Reisa Sperling, MD - US grants

Although a number of promising anti-amyloid (ABeta) agents are currently in large-scale clinical trials, unfortunately, none of the trials at the stages of mild to moderate Alzheimer's disease (AD) dementia has yet demonstrated clear evidence of clinical benefit. Given the mounting evidence that neurodegeneration is well entrenched even by the stage of MCI, there is growing concern in the field that we may need to institute antiamyloid therapies at a much earlier stage of AD to fully impact the course of the disease. Recent imaging, biomarker, and autopsy studies are remarkably consistent in the finding that approximately 1/3 of clinically normal older individuals harbor ABeta pathology, and many of these individuals already demonstrate functional and structural brain imaging abnormalities consistent with preclinical AD. The A4 (Anti-Amyloid treatment in Asymptomatic Alzheimer's disease) study is a secondary prevention trial in clinically normal older subjects with biomarker marker evidence of AD pathology, who at increased risk for progression to AD dementia. The A4 trial will be a 3-year, double-blinded, placebo-controlled trial of a monoclonal anti-ABeta antibody in 1000 older individuals who are ABeta-positive on screening PET amyloid imaging. The primary outcome will be rate of decline on a cognitive composite, heavily weighted towards episodic memory and executive function tests. Secondary biomarker outcomes will include PET amyloid imaging, cerebrospinal fluid levels of tau/phosphotau, and volumetric MRI measures. We will also develop a novel computerized test battery and task-free functional MRI as exploratory outcomes. The A4 study will also include a natural history arm of age and education matched ABeta-negative individuals (n=500) who will undergo longitudinal clinical and cognitive assessments. The A4 study should provide critically needed evidence to support (or refute) ABeta as a promising strategy for disease-modifying therapy in very early AD, and will serve to greatly enhance the efficiency of future prevention studies as additional therapies, including anti-tau agents, become available.

Global Alzheimer's Platform Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (GAP TRC-PAD) Academic PIs: Paul Aisen, Reisa Sperling, Jeff Cummings SUMMARY Based on growing recognition that the long pre-dementia stages of Alzheimer's disease (AD) represent the optimal time for interventions aimed at modifying the neurobiology of the disease, most recent drug development programs enroll participants at the preclinical/asymptomatic and prodromal/mild cognitive impairment stages. However, the timeframe, complexity and expense of the recruitment process and site activation for these secondary prevention trials are extremely challenging, and indeed site start-up and trial enrollment, in general, represent the greatest bottleneck for drug development for AD. Thus, there is growing consensus in our field that we must fundamentally overhaul the current clinical trial recruitment and assessment process for these early intervention trials. The overarching goal of this proposal is to accelerate current and future secondary prevention trial enrollment through an innovative, highly efficient approach to identify, evaluate, and enroll appropriate preclinical and prodromal trial candidates, supported by a new site network with enhanced capacities for more efficient and effective conduct of AD clinical trials. It is our view that this can be accomplished only through a public-private partnership, the GAP Partnership, between this project and the GAP Foundation. Beginning in early 2014, the Global Alzheimer Platform (GAP) brought together academic, industry, advocacy and other Alzheimer's leaders to identify the necessary components to build large ?trial-ready cohorts? (TRC) for preclinical/prodromal AD (PAD) trials (TRC-PAD) and to support a network (GAP-Net) of pre-qualified ?trial-ready sites? with specific expertise in and uniform processes for the clinical and biomarker assessments required for prevention trials. The specific goal of the current project is to build a large TRC-PAD (n=2000; 1000 preclinical/1000 prodromal AD), to facilitate enrollment into ongoing PAD trials using the GAP-Net framework. This application describes a process of connecting existing ?feeder? registries and studies to a GAP Registry to capture demographic, genetic and longitudinal clinical and cognitive information on older, non-demented individuals interested in trials. The Registry data generates risk scores for AD pathology (initially elevated amyloid in brain, but with methods adaptable to tau pathology and other biomarkers), that allows efficient selection of candidates for in-person biomarker (initially amyloid PET scans) and clinical assessment. The results of these assessments, in turn, allow an adaptive statistical algorithm to improve the selection process moving forward. Individuals with PET scans showing amyloid accumulation in brain (or alternative biomarker confirmation) are invited to join the GAP Cohort, with semi-annual in-person follow-up within the GAP-Net network of pre-qualified clinical sites, from which they can be invited to enroll in early stage trials. Overall, the process will dramatically shorten the timeline for preclinical/prodromal trials, and will address a series of scientific hypotheses to guide further development in the field.

SUMMARY. This is a multi-PI application for the U24 Cooperative Agreement to develop a state-of-the-art Alzheimer Clinical Trial Consortium (ACTC) to support the conduct of academic clinical trials across the continuum of Alzheimer's disease (AD). This ACTC will leverage the depth and breadth of AD clinical research teams at USC, Harvard, and the Mayo Clinic, as well as the considerable experience of investigators at 35 expert AD trial sites. We aim to create an optimized infrastructure to more efficiently launch, rapidly recruit, improve the diversity, and successfully complete NIH supported clinical trials in AD and related dementias. We will utilize streamlined contracting processes, a centralized IRB with a specific focus on neurodegenerative diseases, and incorporate state-of-the-art informatics and statistical analyses. We propose to redouble our efforts to improve the diversity of participants in AD clinical trials, incorporating learnings from our recent experience, and establishing a new Minority Outreach and Recruitment (MORE) Team to support both central and local partnerships with communities of color. We will foster continued innovation in AD trial design, providing expertise on novel cognitive, imaging, and biomarker outcomes to support future ACTC trial applications. We will evaluate promising exploratory measures imbedded in our current trials, such as Tau PET imaging and computerized cognitive testing, and work to incorporate these measures into a robust platform for future Proof of Concept (POC) trials to rapidly assess signals of efficacy. We propose a tightly coordinated, distributed leadership model to create a true consortium and take full advantage of the expertise across multiple institutions. The ACTC Coordinating Center will leverage the highly experienced teams in Clinical Operations, Data Systems and Management, and Biostatistics at USC. The MRI Unit, led by Mayo, and PET Unit, led by Harvard and UC Berkeley, will capitalize on unparalleled experience with multi-site protocols through ADNI, the A4 Study, and multiple ongoing clinical trials. The Clinical Outcome Instrument and Biomarkers Units will leverage world-class expertise from Mayo, Harvard, and USC to incorporate both standard and novel outcome measures in future trial designs. This ACTC will provide expertise and infrastructure to design and conduct trials across the full continuum of AD, from primary prevention initiatives to combination trials for advanced symptomatic stages. We also stand ready to collaborate on trials in other age- related dementias, leveraging the experience of the NeuroNext team at Harvard and other expert investigators in vascular and non-AD neurodegenerative diseases. We will build on our successes with public/private partnerships and continue to strengthen our strategic alliances to conduct large scale trials, but will also focus on supporting novel approaches to smaller investigator-initiated POC studies that will better inform Phase 3 decision-making. Finally, we will provide training and leadership opportunities to young clinical investigators to facilitate continued innovation in trial design, and catalyze the next generation of AD clinical trials.

SUMMARY. This is a multi-PI application for the U24 Cooperative Agreement to develop a state-of-the-art Alzheimer Clinical Trial Consortium (ACTC) to support the conduct of academic clinical trials across the continuum of Alzheimer's disease (AD). This ACTC will leverage the depth and breadth of AD clinical research teams at USC, Harvard, and the Mayo Clinic, as well as the considerable experience of investigators at 35 expert AD trial sites. We aim to create an optimized infrastructure to more efficiently launch, rapidly recruit, improve the diversity, and successfully complete NIH supported clinical trials in AD and related dementias. We will utilize streamlined contracting processes, a centralized IRB with a specific focus on neurodegenerative diseases, and incorporate state-of-the-art informatics and statistical analyses. We propose to redouble our efforts to improve the diversity of participants in AD clinical trials, incorporating learnings from our recent experience, and establishing a new Minority Outreach and Recruitment (MORE) Team to support both central and local partnerships with communities of color. We will foster continued innovation in AD trial design, providing expertise on novel cognitive, imaging, and biomarker outcomes to support future ACTC trial applications. We will evaluate promising exploratory measures imbedded in our current trials, such as Tau PET imaging and computerized cognitive testing, and work to incorporate these measures into a robust platform for future Proof of Concept (POC) trials to rapidly assess signals of efficacy. We propose a tightly coordinated, distributed leadership model to create a true consortium and take full advantage of the expertise across multiple institutions. The ACTC Coordinating Center will leverage the highly experienced teams in Clinical Operations, Data Systems and Management, and Biostatistics at USC. The MRI Unit, led by Mayo, and PET Unit, led by Harvard and UC Berkeley, will capitalize on unparalleled experience with multi-site protocols through ADNI, the A4 Study, and multiple ongoing clinical trials. The Clinical Outcome Instrument and Biomarkers Units will leverage world-class expertise from Mayo, Harvard, and USC to incorporate both standard and novel outcome measures in future trial designs. This ACTC will provide expertise and infrastructure to design and conduct trials across the full continuum of AD, from primary prevention initiatives to combination trials for advanced symptomatic stages. We also stand ready to collaborate on trials in other age- related dementias, leveraging the experience of the NeuroNext team at Harvard and other expert investigators in vascular and non-AD neurodegenerative diseases. We will build on our successes with public/private partnerships and continue to strengthen our strategic alliances to conduct large scale trials, but will also focus on supporting novel approaches to smaller investigator-initiated POC studies that will better inform Phase 3 decision-making. Finally, we will provide training and leadership opportunities to young clinical investigators to facilitate continued innovation in trial design, and catalyze the next generation of AD clinical trials.

Project Summary Based on growing recognition that the long pre-dementia stages of Alzheimer's disease (AD) represent the optimal time for interventions aimed at modifying the neurobiology of the disease, most recent drug development programs enroll participants at the preclinical/asymptomatic and prodromal/mild cognitive impairment stages. However, the timeframe, complexity and expense of the recruitment process and site activation for these secondary prevention trials are extremely challenging, and indeed site start-up and trial enrollment, in general, represent the greatest bottleneck for drug development for AD. Thus, there is growing consensus in our field that we must fundamentally overhaul the current clinical trial recruitment and assessment process for these early intervention trials. The overarching goal of this proposal is to accelerate current and future secondary prevention trial enrollment through an innovative, highly efficient approach to identify, evaluate, and enroll appropriate preclinical and prodromal trial candidates, supported by a new site network with enhanced capacities for more efficient and effective conduct of AD clinical trials. The specific goal of the current project is to build a large trial- ready cohort (TRC) for preclinical/prodromal AD (PAD) trials (TRC-PAD). TRC-PAD (n=2000; 1000 preclinical/1000 prodromal AD) will facilitate enrollment into ongoing PAD trials using the ACTC framework. This application describes a process of connecting existing ?feeder? registries and studies to a web based Registry to capture demographic, genetic and longitudinal clinical and cognitive information on older, non-demented individuals interested in trials. The Registry data generates risk scores for AD pathology (initially elevated amyloid in brain, but with methods adaptable to tau pathology and other biomarkers), that allows efficient selection of candidates for in-person biomarker (initially amyloid PET scans) and clinical assessment. The results of these assessments, in turn, allow an adaptive statistical algorithm to improve the selection process moving forward. Individuals with PET scans showing amyloid accumulation in brain (or alternative biomarker confirmation) are invited to join with semi-annual in-person follow-up within the network of pre-qualified clinical sites, from which they can be invited to enroll in early stage trials. Overall, the process will dramatically shorten the timeline for preclinical/prodromal trials, and will address a series of scientific hypotheses to guide further development in the field.

PROJECT SUMMARY This is a multi-PI application for an R01 award under PAR-18-513. The proposed project titled ?Combination Anti-Amyloid Therapy in Preclinical Alzheimer's Disease? is a multicenter randomized placebo-controlled two arm clinical trial of a combination anti-amyloid therapy: an anti-fibrillar amyloid antibody for the initial 18 months combined with BACE inhibition therapy for 4 years, in preclinical AD, defined as asymptomatic individuals with elevated brain amyloid as determined by florbetapir PET scanning. The primary outcome will be a cognitive composite (a modified version of the Preclinical Alzheimer's Cognitive Composite, PACC5), with functional and clinical assessments along with volumetric MR and tau PET as secondary outcomes (and, in a subset, CSF biomarkers). The specific Aims of the proposed study are; 1. to evaluate the impact of a combination anti-amyloid regimen on fibrillar amyloid in brain as indicated by amyloid PET SUVr, 2. to evaluate the efficacy and safety of a combination anti-amyloid regimen in individuals with preclinical AD, and 3. to evaluate the impact of the combination anti-amyloid regimen on AD biomarkers. Drs. Sperling and Aisen will share responsibility for scientific oversight of the clinical design and execution of the study and Imaging oversight will be provided by Dr. Johnson. The ACTC will provide the administrative and operational support, data capture and data management, clinical monitoring and site management, safety oversight, biostatistical support, and biomarker sample processing storage and support. Final selection of therapeutic agents for this trial will be made by a compound selection committee composed of field experts. Committee membership will include external experts in AD drug development and AD neurobiology, appointed in concert with NIA. The study team will work collaboratively with the pharmaceutical company researchers who have clinical experience with these therapeutics in development. This will be the first study of its kind: a potentially synergistic combination approach to dramatically reducing amyloid from asymptomatic individuals on the AD spectrum. Combination therapy trials are increasingly proposed by investigators and regulators to improve the likelihood of success in trials aiming for disease-modification. This approach could ultimately prevent the onset of AD symptoms