S2‐04–04: Rational therapeutic strategies for modifying Alzheimer's disease: Abeta oligomers as the validated target

not available. S2-04-04 RATIONAL THERAPEUTIC STRATEGIES FOR MODIFYING ALZHEIMER’S DISEASE: ABETA OLIGOMERS AS THE VALIDATED TARGET Colin L. Masters, Mental Health Research Institute, Parkville, Australia; The University of Melbourne, Parkville, Australia. Contact e-mail: c.masters@unimelb.edu.au Background: In 1984 we described the oligomerization of A and some of the biochemical factors which affect its stability. Subsequently, we found that metal ions such as Zn and Cu play a major role in the oligomerization process, and that the soluble oligomeric species of A are the principal determinants of the degree of neurodegeneration. We next identified compounds which were capable of interfering with the metalinduced oligomerization of A . Prana Biotechnology (PBT) was founded to commercialize these discoveries, and the first compound (clioquinol CQ) was shown to have favorable preclinical properties and some efficacy in an early Phase 2 clinical trial. Further medicinal chemistry on the 8-OH quinoline scaffold yielded a much-improved compound, PBT2, with high brain penetrability. CQ and PBT2 are efficient at inhibiting Zn and Cu -induced A oligomerization and Cu -induced dityrosine formation. In transgenic mouse AD models, CQ and PBT2 effectively: lower soluble oligomer and insoluble A levels in brain interstitial fluid dialysate and A plaque levels; reverse A -induced inhibition of LTP in hippocampal slices; improve the behavioral phenotype in the Morris Water Maze; lower tau, and increase synaptophysin levels. Results: PBT2 has now been taken through early clinical development. In a recently completed Phase 2 study, the compound was found to be safe at 50 and 250mg per day for 12 weeks. CSF A 42 was significantly reduced at the higher dose, with a significant dose-effect. Two tests of cognitive executive function also showed significant improvements at the higher dose. A -amyloid neuroimaging using PET offer the tools for monitoring the efficacy of A -directed drug interventions, and shows a highly significant correlation of A -amyloid burden with cognitive impairment during the evolution of the preclinical phases of AD. Conclusions: Collectively, these data provide evidence that orally bioavailable drugs designed to inhibit toxic oligomeric species of A in human subjects with Alzheimer’s disease have the potential to modify the course of the illness. S2-04-05 ABETA IMMUNOTHERAPY IN ALZHEIMER’S DISEASE Roger M. Nitsch, University of Zurich, Zurich, Switzerland. Contact e-mail: nitsch@bli.uzh.ch Background: A rapidly growing body of data indicates that Abeta immunotherapy can be efficacious both in model systems and in human patients. Methods: Tansgenic mouse models as well as human patients with Alzheimer’s disease with chronically elevated plasma and CSF levels of antibodies against beta-amyloid were analyzed. Results: Evidence includes reductions in brain beta-amyloid deposits, improved neurite and synapse morphology, reduced astrocytosis, restored neural functions including LTP and behaviour. On the other hand, major challenges in the current development of safe immunotherapies include autoimmune disease, brain inflammation, microhemorrhage, increased amyloid angiopathy, blood brain barrier passage of antibodies, remaining neurofibrillary tangles, reductions in brain volume as well as the precise molecular definition of the therapeutic target. Conclusions: Growing understanding of the pathophysiological basis of these challenges will lead to safer forms of Abeta immunotherapy with a fair chance to become first choice among future amyloidreducing treatment options for large populations of patients suffering from Alzheimer’s disease. S2-04-06 SAFETY, TOLERABILITY AND IMMUNOGENICITY OF THE A IMMUNOTHERAPEUTIC VACCINE CAD106 IN A FIRST-IN-MAN STUDY IN ALZHEIMER PATIENTS Bengt Winblad, Karolinska Institutet, Stockholm, Sweden. Contact email: bengt.winblad@ki.se Background: CAD106 is an immunotherapeutic vaccine comprising the A 1-6 peptide coupled to the Q virus-like particle. In animals, CAD106 induced A -antibody titers without activating A -reactive T-cells. Administration of CAD106 to APP transgenic mice showed a considerable reduction of amyloid accumulation. Methods: Safety, tolerability and immunogenicity of CAD106 was assessed in a first-in-man study CCAD106A2101. This was a 52-week, two-center, randomized, doubleblind, placebo-controlled, time-lagged, parallel group study in patients with mild to moderate AD in Sweden. Patients underwent regular safety monitoring, which included five brain MRIs, three lumbar punctures and five electroencephalograms. An independent Data Safety Monitoring Board was monitoring the study. Results: Results are available from the first cohort of patients. This included a total of 31 Caucasians (19 m, 12 f) with a mean age of 69.3 yrs and a mean MMSE score of 21.1. At weeks 0, 6 and 18, 24 patients received 50ug of CAD106 s.c. and 7 patients received placebo. None of the 31 patients discontinued the study prior to week 52. Adverse events were reported by a total of 29 patients, and were predominantly mild. The most common adverse events were nasopharyngitis (CAD106 42% vs placebo 29%), fatigue (29% vs 0) and headache (21% vs 0). Injection-site reactions were reported by three CAD106-treated patients and one placebo-treated patient. Serious adverse events were reported for four patients on CAD106 (trauma, aorta stenosis, fainting, chest pain) and one patient on placebo. They were not considered related to the study medication. Antibody titers were measured by specific sandwich ELISA assays. CAD106 induced a specific antibody response against A and against Q in 16 of the 24 treated patients, while no such response was observed in placebo patients. Peak mean A IgG antibody titers were observed at week 8 and persisted above the defined threshold for 4 weeks. Conclusions: Overall, the results of this study indicate CAD106 50ug to be safe and well tolerated, with antibody response achieved in two thirds of the patients. A second cohort of patients was initiated based on the findings from this initial cohort. Planning for further studies is ongoing. MONDAY, JULY 28, 2008 SYMPOSIA S2-05 ENHANCING CARE OF PERSONS WITH DEMENTIA THROUGH COORDINATION OF MEDICAL AND COMMUNITY CARE S2-05-01 BEYOND PRIMARY CARE: IMPROVING THE IMPACT AND REACH OF COLLABORATIVE CARE MODELS FOR ALZHEIMER’S DISEASE Christopher M. Callahan, Indiana University Center for Aging Research, Regenstrief Institute, Inc, Indianapolis, IN, USA. Contact email: ccallaha@iupui.edu Background: Most older adults with Alzheimer’s disease are cared for by primary care physicians. Recent collaborative care models demonstrate the capacity to improve the process and outcomes of care in primary care. However, these models still suffer from limited impact and reach. Methods: We recently reported the results of a controlled clinical trial that tested the effectiveness of collaborative care for older adults with Alzheimer’s T128 Symposia S2-05: Enhancing Care of Persons With Dementia Through Coordination of Medical and Community Care