Long-Term Follow-Up of Patients Immunized with AN1792 Current Alzheimer Research, 2009, Vol. 6, No. 2 149 Changes in Living Situation Changes in living situation were available for all partici- pating subjects in the follow-up study. After approximately 4.6 years, 19/25 (76.0%) antibody responders remained in their own home compared with 16/30 (53.3%) placebo- treated patients (p=0.099). Similarly, only 4/25 (16.0%) an- tibody responders were in long-term care institutions after approximately 4.6 years compared with 9/30 (30.0%) pla- cebo-treated patients (p=0.341). MRI Brain Volume Analysis Patients who were antibody responders in the phase 2a study demonstrated increased WBV loss compared with pla- cebo-treated patients, with no associated increase in cogni- tive decline [10]. This follow-up study compared changes in brain volume measurements between antibody responders and placebo-treated patients from the last visit in the phase 2a study with those observed at the time of the follow-up study visit. MRIs were available for 8/30 (26.7%) placebo- treated patients and 8/25 (32.0%) antibody responders. From the time of the last MRI in the original phase 2a study, anti- body responders demonstrated no significant differences in WBV loss compared with placebo-treated patients (mean percent change ± SD of -5.11% ± 3.96% for placebo vs - 5.66% ± 2.62% for antibody responders, p=0.854). No sig- nificant difference on brain boundary shift integral (mean percent change ± SD of 4.69% ± 2.36% for placebo vs 6.61% ± 2.86% for antibody responders, p=0.211) was ob- served; however, because of changes in scan acquisition, the boundary shift integral was only available for 7 placebo- treated patients and 6 antibody responders. There was also no significant difference in the percentage increase in ven- tricular volume, expressed as a percentage of baseline whole- brain volume, between placebo-treated patients and antibody responders (mean percent change ± SD of 1.25% ± 0.70% for placebo vs 2.00% ± 0.88% for antibody responders, p=0.285) after 3.6 years from the last MRI in the phase 2a study. Similarly, there was no significant difference in either left hippocampal loss (mean percent change ± SD of - 12.44% ± 8.78% for placebo vs -15.28% ± 7.62% for anti- body responders, p=0.436) or right hippocampal loss (mean percent change ± SD of -10.57% ± 7.58% for placebo vs - 13.51% ± 5.74% for antibody responders, p=0.402). This follow-up study also compared changes in brain volume measurements between antibody responders and placebo-treated patients from the baseline MRI in the phase 2a study with those observed at the time of the follow-up study. MRI scan pairs were available for 7/30 (23.3%) pla- cebo-treated patients and 8/25 (32.0%) antibody responders at baseline. Antibody responders demonstrated no significant differences in WBV loss compared with placebo-treated pa- tients after approximately 4.6 years from the first MRI per- formed in the original phase 2a study (mean percent change ± SD of -6.24% ± 4.58% for placebo vs -7.94% ± 1.70% for antibody responders, p=0.383). Brain boundary shift integral measures were available for 6 placebo-treated patients and 5 antibody responders, and demonstrated no significant differ- ence (mean percent change ± SD of 5.10% ± 2.70% for pla- cebo vs 8.48% ± 3.81% for antibody responders, p=0.119). Similarly, there was no significant difference in either left hippocampal loss (mean percent change ± SD of -13.54% ± 8.47% for placebo vs -17.03% ± 8.76% for antibody re- sponders, p=0.346) or right hippocampal loss (mean percent change ± SD of -10.86% ± 6.49% for placebo vs -14.74% ± 5.92% for antibody responders, p=0.164). However, a sig- nificant difference in ventricular volume enlargement, ex- pressed as a percentage of baseline whole-brain volume, was observed from baseline after approximately 4.6 years in this subgroup of patients with MRI follow up (mean percent change ± SD of 1.39% ± 0.82% for placebo vs 2.83% ± 1.29% for antibody responders, p=0.021). Safety Patients and caregivers who enrolled in the follow-up study were asked to provide information on any SAEs that occurred from the time of their final visit in the phase 2a study. There was a similar overall incidence of SAEs for placebo-treated patients (33.3%) compared with antibody responders (40.0%). No SAEs were considered by the inves- tigator to be related to AN1792. No cases of encephalitis were reported in this follow-up study. No deaths were con- sidered related to study drug by the investigator. Vital status information was available for 53/72 (73.6%) of placebo- treated patients and 45/59 (76.3%) antibody responders who were participants in the original phase 2a study. Survival was not significantly different between antibody responders and placebo-treated patients. For subjects in whom vital status information was available, 44/53 (83.0%) placebo-treated patients remained alive compared with 32/45 (71.1%) of antibody responders (p=0.220). DISCUSSION The comparisons conducted in this AN1792 follow-up study were performed between patients classified as anti- body responders and those treated with placebo in the origi- nal phase 2a study. The prospectively defined goal of these analyses was to determine if benefits might accrue over time in patients who developed prospectively defined antibody titers ( 1:2,200) that were considered adequately therapeutic in the phase 2a study. This follow-up study suggests that 1 to 3 doses of AN1792 administered to patients with mild-to-moderate AD may have had long-term clinical benefits in patients who developed anti-AN1792 antibodies. Patients classified as antibody responders at the end of the phase 2a study retained low but persistent anti-AN1792 antibody titers after ap- proximately 4.6 years. Compared with placebo-treated pa- tients, antibody responders demonstrated significantly less impairment in activities of daily living and significantly less dependence on caregivers. A higher percentage of antibody responders remained at home and a lower percentage were institutionalized. These results provide further support for the A immunotherapeutic approach in patients with mild- to-moderate AD. In contrast to testing of functional and dependence meas- ures (for which caregiver assessments were available for the majority of participating subjects), fewer assessments of cognitive outcomes (including the NTB, MMSE, and ADAS-Cog) were able to be performed, as patients became less amenable to or were unable to undergo cognitive evalua-