Investigational Nuclear Receptor Therapy Associated with Favorable Outcomes as Potential Alzheimer Disease Treatment

Treatment with T3D-959 (T3D Therapeutics, Research Triangle Park, NC), an oral small molecule brain-penetrating PPARδ/γ dual nuclear receptor agonist, was shown to slow cognitive decline and reduce amyloid plaque burden in people with mild-to-moderate Alzheimer disease (AD). T3D-959 treatment also was associated with improvements in other biomarker levels including amyloid and tau. Results of the phase 2 PIONEER clinical trial (NCT04251182) were presented at the 2024 meeting of the Alzheimer’s Association International Conference.

PIONEER was a phase 2 placebo-controlled, multicenter clinical trial in which 250 participants with mild-to-moderate AD were randomized into the intent-to-treat population to receive either placebo (n=65) or T3D-959 at either 15 mg (n=63), 30 mg (n=62) or 45 mg (n=60) via daily oral administration. Primary endpoints included Alzheimer Disease Assessment Scale cognitive subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scores, with secondary endpoints assessing amyloid beta (Aβ) 40/42 ratio and Digit Symbol Coding Test. Proteomic biomarkers were assessed as exploratory endpoints.

After 24 weeks:

• Participants treated with 30 mg of T3D-959 showed 73% slower cognitive decline vs placebo on the ADAS-Cog11 scale.
• Participants treated with T3D-959 at all doses showed numerically improved ADCS-CGIC scores and Digit Symbol Coding Test results.
• The potential for disease-modifying behavior was identified through the improvement of multiple biomarkers, including those associated with amyloid plaque burden.
• There were 13 treatment-related adverse events (AEs) and no treatment-related serious adverse events (SAEs).

The greatest frequency of improvement was associated with the 30 mg dose level for T3D-959, which, according to the study authors, supports the use of this dose level in a larger, future phase 3 study. This study was supported by the Clinical National Institute on Aging and the Alzheimer’s Association, and its presenting author, John Didsbury, PhD, is affiliated with T3D Therapeutics.

Researchers noted irregularities with data from 5 sites in the trial; data associated with participants from these sites was excluded from the final analysis. Additional details about the irregularities are reported on the poster presented at the AAIC meeting.