Developing Topics.

Background: PIONEER was a Phase 2 randomized, placebo-controlled, multi-center trial evaluating efficacy and safety of the dual PPARδ/γ agonist T3D-959 in patients with mild-to-moderate Alzheimer's disease (AD).

Method: Enrolled patients (N = 250) had mild-to-moderate AD per NIA-AA criteria. No AD biomarker enrollment criteria were defined. Study data revealed a cluster of sites with common data irregularities, including (1) no drug in plasma at end of treatment in patients assigned to drug (2) baseline p-tau217 ratio inconsistent with biological AD, and (3) placebo response outside of historic norms for mild-to-moderate AD. These sites were excluded to form an mITT study population. Primary endpoints were ADAS-Cog11 and ADCS-CGIC. Secondary endpoints were plasma Aβ42/40 ratio and Digit Symbol Coding Test. Proteomic biomarkers including p-tau217 and neurogranin were exploratory endpoints. Efficacy was evaluated as least-squares mean changes from baseline to week 24.

Result: 141 patients were included in the mITT population randomized to placebo (n = 32) or T3D-959 (15mg, n = 38; 30mg, n = 39; or 45mg, n = 32). Both primary endpoints were met, approaching statistical significance, ADAS-Cog11 in the 30mg group (0.73 vs 2.70; p = 0.073) and ADCS-CGIC in the 15mg group (0.39 vs 0.86; P = 0.060), consistent with slowing of clinical decline. Secondary endpoint plasma Aβ42/40 ratio was met, with significant improvement in the T3D-959 30mg and 45mg groups vs placebo (30mg: P = 0.011; 45mg: P = 0.033), with a similar magnitude of effect as lecanemab at 6-months. T3D-959 30mg and 45mg groups significantly improved on neurodegeneration biomarker neurogranin (T3D-959 30mg: P = 0.035; T3D-959 45mg: P = 0.051) and changed proteomic markers suggesting pluripotent effects on dysregulated AD pathways including inflammation, oxidative stress and metabolism. T3D-959 was safe and well-tolerated.

Conclusion: Co-primary endpoints ADAS-Cog11 and ADCS-CGIC were met per protocol, approaching statistical significance at week 24. T3D-959 demonstrated significant improvement over placebo in plasma Aβ42/40 ratio and in plasma neurogranin. Biomarkers of all three AD diagnostic criteria, Amyloid/Tau/Neurodegeneration, were improved, as well as markers of inflammation, insulin resistance and dysfunctional lipid metabolism. Results demonstrate a strong safety profile and evidence of slowing of clinical and biological decline.