P2-412

S368 P2-412

Poster P2:: Monday Posters MPC-7869 (R-FLURBIPROFEN), A SELECTIVE A␤42-LOWERING AGENT, DELAYS TIME TO CLINICALLY SIGNIFICANT PSYCHIATRIC EVENTS IN ALZHEIMER’S DISEASE (AD): ANALYSIS FROM A 12-MONTH PHASE 2 TRIAL

Jacobo E. Mintzer1, Gordon K. Wilcock2, Sandra E. Black3, Kenton H. Zavitz4, Suzanne B. Hendrix4, MPC-7869 Phase 2 Study Investigators, 1Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA; 2University of Bristol, Bristol, United Kingdom; 3Sunnybrook & Women’s, University of Toronto, Toronto, ON, Canada; 4Myriad Pharmaceuticals, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: MPC-7869 is a Selective A␤42-Lowering Agent (SALA). In a mouse model of AD (Tg2576), MPC-7869 lowers brain levels of A␤42 and chronic dosing in this model reduces brain amyloid pathology and prevents defects in learning and memory. These data and the Phase 2 study indicating sustained benefit in activities of daily living, global function and cognition in mild AD patients suggest a potential for MPC-7869 to have disease-modifying properties. Objective(s): The goal of this analysis is to explore a possible effect of MPC-7869 on time to onset of psychiatric adverse events in AD subjects. Methods: This was a placebo-controlled, double-blind, 1-year trial evaluating MPC-7869 in 207 patients with mildto-moderate AD (MMSE 15-26, with an average MMSE score of 21). 94% of subjects were on stable acetylcholinesterase inhibitor therapy. An exploratory analysis was performed which compared time to adverse psychiatric events between treatment groups. Results: A prespecified interaction analysis revealed that mild and moderate AD patients responded differently to MPC-7869 (P⫽ 0.03). In mild AD patients (MMSE 20-26) there was a significant delay in time to clinically significant adverse psychiatric events in the 800 mg BID group compared to Placebo (P⫽0.011). The median time to event was approximately 106 days in the Placebo group among the 35% of Placebo patients who had an event. In the 800 mg BID group, the median time to event was greater than 333 days, and could not be precisely estimated since only 14% of 800 mg BID patients had an event. The most common psychiatric events reported in the placebo group were agitation, aggression, confusional state and depression. Conclusions: MPC-7869 has an attractive therapeutic and safety profile in patients with mild AD, the vast majority of whom were already on standard of care therapy (acetylcholinesterase inhibitors). In addition to the reported significant benefit observed in activities of daily living (P⫽0.033), global function (P⫽0.042) and a positive trend in cognition, this analysis revealed a significant delay in time to psychiatric events. These results are consistent with the hypothesis that treatment with MPC-7869 may delay progression of AD. P2-413

THE EFFICACY OF DONEPEZIL IN THE TREATMENT OF MILD TO MODERATE ALZHEIMER’S DISEASE (AD): RESULTS FROM A RESPONDER ANALYSIS SUBMISSION TO NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE (NICE)

Andrew Yeates1, Latif Akintade1, Megan del Valle2, Carlos A. Perdomo3, Richard Y. Zhang2, Elias M. Schwam2, 1Eisai Europe, Ltd, London, United Kingdom; 2Pfizer Inc, New York, NY, USA; 3 Eisai Medical Research Inc, Ridgefield Park, NJ, USA. Contact e-mail: [email protected] Background: Current NICE guidance on the use of cholinesterase inhibitors states “the drug should be continued only where there has been an improvement or no deterioration in MMSE score, together with evidence of global improvement on the basis of behavioral and/or functional assessment.” There may, however, be patients who derive cognitive benefit from treatment but show no apparent global improvement. Objective: To conduct analyses to explore and compare the impact of using two definitions to categorize responders. Methods: Data from five, randomized, placebocontrolled studies of donepezil were analyzed using two definitions of

“responder”: “NICE-based” and “cognition only.” Cognition was assessed using the MMSE or ADAS-cog. Global function was assessed using all global, behavioral, and functional measures collected with improvement on any measure meeting criteria. The percent of responders and the magnitude of effect on cognition were determined. Results: Overall, at six months placebo patients showed cognitive deterioration and donepezil patients showed improvement, with an average improvement (relative to placebo) of 2.90 on the ADAS-cog and 1.57 on the MMSE. In the pooled analysis using the “NICE definition”, 34% of donepezil patients were responders using the ADAS-cog and 42% for MMSE; the magnitude of change (relative to overall placebo) was 6.70 and 3.52 respectively. The change from baseline was largest in the donepezil responders followed by donepezil non-responders, then the total placebo group. Using “cognition-only” criteria, 63% of donepezil patients were responders using the ADAS-cog and 65% for the MMSE; their pooled magnitude of improvement (relative to overall placebo) was 5.82 and 3.54 respectively. Conclusion: Using the NICE criteria, donepezil responders demonstrated an improvement of ⬃7 ADAS-cog points (⬃3 MMSE points) relative to placebo. This treatment effect translates into benefits that are likely to be real and meaningful to patients and their caregivers. P2-414

OMENTAL TREATMENT OF ALZHEIMER’S DISEASE: A CASE SERIES

William R. Shankle1,2, Junko Hara1,2, Peter Leport3, Mir Ali3, Lynda Bjornsen2, George Gade3, Maryellen Raimo3, Linda Reyes3, Terrence O’Heany3, 1UC Irvine, Irvine, CA, USA; 2The Shankle Clinic, Irvine, CA, USA; 3Fountain Valley Regional Medical Center, Fountain Valley, CA, USA. Contact e-mail: [email protected] Background: Surgical transposition of the omentum to the brain (OT) has been performed for over 30 years, with clinical improvement seen in stroke, spinal cord injury, viral encephalitis, and cerebral palsy. In one Alzheimer’s disease (AD) patient, Relkin reported clinical improvements in behavioral and cognitive measures. Autopsy pathologically confirmed AD, but found no neuritic plaques in cortical areas directly contacting the omentum. Objective: To further investigate these findings, OT was performed on 6 biopsy-proven AD patients who were declining more rapidly after being relatively stable for years on cholinesterase inhibitor (CheI) therapy. Methods: OT was applied to the right hemisphere of 3 AD patients and to the left hemisphere of the others. Postoperative longitudinal follow-up ranged from 17 to 41 months. Outcome measures included serial global (Clinical Dementia Rating Scale [CDRS], Dementia Severity Rating Scale [DSRS]), cognitive (CERAD battery, Mini-Mental State Exam [MMSE]), functional (activities of daily living), behavioral (Neuropsychiatric Inventory [NPI]), and neuroimaging studies every 3-6 months. Results: All non-imaging outcome measures were normalized to a scale of 0-1. Dementia severity as measured by the CDRS and DSRS sub-score totals, showed mean maximal reductions of 32% and 22% respectively, at 19 months follow-up relative to the expected course on CheI therapy (P ⬍ 0.0002). MMSE scores, which measure left hemisphere cognitive function, showed smaller improvements for 10 to 35 months in the three left hemisphere OT patients, but declined more rapidly than expected in the right hemisphere OT patients. Behaviorally, NPI scores of the three patients who had significant preoperative behavioral problems markedly improved, with changes of 29 to 81 points that were sustained for 6 to 34 months. These clinical findings were consistent with HMPAO SPECT brain activity changes, which increased up to 20% in cortical areas underlying the omentum. Conclusion: Four of the six AD patients showed objective improvement and stabilization for up to 3.5 years. These treatment effects may arise from gangliosides and/or stem cells produced by omental growth factors (i.e., TGF-alpha, basic FGF, NGF, and vascular EGF). Basic research is needed to better elucidate these therapeutic omental effects in AD and possibly other disorders.