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Development of AFFITOPE Alzheimer vaccines: Results of phase I studies with AD01 and AD02
Poster Presentations P4 DAAT and at the recovery of microcirculatory and collateral bed of the brain by means of low-energy laser radiation. Methods: The study included 46 operated patients aged 34-79 (average 65) who had long had AD, of whom: -Group (CDR-0) - 4 (8.7%): with an increased risk of AD, with growing memory disorders, without much cognitive disorders and dementia manifestations, whose 2 or more close relatives had had AD; -Group (CDR1) - 15 (32.6%): mild dementia, mild cognitive disorders, moderate manifestations of AD (history of up to 2 years); -Group (CDR-2) - 20 (43.5%): moderate dementia, persistent cognitive disorders, more severe manifestations of AD (history of up to 6 years); -Group (CDR-3) - 7 (15.2%): severe dementia, gross cognitive disorders, late-stage AD (history of 7-12 years). The patients underwent CT or MRI, scintigraphy (SG), rheoencephalography (REG) and cerebral MUGA. Endovascular surgery was done prophylactically in Group CDR-0, against the background of growing memory disorders; in the other groups - in the period of 1-12 years after the disease symptoms had appeared. Results: All the patients, regardless of the disease stage, had DAAT manifested by reduction of capillary blood flow with the development of multiple arteriovenous shunts in the fronto-parietal and temporal brain regions, and the phenomena of atrophy of the temporal lobes. The endovascular treatment made it possible to restore capillary and collateral blood flow and reduce the arterio-venous shunts in all the cases. In the long-term period, the clinical result accompanied by decrease of dementia level, improved memory, and decrease in cognitive impairment was obtained in all the cases, though its degree was different in each group of the patients. Conclusions: The treatment given to patients with DAAT and with different AD stages helps not only halt further disease progression, but may also cause its regress. We cannot exclude that endovascular laser treatment promotes the development of regenerative processes in the brain tissue. But this question requires further study. P4-248
CLINICAL TRIAL SIMULATION TO ASSESS THE PROBABILITIES OF TECHNICAL SUCCESS FOR DRUGS IN ALZHEIMER’S DISEASE PROOF-OF-CONCEPT STUDIES
James Rogers1, Brian Corrigan2, Terence Fullerton2, 1Metrum Research Group,, Tariffville, Connecticut, United States; 2Pfizer, Inc, New London, Connecticut, United States. Background: A longitudinal model to describe the progression of ADAS-cog in patients with Alzheimer’s disease (AD) is available [1]. We performed trial simulation to evaluate the probabilities of success for potential candidates with different characteristics of interest in AD proof-of-concept (POC) studies. Methods: In the simulation, various drug characteristics regarding symptomatic and disease stabilizing actions were assumed. For drugs with only a symptomatic effect, the same onset as donepezil was assumed. For drug with both actions, an effect similar to donepezil was assumed for the symptomatic component, while various inhibition on slope of the decline were evaluated. The trial was a parallel study having two arms (placebo and drug) of 100 patients/ arm, 12-weeks of treatment and a baseline MMSE of 14-26. For each drug effect, patient-level ADAS-cog over time was simulated in 1000 trials. The treatment effect at week 12 was estimated in each trial using a defined statistical method. The percentage of trials that achieved prespecified criteria was calculated as the probability of success. Simulations were performed in R program. Results: When a candidate had only a symptomatic effect and the onset was as rapid as donepezil, the drug effect at week 12 was close (90%) to that at week 26. When the drug had an additional disease stabilizing action, the drug effect became greater at week 26 compared to week 12. As would be expected, the difference was larger with a greater assumed disease stabilizing effect. For drug with only a symptomatic effect, there was 57% probability of success in a 12-week study when the true treatment effect was 4 points at week 26, the desirable target effect. For a drug with a symptomatic effect similar to donepezil and a moderate disease stabilizing effect, there was only 27% probability of success in a 12-week study even if the true drug effect was 4 points at week 26. Conclusions: The trial simulations
S793
in mild to moderate AD patients suggest that a 12-week POC study may not be long enough to test drugs with some degree of disease stabilizing effects. This trial simulation can be used to quantitatively evaluate other clinical trial of interest.
P4-249
DEVELOPMENT OF AFFITOPE ALZHEIMER VACCINES: RESULTS OF PHASE I STUDIES WITH AD01 AND AD02
Markus Mandler1, Walter Schmidt1, Frank Mattner1, 1AFFiRiS AG, Vienna, Austria. Background: Based on the notion that cerebral accumulation of certain Aß species (e.g., unprocessed, N-terminally modified molecules) is central to the pathogenesis of Alzheimer’s disease (AD) and endowed with the knowledge that emerged during clinical testing of the first Alzheimer vaccine, AN1792, AFFiRiS designed a new type of AD vaccines. Methods: Rather than relying on full-length Aß or fragments thereof, AFFITOPE vaccines use short peptides mimicking parts of the native Aß sequence as their antigenic component. The technology created to identify these peptides, termed AFFITOME-technology, concomitantly provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are non-self, AFFITOPES don’t need to break tolerance typically established against self proteins. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Aß-specific autoreactive T cells. Third, the AFFITOME technology allows for tailoring the specificity of the vaccine-induced antibody response focusing it exclusively on Aß species and preventing crossreactivity with APP. Results: In a program based on two AFFITOPES, AD01 and AD02, both targeting the N-terminus of Aß, this approach was taken all the way from concept to clinical testing. Phase I data on both vaccines confirm the safety concept inherent to the new generation of AFFITOPE AD vaccines. Data on their clinical activity, to be presented, support further development of AD02 towards phase II. Conclusions: The current AD02 phase II AD project includes new diagnostic criteria and aims at generating initial evidence for a disease-modifying effect of AD02. P4-250
EFFECTIVENESS OF REMOTE ASSISTANCE FOR PEOPLE WITH DEMENTIA AT HOME USING REMINISCENCE SYSTEM AND A SCHEDULE PROMPTER
Noriaki Kuwahara1, Kazunari Morimoto2, Nobuji Tetsutani3, 1Kyoto Institute of Technology, kyoto, Japan; 2Kyoto Institute of Technology, Kyoto, Japan; 3Tokyo Denki University, Tokyo, Japan. Background: We intended to provide various types of communicative intervention such as talking on video phones, providing appropriate contents, and managing daily-life scheduling through a TV monitor. This system uses a set-top box with a camera and controls various types of intervention. Remote Reminiscence talking system: In this system, the start of intervention is triggered by operation of a remote partner. Scheduling prompter system This system is to deliver individuals video contents for prompting the individual’s willingness to keep the schedule, such as medicine dosing, hospital visits, and so on. Methods: The first week was the A period. In this period, the subject was requested to see the TV programs which they like. The next week was the B period. In this period, the partner made a call to the subject PC (video phone),and had some conversation. The partner was asked to use the subject’s old photos when she could not find any topics to talk. For the scheduling prompter, the first week was the A period. In this period, the caregiver asked in the usual manner the subject to carry out the above tasks. The next week was the B period. The video content for scheduled task was output automatically. The subject was also asked to carry out the tasks. Subjects: Four subjects with Alzheimer’s disease were selected. Their average age was 79 year old and MMSE scores was 20. Results:
CLINICAL TRIAL SIMULATION TO ASSESS THE PROBABILITIES OF TECHNICAL SUCCESS FOR DRUGS IN ALZHEIMER’S DISEASE PROOF-OF-CONCEPT STUDIES
James Rogers1, Brian Corrigan2, Terence Fullerton2, 1Metrum Research Group,, Tariffville, Connecticut, United States; 2Pfizer, Inc, New London, Connecticut, United States. Background: A longitudinal model to describe the progression of ADAS-cog in patients with Alzheimer’s disease (AD) is available [1]. We performed trial simulation to evaluate the probabilities of success for potential candidates with different characteristics of interest in AD proof-of-concept (POC) studies. Methods: In the simulation, various drug characteristics regarding symptomatic and disease stabilizing actions were assumed. For drugs with only a symptomatic effect, the same onset as donepezil was assumed. For drug with both actions, an effect similar to donepezil was assumed for the symptomatic component, while various inhibition on slope of the decline were evaluated. The trial was a parallel study having two arms (placebo and drug) of 100 patients/ arm, 12-weeks of treatment and a baseline MMSE of 14-26. For each drug effect, patient-level ADAS-cog over time was simulated in 1000 trials. The treatment effect at week 12 was estimated in each trial using a defined statistical method. The percentage of trials that achieved prespecified criteria was calculated as the probability of success. Simulations were performed in R program. Results: When a candidate had only a symptomatic effect and the onset was as rapid as donepezil, the drug effect at week 12 was close (90%) to that at week 26. When the drug had an additional disease stabilizing action, the drug effect became greater at week 26 compared to week 12. As would be expected, the difference was larger with a greater assumed disease stabilizing effect. For drug with only a symptomatic effect, there was 57% probability of success in a 12-week study when the true treatment effect was 4 points at week 26, the desirable target effect. For a drug with a symptomatic effect similar to donepezil and a moderate disease stabilizing effect, there was only 27% probability of success in a 12-week study even if the true drug effect was 4 points at week 26. Conclusions: The trial simulations
S793
in mild to moderate AD patients suggest that a 12-week POC study may not be long enough to test drugs with some degree of disease stabilizing effects. This trial simulation can be used to quantitatively evaluate other clinical trial of interest.
P4-249
DEVELOPMENT OF AFFITOPE ALZHEIMER VACCINES: RESULTS OF PHASE I STUDIES WITH AD01 AND AD02
Markus Mandler1, Walter Schmidt1, Frank Mattner1, 1AFFiRiS AG, Vienna, Austria. Background: Based on the notion that cerebral accumulation of certain Aß species (e.g., unprocessed, N-terminally modified molecules) is central to the pathogenesis of Alzheimer’s disease (AD) and endowed with the knowledge that emerged during clinical testing of the first Alzheimer vaccine, AN1792, AFFiRiS designed a new type of AD vaccines. Methods: Rather than relying on full-length Aß or fragments thereof, AFFITOPE vaccines use short peptides mimicking parts of the native Aß sequence as their antigenic component. The technology created to identify these peptides, termed AFFITOME-technology, concomitantly provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are non-self, AFFITOPES don’t need to break tolerance typically established against self proteins. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Aß-specific autoreactive T cells. Third, the AFFITOME technology allows for tailoring the specificity of the vaccine-induced antibody response focusing it exclusively on Aß species and preventing crossreactivity with APP. Results: In a program based on two AFFITOPES, AD01 and AD02, both targeting the N-terminus of Aß, this approach was taken all the way from concept to clinical testing. Phase I data on both vaccines confirm the safety concept inherent to the new generation of AFFITOPE AD vaccines. Data on their clinical activity, to be presented, support further development of AD02 towards phase II. Conclusions: The current AD02 phase II AD project includes new diagnostic criteria and aims at generating initial evidence for a disease-modifying effect of AD02. P4-250
EFFECTIVENESS OF REMOTE ASSISTANCE FOR PEOPLE WITH DEMENTIA AT HOME USING REMINISCENCE SYSTEM AND A SCHEDULE PROMPTER
Noriaki Kuwahara1, Kazunari Morimoto2, Nobuji Tetsutani3, 1Kyoto Institute of Technology, kyoto, Japan; 2Kyoto Institute of Technology, Kyoto, Japan; 3Tokyo Denki University, Tokyo, Japan. Background: We intended to provide various types of communicative intervention such as talking on video phones, providing appropriate contents, and managing daily-life scheduling through a TV monitor. This system uses a set-top box with a camera and controls various types of intervention. Remote Reminiscence talking system: In this system, the start of intervention is triggered by operation of a remote partner. Scheduling prompter system This system is to deliver individuals video contents for prompting the individual’s willingness to keep the schedule, such as medicine dosing, hospital visits, and so on. Methods: The first week was the A period. In this period, the subject was requested to see the TV programs which they like. The next week was the B period. In this period, the partner made a call to the subject PC (video phone),and had some conversation. The partner was asked to use the subject’s old photos when she could not find any topics to talk. For the scheduling prompter, the first week was the A period. In this period, the caregiver asked in the usual manner the subject to carry out the above tasks. The next week was the B period. The video content for scheduled task was output automatically. The subject was also asked to carry out the tasks. Subjects: Four subjects with Alzheimer’s disease were selected. Their average age was 79 year old and MMSE scores was 20. Results: