P4–417: Incidence and clinical progression of placebo‐treated amyloid‐negative subjects with mild‐to‐moderate Alzheimer's disease (AD): Results from the phase III PET substudies of bapineuzumab and solanezumab

Bapineuzumab and solanezumab are anti-amyloid-beta monoclonal antibodies evaluated in Phase 3 trials in mild-moderate AD. A subset of subjects was classified as “amyloid-negative” based on amyloid PET imaging at baseline. To compare the clinical course of amyloid-negative (Aβ-) and -positive subjects (Aβ+) randomized to placebo. Baseline amyloid scans were obtained in PET sub-studies of bapineuzumab (11 C-PiB; 45 APOE ε 4 carriers, 22 non-carriers)and solanezumab (18 F-florbetapir;73 APOE ε 4 carriers, 60 non-carriers) trials. Cortical average standard uptake value ratios (SUVr) were calculated in regions known to accumulate substantial fibrillar amyloid in AD. Subjects were classified as Aβ- or Aβ+ based on predefined study-specific SUVr cutpoints. Subjects were evaluated on cognitive measures at ∼3 month intervals for 78 weeks. We compared the change from baseline to 78 weeks between Aβ- and Aβ+ subjects on the ADAS-Cog/11, MMSE, and CDR-SB, co-varying for age and baseline values, in placebo-treated completers, (subjects with a baseline amyloid PET scan who completed at least one of these outcome measures at week 78), in each program. In placebo completers,22.4% bapineuzumab subjects and 23.3% solanezumab subjects were Aβ-. The proportion of Aβ- subjects was lower in APOE ε4 carriers than non-carriers (11.1% vs 45.5% for the bapineuzumab studies and 8.2% vs 41.7% for solanezumab) and higher in mild vs moderate dementia subjects (33.3% vs 4.0% for bapineuzumab and 27.5% vs 14.3% for solanezumab). Baseline scores on the ADAS and MMSE tended to be worse for Aβ+ subjects. The LS mean decline over 18 months in Aβ- vs Aβ+ subjects were: ADAS - bapineuzumab 5.7 (2.12) vs 7.4 (1.09) and solanezumab 0.9 (1.48) vs 6.1 (0.80), MMSE - bapineuzumab 0.9 (1.40) vs 3.1 (0.71) and solanezumab -0.1 (0.81) vs 3.9 (0.44), and CDR-SB- bapineuzumab 0.5 (0.79) vs 2.5 (0.41) and solanezumab 0.6 (0.45) vs 2.3 (0.24). More than 20% of patients diagnosed with AD based on clinical criteria were amyloid negative in the PET sub-studies of bapineuzumab and solanezumab, with higher proportions of Aβ- among APOE ε4 non-carriers and mild dementia. Aβ- subjects did not demonstrate the same rate of cognitive decline typically observed in AD dementia.