O4‐11‐04: LINKING DIABETES AND ALZHEIMER'S DISEASE THROUGH RAGE: A RETROSPECTIVE ANALYSIS OF AZELIRAGON PHASE 2 AND PHASE 3 STUDIES

The role of inflammation and the Receptor for Advanced Glycation Endproducts (RAGE) expression/signaling associated with Alzheimer's disease (AD) and type 2 diabetes (T2D) supports RAGE as a common factor between AD and T2D, and that treatment with azeliragon could have an effect in patients presenting both T2D and AD. Azeliragon, an oral antagonist of RAGE, was evaluated in an 18-month Phase 3 study as a treatment for patients with mild Alzheimer's disease (AD) (the STEADFAST Study). While results of the STEADFAST Study were negative, post-hoc analysis of ADAS-cog11 in a T2D subgroup (baseline HbA1c ≥ 6.5%) found that subjects treated with azeliragon did not show a statistically significant cognitive decline vs. baseline. In contrast, subjects treated with placebo showed a statistically significant decline, vs. baseline, beginning at month 6. Treatment differences between azeliragon and placebo were significant (nominal p<0.05). Data from STEADFAST and the preceding Phase 2b study were analyzed to further understand the relationship between azeliragon's effects on ADAS-cog and HbA1c, as a surrogate marker for RAGE ligand concentrations. HbA1c and ADAS-cog11 change from baseline at Month 18 were evaluated in (i) the subjects with mild (MMSE 21-26) and moderate (MMSE <21) AD in the Phase 2b 18-month study of azeliragon in subjects with mild-to-moderate AD taking 5mg/day and (ii) the subjects in the A-study of STEADFAST (MMSE 21-26, CDR-global 0.5 or 1). As Phase 2b excluded subjects with diabetes, the population was characterized as non-diabetes (HbA1c < 5.7%) or pre-diabetes (HbA1c 5.7-6.5%). The STEADFAST Study allowed subjects with T2D with baseline HbA1c < 7.7%, allowing evaluation of treatment effects in non-diabetes (HbA1c < 5.7%), pre-diabetes (HbA1c 5.7-6.5%), and diabetes (HbA1c ≥ 6.5%) subgroups. Phase 2b placebo-subtracted M18 changes in ADAS-cog11 favored azeliragon. Results for the sub-groups in the STEADFAST Study will be presented.