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P.5.a.007 Aβ AFFITOPES as active vaccines in the treatment of Alzheimer's disease: preliminary results of two phase I studies
P.5.a Dementia and neurological disorders - Dementia (clinical) of patient's symptoms and ensure the administration of treatment, MMSE scores under 20. Exclusion criteria: substance related disorders, severe organic diseases, known intolerance to rivastigmine. The intent-to-treat (ITT) and last observation carried forward (LOCF) analysis were used for the statistic interpretation of this study data. Results: Patients that reach the end-point presented a favourable tolerability profile ofthe rivastigmine transdermal patch treatment. Only 4 drop-outs were recorded, due to the exacerbation of psychomotor excitement, insomnia or gastrointestinal symptoms. The evolution of MMSE scores was relatively stable, after 12 weeks (-0.3±O.9) and at endpoint (-1.2±0.6). The ADAS scores had a similar evolution (+1.3 at 3 months and +5.3±1.2 at endpoint), while the impact of the disease over the caregivers decreased (-2.2 on BI). BPRS scores decreased moderately during the first 3 months (-2.2) and remained stable after that, while the GAF scores minimally decreased (-4.5 at week 12 and -5.9 at week 24). Conclusion: Rivastigmine transdermal patch is well tolerated and efficient in controlling both cognitive and non-cognitive symptoms in moderate to severe AD and therefore it decreases also the caregivers burden. Honoraria: Speaker for: Astra Zeneca, Bristol Myers Squibb, CSC Pharmaceuticals, Eli Lilly, Janssen Cilag, Lundbeck, Organon, Pfizer, Servier, Sanofi Aventis References [I] Guay DR. Rivastigmine transdermal patch: role in the management of Alzheimer's disease. Consult Pharm 2008 Aug; 23(8):598---{)09. [2] Schmidt R, AIf C, Bancher C et al. Transdermal rivastigmine patch in outpatient services in Austria: a naturalistic study in 103 patients with Alzheimer dementia. Neuropsychiatr., 2009;23(1):58-63. [3] Salmon E. A transdermal patch ofrivastigmine. Rev Med Liege, 2008 Sep;63(9):57Q-571.
1p,5.a.oo?1 ~ AFFITOPES
as active vaccines in the treatment of Alzheimer's disease: preliminary results of two phase I studies
A. Kutzelnigg1 ., A. Schneebergeri, M. Brunneri, D. Meshkat", p. Dal-Bianc05 , A. Laggner'', D. Winkler7 , S. Kasper", E. Auffi, M. Schmitz", M. Miiller3. I Medical University of Vienna, Department for Psychiatry and Psychotherapy Division of Biological Psychiatry, Vienna, Austria; 2Affiris AG, Clinical Development, Vienna, Austria; 3 Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria; 4 Institute for Psychosomatic Medicine, Psychosomatic Medicine, Vienna, Austria; 5 Medical University Vienna, Department of Neurology, Vienna, Austria; 6 Medical University Vienna, Department of Emergency Medicine, Vienna, Austria; 7 Medical University Vienna, Department for Psychiatry and Psychotherapy Division of Biological Psychiatry, Vienna, Austria Active immunotherapy has been shown to reduce Amyloid-beta (A/3), a protein that accumulates in Alzheimer brains. As human use of the first A/3-vaccine AN1792 was afllicted with the occurrence of meningoencephalitis (most likely caused by the activation of A/3-specific T-cells), a new technology for A/3-vaccines was developed. Using A/3-AFFITOPES to induce A/3-neoepitope targeting antibodies likely offers several advantages. The short length of the peptides prevents the activation of A~-specific T-cells. Furthermore, the antibody response exclusively targets A/3 but not its precursor APp.
S623
Two independent, single-center, randomized, phase I, first-inman (FIM) clinical studies were conducted with the active A/3 vaccines AFFITOPE ADOI and AD02. In both studies, following informed consent capability evaluation, a total of 48 patients, i.e. 24 patients per study were included. Patients were diagnosed as having probable AD of mild to moderate severity (MMSE 16-26) according to NINCDS-ADRDA criteria. They were randomized in a 1:1 ratio into two groups, the first group receiving a peptide/carrier protein conjugate alone, the second group receiving the same conjugate adsorbed to aluminium hydroxide. Patients meeting all in- and exclusion criteria received 4 vaccinations at 4-week intervals. The vaccines' safety and tolerability, primary objectives of either study, were assessed weekly in a standardized manner. All safety data were reviewed by an external Data Safety Committee. The vaccines' inununological and clinical activities, both secondary parameters of either study, will be analyzed in an explorative manner only. As of February 2009, a total of 576 adverse events have been reported in both studies. Ofthese, five were serious adverse events, which were all classified as having no causal relationship to the vaccines ADOI and AD02. Injection site reactions made up 63% of all adverse events with ADOI and 66% of all adverse events with AD02, a finding that is typical of vaccines. With the exception of granulomas, all local reactions were short lived (ranging from several hours to a few days). Comparison of adjuvanted and non-adjuvanted groups regarding local reactions revealed the expected outcome. Most local reactions reported (>90%) were confined to patients receiving the conjugate adsorbed to aluminium hydroxide while only a few local reactions (<10%) were observed in the absence of aluminium. All reported local reactions were of mild to moderate degree. All systemic adverse events were of mild to moderate degree and were relatively equally distributed between the two groups. Up to now, none of the patients presented with symptoms that would be reminiscent of meningoencephalitis. The vaccines' immunological and clinical activity will be assessed at the end of each study. Safe and effective Alzheimer treatment is urgently needed. The vaccines investigated in the studies above target the N-terminal neoepitope of A~. Most importantly, they are designed to offer maximal safety (e.g., prevention of meningoencephalitis and of the induction of antibodies that would crossreact with APP). Preliminary analysis of phase I data indicate a favourable toxicityand tolerability profile for both vaccines, ADOI and AD02. References
[I] Orgogozo lM, Gilman S, Dartigues JF, Laurent B, Fuel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C, 2003. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46-54.
1p,5.a.oo?1 ~ AFFITOPES
as active vaccines in the treatment of Alzheimer's disease: preliminary results of two phase I studies
A. Kutzelnigg1 ., A. Schneebergeri, M. Brunneri, D. Meshkat", p. Dal-Bianc05 , A. Laggner'', D. Winkler7 , S. Kasper", E. Auffi, M. Schmitz", M. Miiller3. I Medical University of Vienna, Department for Psychiatry and Psychotherapy Division of Biological Psychiatry, Vienna, Austria; 2Affiris AG, Clinical Development, Vienna, Austria; 3 Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria; 4 Institute for Psychosomatic Medicine, Psychosomatic Medicine, Vienna, Austria; 5 Medical University Vienna, Department of Neurology, Vienna, Austria; 6 Medical University Vienna, Department of Emergency Medicine, Vienna, Austria; 7 Medical University Vienna, Department for Psychiatry and Psychotherapy Division of Biological Psychiatry, Vienna, Austria Active immunotherapy has been shown to reduce Amyloid-beta (A/3), a protein that accumulates in Alzheimer brains. As human use of the first A/3-vaccine AN1792 was afllicted with the occurrence of meningoencephalitis (most likely caused by the activation of A/3-specific T-cells), a new technology for A/3-vaccines was developed. Using A/3-AFFITOPES to induce A/3-neoepitope targeting antibodies likely offers several advantages. The short length of the peptides prevents the activation of A~-specific T-cells. Furthermore, the antibody response exclusively targets A/3 but not its precursor APp.
S623
Two independent, single-center, randomized, phase I, first-inman (FIM) clinical studies were conducted with the active A/3 vaccines AFFITOPE ADOI and AD02. In both studies, following informed consent capability evaluation, a total of 48 patients, i.e. 24 patients per study were included. Patients were diagnosed as having probable AD of mild to moderate severity (MMSE 16-26) according to NINCDS-ADRDA criteria. They were randomized in a 1:1 ratio into two groups, the first group receiving a peptide/carrier protein conjugate alone, the second group receiving the same conjugate adsorbed to aluminium hydroxide. Patients meeting all in- and exclusion criteria received 4 vaccinations at 4-week intervals. The vaccines' safety and tolerability, primary objectives of either study, were assessed weekly in a standardized manner. All safety data were reviewed by an external Data Safety Committee. The vaccines' inununological and clinical activities, both secondary parameters of either study, will be analyzed in an explorative manner only. As of February 2009, a total of 576 adverse events have been reported in both studies. Ofthese, five were serious adverse events, which were all classified as having no causal relationship to the vaccines ADOI and AD02. Injection site reactions made up 63% of all adverse events with ADOI and 66% of all adverse events with AD02, a finding that is typical of vaccines. With the exception of granulomas, all local reactions were short lived (ranging from several hours to a few days). Comparison of adjuvanted and non-adjuvanted groups regarding local reactions revealed the expected outcome. Most local reactions reported (>90%) were confined to patients receiving the conjugate adsorbed to aluminium hydroxide while only a few local reactions (<10%) were observed in the absence of aluminium. All reported local reactions were of mild to moderate degree. All systemic adverse events were of mild to moderate degree and were relatively equally distributed between the two groups. Up to now, none of the patients presented with symptoms that would be reminiscent of meningoencephalitis. The vaccines' immunological and clinical activity will be assessed at the end of each study. Safe and effective Alzheimer treatment is urgently needed. The vaccines investigated in the studies above target the N-terminal neoepitope of A~. Most importantly, they are designed to offer maximal safety (e.g., prevention of meningoencephalitis and of the induction of antibodies that would crossreact with APP). Preliminary analysis of phase I data indicate a favourable toxicityand tolerability profile for both vaccines, ADOI and AD02. References
[I] Orgogozo lM, Gilman S, Dartigues JF, Laurent B, Fuel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C, 2003. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46-54.