cognitive 11 (ADAS-Cog 11) and ADCS-CGIC global function scores. Secondary outcome measures include the DCST scores and plasma Aβ42/40 ratio.
Exploratory outcome measures include plasma levels of neurofilament light (NfL), tau, phophorylated tau217 and 181; apathy as measured by the neuropsychiatric inventory (NPI); expressive language function; physical activity; plasma metabolomic and proteomic biomarkers; and change in absolute regional and whole brain cerebral metabolic rate for glucose (CMRgl) as assayed by FDG-PET.
As noted, these results are preliminary and do not provide statistical comparisons of the PPAR δ/γ agonist vs placebo, but rather show what is occurring in those groups as a whole. Topline results comparing drug vs placebo from the PIONEER trial are expected in 2023.