- Email: [email protected]
70 AFFITOPE® — based vaccines: results from phase I support the further clinical development of AFFITOPE® AD02
S30
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
when there are no symptoms and just signs detected by image or biomarkers. In this context the situation is somewhat more controversial. In the case of the familiar forms of AD, the carriers of the mutation sooner or later will have AD. Trials in these populations, those are rare but can be done due to the collaboration of networks. These populations have a very particular high risk and this will be considered by the regulators as a special case. Populations of elderly patients with high amyloid load without clinical symptoms are under research but not yet an important regulatory target. In particular the issue of safety in this population is of the utmost importance.
68
CEREBRAL MICROBLEEDS: IDENTIFICATION, PREVALENCE AND CLINICAL RELEVANCE
Philip Scheltens, VU University Medical Center, Amsterdam, The Netherlands. Contact e-mail: [email protected] -Lobar microbleeds in patients with Dementia are found to be associated with high amyloid burden -Microbleeds are shown to have different etiologies and associated risk of mortality on the basis of their location in the brain. New terminology for amyloid-related imaging abnormalties (ARIA) and a new cut-off point for microbleeds in participants of amyloid-modifying clinical trials were recently introduced. Susceptibility-weighted imaging showed enhanced sensitivity for detecting microbleeds compared with gradientecho imaging, and may help in future for identifying associations between microbleeds and clinical outcomes. Studies that compared imaging with histopathology of microbleeds suggest that further refinement of imaging techniques is required to accurately detect these lesions.
69
PRECLINICAL AND CLINICAL CONSIDERATIONS FOR ABETA IMMUNOTHERAPY
Dale Schenk, Janssen Alzheimer Immunotherapy, South San Francisco, CA, USA. Contact e-mail: [email protected] Abeta immunotherapy as a potential treatment for Alzheimer’s disease was first described over a decade ago. This approach has been instrumental in better understanding the biological role and pathological effects of both soluble and deposited forms of abeta in animal models and patients suffering from Alzheimer’s disease. Extensive research has suggested that multiple mechanisms are involved in the clearance of abeta from brain by abeta immunotherapy. Recent findings have suggested that the epitope specificity
of an antibody to abeta can have differential biological consequences in vivo. These consequences appear to result in not only differential clearance of various form of abeta, but also downstream changes in synaptic markers as well as differences in protective effects on behavior in animal models of the disease. The molecular basis for these differences likely are a result of the effects of different antibodies binding to abeta differentially thereby inducing changes in the resulting structure of the peptide as revealed by X ray crystallography. Through an understanding of these molecular changes, together with extensive animal model analysis, biomarker investigations and ultimately clinical outcomes, it appears that abeta immunotherapy is leading to a very deep understanding of the role of abeta in Alzheimer’s disease as well as a potentially new approach to treament aimed at the underlying pathology of the disease.
70
AFFITOPE® — BASED VACCINES: RESULTS FROM PHASE I SUPPORT THE FURTHER CLINICAL DEVELOPMENT OF AFFITOPE® AD02
Achim Schneeberger, M. Mandler, F. Mattner, W. Schmidt, AFFiRiS AG, Vienna, Austria. Contact e-mail: [email protected] Based on the notion that cerebral accumulation of certain forms of A (unprocessed as well as N-terminally truncated/modified versions) 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 (Elan/Wyeth), AFFiRiS introduced a new generation of AD vaccines. Rather than relying on full-length A itself or fragments thereof, AFFITOPE® vaccines use short peptides, mimicking parts of the native A 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 (short antigens preclude activation of encephalitogenic T cells; AFFITOME®-technology controls specificity of antibodies induced) realized in AFFITOPE® vaccines. The AFFiRiS AD immunotherapy program focuses on two targets: AFFITOPEs® AD01 and AD02 (which differ in their peptide sequence) target the native N-terminus of A while AFFITOPE® AD03 addresses N-terminally-truncated and pyroglutamate-modified forms of A. AD03 just finished phase I clinical testing. Phase I testing of AD01 and AD02 was done in parallel, monocenter studies run at two different sites. In each study, 24 patients were vaccinated; 12 received the vaccine with adjuvant and 12 without. Clinical phase I data to the safety of AFFITOPE® AD01, AD02 (and AD03 – as available), spanning a time period of 20⫹ months (AD01/AD02), support the safety concept inherent
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
to AFFITOPE® AD vaccines. The recently completed analysis of secondary clinical endpoints of AD02-based treatment – regarding parameters such as the cognitive/functional performance of the patients (as assessed among others by MMSE, ADAScog, ADL), body weight development and vaccine induced immune responses over a time period of 20⫹ months – provides evidence for a disease modifying activity of AFFITOPE AD02®. This was particularly evident in patients who entered the phase I study at an early stage of their disease. The above results led AFFiRiS to initiate a multicenter phase II study aimed at evaluating the clinical activity AFFITOPE AD02®. The study design already takes into account the indicatory results of the phase I study and will include a several hundred patients with early AD.
able, often not linear in its progression, many patients don’t decline over a given 1 to 3 year observed period. Measuring reliable change with any outcome is formidable when there is little change. Measures that seem to be more precise and change the most are fraught with expectation bias. The accuracy of early AD diagnosis will improve. We need however, to develop outcomes specific to individual patients and efficient trials methods that take into account the varieties of individual responses and that only a subset of patients will likely benefit from any particular drug. Onesize-fits-all-outcomes will not be efficient. The model of action of a drug being developed should determine inclusion criteria, trials durations, and outcomes.
72 71
ARE WE READY TO PERFORM CLINICAL TRIALS IN EARLY AD PATIENTS? WHICH PATIENTS, WHICH OUTCOMES?
Lon S. Schneider, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Contact e-mail: [email protected] Trials in early AD have been performed for 2 decades; we are beyond ready. An accurate title for the session could be, “Are We Ready to Explicitly Recognize Early AD and Do Better Trials?” The early cognitive impairment phase of AD was recognized since the late 1980s but called different names. Trials inclusion criteria from the late 1980s onward implicitly provided for early AD patients by allowing MMSE scores 24 to 27 and clinicians’ judgments of impaired ADLs. Similarly, MCI studies included patients with early AD. MCI trials, from 1999 onward, and ADNI used Mayo Clinic criteria, essentially MCI due to AD, and the same as the proposed AA/NIH research criteria. The more memoryimpaired patients in these cohorts — about two-thirds — are indistinguishable from and could have been diagnosed as AD. As a group, they were very likely to progress over a short time; and far more likely to have putative AD biomarkers or be ApoE4 carriers. Conversely, the less impaired were not likely to progress or to have positive biomarkers. Distinctions between MCI due to AD, prodromal AD, early AD, mild AD, and similar terms may be without practical differences or too subtle for reliable use, with judgments about the extent of impaired function mainly determining diagnosis. In the context of MCI or early AD diagnoses, current biomarkers, claimed to be useful in identifying AD early in its course, may ironically identify more advanced AD. As AD is very slowly progressive on average, highly vari-
S31
INFLUENCE OF MID-LIFE RISK FACTORS ON LATE LIFE COGNITIVE AND WHITE MATTER CHANGES: HOW SHOULD WE TIME PREVENTIVE INTERVENTIONS?
Ingmar Skoog, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unite, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden. Contact e-mail: [email protected] Late-life cognitive disorders are common. The most common causes are Alzheimer’s disease and vascular brain lesions, such as cerebral white matter lesions (WMLs). During recent years evidence has accumulated that mid-life factors may influence the risk for both Alzheimer’s disease and WMLs. These include factors previously known to affect vascular disease, such as hypertension, diabetes mellitus and hypercholesterolemia. Late-life cognitive disorders have also been related to other life-style factors in mid-life, such as psychological stress, physical activity and lung function, engagement in different hobbies, wine consumption, diet and intellectual activity. Most of these have also been related to WMLs in late life, although hypertension is the main risk factor for these lesions. In the PROGRESS trial, which included individuals with a history of stroke, treatment with antihypertensives reduced the occurrence of new white matter lesions significantly. Vascular risk factors, such as hypertension and hypercholesterolemia, already have indications for treatment due to the proven effect in randomized controlled trials on risk for cardiovascular and cerebrovascular end-points and mortality. The main problem here is to detect individuals with these risk factors. It is not likely that it will ever be practically possible to conduct RCTs in middle aged populations to test whether preventive strategies will decrease the risk of dementia in old age (maybe 30 years later). Detection of vascular risk factors is however most likely important to prevent Alzheimer’s disease and WMLs in late life. Advice regarding a healthy life
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
when there are no symptoms and just signs detected by image or biomarkers. In this context the situation is somewhat more controversial. In the case of the familiar forms of AD, the carriers of the mutation sooner or later will have AD. Trials in these populations, those are rare but can be done due to the collaboration of networks. These populations have a very particular high risk and this will be considered by the regulators as a special case. Populations of elderly patients with high amyloid load without clinical symptoms are under research but not yet an important regulatory target. In particular the issue of safety in this population is of the utmost importance.
68
CEREBRAL MICROBLEEDS: IDENTIFICATION, PREVALENCE AND CLINICAL RELEVANCE
Philip Scheltens, VU University Medical Center, Amsterdam, The Netherlands. Contact e-mail: [email protected] -Lobar microbleeds in patients with Dementia are found to be associated with high amyloid burden -Microbleeds are shown to have different etiologies and associated risk of mortality on the basis of their location in the brain. New terminology for amyloid-related imaging abnormalties (ARIA) and a new cut-off point for microbleeds in participants of amyloid-modifying clinical trials were recently introduced. Susceptibility-weighted imaging showed enhanced sensitivity for detecting microbleeds compared with gradientecho imaging, and may help in future for identifying associations between microbleeds and clinical outcomes. Studies that compared imaging with histopathology of microbleeds suggest that further refinement of imaging techniques is required to accurately detect these lesions.
69
PRECLINICAL AND CLINICAL CONSIDERATIONS FOR ABETA IMMUNOTHERAPY
Dale Schenk, Janssen Alzheimer Immunotherapy, South San Francisco, CA, USA. Contact e-mail: [email protected] Abeta immunotherapy as a potential treatment for Alzheimer’s disease was first described over a decade ago. This approach has been instrumental in better understanding the biological role and pathological effects of both soluble and deposited forms of abeta in animal models and patients suffering from Alzheimer’s disease. Extensive research has suggested that multiple mechanisms are involved in the clearance of abeta from brain by abeta immunotherapy. Recent findings have suggested that the epitope specificity
of an antibody to abeta can have differential biological consequences in vivo. These consequences appear to result in not only differential clearance of various form of abeta, but also downstream changes in synaptic markers as well as differences in protective effects on behavior in animal models of the disease. The molecular basis for these differences likely are a result of the effects of different antibodies binding to abeta differentially thereby inducing changes in the resulting structure of the peptide as revealed by X ray crystallography. Through an understanding of these molecular changes, together with extensive animal model analysis, biomarker investigations and ultimately clinical outcomes, it appears that abeta immunotherapy is leading to a very deep understanding of the role of abeta in Alzheimer’s disease as well as a potentially new approach to treament aimed at the underlying pathology of the disease.
70
AFFITOPE® — BASED VACCINES: RESULTS FROM PHASE I SUPPORT THE FURTHER CLINICAL DEVELOPMENT OF AFFITOPE® AD02
Achim Schneeberger, M. Mandler, F. Mattner, W. Schmidt, AFFiRiS AG, Vienna, Austria. Contact e-mail: [email protected] Based on the notion that cerebral accumulation of certain forms of A (unprocessed as well as N-terminally truncated/modified versions) 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 (Elan/Wyeth), AFFiRiS introduced a new generation of AD vaccines. Rather than relying on full-length A itself or fragments thereof, AFFITOPE® vaccines use short peptides, mimicking parts of the native A 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 (short antigens preclude activation of encephalitogenic T cells; AFFITOME®-technology controls specificity of antibodies induced) realized in AFFITOPE® vaccines. The AFFiRiS AD immunotherapy program focuses on two targets: AFFITOPEs® AD01 and AD02 (which differ in their peptide sequence) target the native N-terminus of A while AFFITOPE® AD03 addresses N-terminally-truncated and pyroglutamate-modified forms of A. AD03 just finished phase I clinical testing. Phase I testing of AD01 and AD02 was done in parallel, monocenter studies run at two different sites. In each study, 24 patients were vaccinated; 12 received the vaccine with adjuvant and 12 without. Clinical phase I data to the safety of AFFITOPE® AD01, AD02 (and AD03 – as available), spanning a time period of 20⫹ months (AD01/AD02), support the safety concept inherent
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
to AFFITOPE® AD vaccines. The recently completed analysis of secondary clinical endpoints of AD02-based treatment – regarding parameters such as the cognitive/functional performance of the patients (as assessed among others by MMSE, ADAScog, ADL), body weight development and vaccine induced immune responses over a time period of 20⫹ months – provides evidence for a disease modifying activity of AFFITOPE AD02®. This was particularly evident in patients who entered the phase I study at an early stage of their disease. The above results led AFFiRiS to initiate a multicenter phase II study aimed at evaluating the clinical activity AFFITOPE AD02®. The study design already takes into account the indicatory results of the phase I study and will include a several hundred patients with early AD.
able, often not linear in its progression, many patients don’t decline over a given 1 to 3 year observed period. Measuring reliable change with any outcome is formidable when there is little change. Measures that seem to be more precise and change the most are fraught with expectation bias. The accuracy of early AD diagnosis will improve. We need however, to develop outcomes specific to individual patients and efficient trials methods that take into account the varieties of individual responses and that only a subset of patients will likely benefit from any particular drug. Onesize-fits-all-outcomes will not be efficient. The model of action of a drug being developed should determine inclusion criteria, trials durations, and outcomes.
72 71
ARE WE READY TO PERFORM CLINICAL TRIALS IN EARLY AD PATIENTS? WHICH PATIENTS, WHICH OUTCOMES?
Lon S. Schneider, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Contact e-mail: [email protected] Trials in early AD have been performed for 2 decades; we are beyond ready. An accurate title for the session could be, “Are We Ready to Explicitly Recognize Early AD and Do Better Trials?” The early cognitive impairment phase of AD was recognized since the late 1980s but called different names. Trials inclusion criteria from the late 1980s onward implicitly provided for early AD patients by allowing MMSE scores 24 to 27 and clinicians’ judgments of impaired ADLs. Similarly, MCI studies included patients with early AD. MCI trials, from 1999 onward, and ADNI used Mayo Clinic criteria, essentially MCI due to AD, and the same as the proposed AA/NIH research criteria. The more memoryimpaired patients in these cohorts — about two-thirds — are indistinguishable from and could have been diagnosed as AD. As a group, they were very likely to progress over a short time; and far more likely to have putative AD biomarkers or be ApoE4 carriers. Conversely, the less impaired were not likely to progress or to have positive biomarkers. Distinctions between MCI due to AD, prodromal AD, early AD, mild AD, and similar terms may be without practical differences or too subtle for reliable use, with judgments about the extent of impaired function mainly determining diagnosis. In the context of MCI or early AD diagnoses, current biomarkers, claimed to be useful in identifying AD early in its course, may ironically identify more advanced AD. As AD is very slowly progressive on average, highly vari-
S31
INFLUENCE OF MID-LIFE RISK FACTORS ON LATE LIFE COGNITIVE AND WHITE MATTER CHANGES: HOW SHOULD WE TIME PREVENTIVE INTERVENTIONS?
Ingmar Skoog, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unite, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden. Contact e-mail: [email protected] Late-life cognitive disorders are common. The most common causes are Alzheimer’s disease and vascular brain lesions, such as cerebral white matter lesions (WMLs). During recent years evidence has accumulated that mid-life factors may influence the risk for both Alzheimer’s disease and WMLs. These include factors previously known to affect vascular disease, such as hypertension, diabetes mellitus and hypercholesterolemia. Late-life cognitive disorders have also been related to other life-style factors in mid-life, such as psychological stress, physical activity and lung function, engagement in different hobbies, wine consumption, diet and intellectual activity. Most of these have also been related to WMLs in late life, although hypertension is the main risk factor for these lesions. In the PROGRESS trial, which included individuals with a history of stroke, treatment with antihypertensives reduced the occurrence of new white matter lesions significantly. Vascular risk factors, such as hypertension and hypercholesterolemia, already have indications for treatment due to the proven effect in randomized controlled trials on risk for cardiovascular and cerebrovascular end-points and mortality. The main problem here is to detect individuals with these risk factors. It is not likely that it will ever be practically possible to conduct RCTs in middle aged populations to test whether preventive strategies will decrease the risk of dementia in old age (maybe 30 years later). Detection of vascular risk factors is however most likely important to prevent Alzheimer’s disease and WMLs in late life. Advice regarding a healthy life