Alzheimer's disease research and development: a call for a new research roadmap.

Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Annals Reports

Alzheimer’s disease research and development: a call for a new research roadmap Howard H. Feldman,1 Magali Haas,2 Sam Gandy,3 Darryle D. Schoepp,4 Alan J. Cross,5 Richard Mayeux,6 Reisa A. Sperling,7 Howard Fillit,8 Diana L. van de Hoef,9 Sonya Dougal,10 Jeffrey S. Nye,11 and on behalf of One Mind for Research and the New York Academy of Sciences. 1

Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada. 2 One Mind for Research, Seattle, Washington. 3 Icahn School of Medicine and James J. Peters VA Medical Center, New York, New York. 4 Merck and Company, Inc, North Wales, Pennsylvania. 5 AstraZeneca, Pharmaceuticals, LP., Wilmington, Delaware. 6 Department of Neurology, Sergievsky Center Columbia University, New York, New York. 7 Department of Neurology, Center for Alzheimer Research and Treatment, Harvard Medical School, Boston, Massachusetts. 8 Alzheimer’s Drug Discovery Foundation, New York, New York. 9 The New York Academy of Sciences, New York, New York. 10 Steven and Alexandra Cohen Veterans Center at New York University Langone Medical Center, New York, New York. 11 Janssen R&D, LLC, Johnson and Johnson Innovation, Titusville, New Jersey Address for correspondence: Dr. Howard H. Feldman, S151 University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5. [email protected]

Epidemiological projections of the prevalence of Alzheimer’s disease (AD) and related dementias, the rapidly expanding population over the age of 65, and the enormous societal consequence on health, economics, and community foretell of a looming global public health crisis. Currently available treatments for AD are symptomatic, with modest effect sizes and limited impact on longer term disease outcomes. There have been no newly approved pharmaceutical treatments in the last decade, despite enormous efforts to develop disease-modifying treatments directed at Alzheimer’s-associated pathology. An unprecedented collaborative effort of government, regulators, industry, academia, and the community at-large is needed to address this crisis and to develop an actionable plan for rapid progress toward successfully developing effective treatments. Here, we map out a course of action in four key priority areas, including (1) addressing the fundamental mechanisms of disease, with the goal of developing a core set of research tools, a framework for data sharing, and creation of accessible validated and replicated disease models; (2) developing translational research that emphasizes rapid progress in disease model development and better translation from preclinical to clinical stages, deploying leading technologies to more accurately develop predictive models; (3) preventing AD through the development of robust methods and resources to advance trials and creating fundamental resources such as continuous adaptive trials, registries, data repositories, and instrument development; and (4) innovating public/private partnerships and global collaborations, with mechanisms to incentivize collaborations and investments, develop larger precompetitive spaces, and more rapid data sharing. Keywords: Alzheimer’s disease; dementia; research and development; therapy; treatment; economics; epidemiology

Introduction

Background Dementia is a condition with a set of symptoms, signs, and clinical features that reflects a progressive loss of higher cognitive functions, including memory, language, executive function, and problem solving. Frequently there are significant neuropsy-

chiatric symptoms, such as apathy, aggression, and agitation that develop in the course of the condition and that are particularly challenging to effectively manage. Etiologically, there are more than 50 diseases associated with dementia, though the most common one is Alzheimer’s disease (AD), which accounts for an estimated 50–70% of late-life cases.1 Dementia is also manifest across a range of diseases

doi: 10.1111/nyas.12424 C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1313 (2014) 1–16

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burden of AD and dementia will increase dramatically. In 2010, the World Health Organization estimated the worldwide prevalence of dementia to be 35.6 million. This is expected to increase to 65.7 million by 2030, and 115.4 million by 2050.5

Figure 1. Distribution of estimated total global society costs of dementia in 2010.5 ADL, activities of daily living.

associated with neurodegenerative pathologies, including Parkinson’s disease, Huntington’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis.2 In addition, it has been recognized that the multiple comorbid pathologies accruing with advanced age and survivorship contribute to the clinical manifestations of dementia, whereas genetic determinants are stronger at younger ages.3,4 Progressive changes in cognition are invariably associated with functional disability across the continuum of severity, where full-time care is required in severe stages. Such care may be provided within institutional settings or in the community with parttime or full-time caregivers. The cognitive, functional, and neuropsychiatric symptoms of dementia place an intense burden on families and caregivers, leading to profound effects on those involved in informal caregiving and within the extended-care community.5 For example, negative effects of caregiving for persons with dementia have been reported in the domains of mental and physical health, life expectancy, quality of life, and economic security.6,7 On a global scale, the measurable socioeconomic costs of dementia are staggering. In 2010, the estimated total cost, including informal costs delivered by caregivers (all activities of daily living), direct medical costs, and direct social costs (direct costs of care in the community by paid social care professionals and of nursing homes), was $604 billion (US dollars). The distribution of costs, by percentage of the aggregated total, is shown in Figure 1.5 Demographic trends projecting growth in the elderly population, coupled with a late-life onset of most dementia cases, suggests that the global societal 2

Current treatment and status of drug development Current available therapies (cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and an N-methyl-d-aspartate (NMDA) receptor antagonist (memantine)) developed for the treatment of AD address only symptoms. Although clinical trials have demonstrated that these agents are associated with statistically significant improvements in cognition and global function, overall clinical benefits are modest.9 Attempts to develop treatments that prevent or modify disease have not been successful. Much of the research effort over the past 20 years has focused on the amyloid cascade hypothesis, with several promising drug candidates advancing to, but failing in, late-stage clinical trials.10 The track record of phase III failures in the AD field should be seen in perspective. On the one hand, studies were termed phase III, pivotal or confirmatory trials, and may have proven sufficient, if positive, to garner regulatory approval. However, in reality, they were not in most cases preceded by a more traditional phase II or proof of concept study that showed a clear efficacy signal when clinical measures or progression of dementia were taken into account. Thus, enormous studies were undertaken at the preproof of concept stage with costs estimated in the hundreds of millions of dollars each. Such studies were initiated to test hypotheses and accelerate the introduction of important new medicines. Their failure likely signals the end of continued high-risk investment at this level in hypothesis testing. A more stepwise approach is emerging in AD research with the development of evidence of target engagement, effect on biomarkers of efficacy (pharmacodynamics), and a clearer understanding of patient segments that are appropriate for the mechanism being tested. The latest drugs failing to meet their phase III primary objectives include the gamma secretase inhibitor semagacestat, the gamma secretase modulator flurizan, the nootropic dimebon, and the passive immunotherapies designed to lower brain (or central) amyloid, including bapineuzumab, solanezumab, and intravenous gamma

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globulin. The preliminary phase III results for bapineuzumab and solanezumab were reported in the fall of 2012. In patients with mild-to-moderate AD, bapineuzumab was not significantly better than placebo on the two co-primary endpoints— cognitive and functional performance—as measured by the Alzheimer’s Disease Assessment ScaleCognitive (ADAS-Cog 11) and the Disability Assessment for Dementia (DAD) (Fig. 2).11 No treatment benefit was seen in either carriers or non-carriers of the apolipoprotein E4 allele, in pooled studies, or in prespecified subgroups with mild or moderate AD.11 Phase III trial results for solanezumab were slightly more encouraging. The primary endpoints (the ADAS-Cog 11 and the Alzheimer’s Disease Cooperative Study—Activities of Daily Living (ADCS-ADL) for EXPEDITION 1 and the ADASCog 14 for the overall cohort or the mild AD subgroup in EXPEDITION 2) were not met in either of two individual phase III trials.12,13 However, a secondary analysis of pooled data found that solanezumab slowed cognitive decline and conferred functional benefits in patients with mild AD. Owing to the small but distinct improvement observed in the phase III trials, an additional phase III study of solanezumab in patients with mild AD is planned.12,13 Solanezumab is also being investigated as a treatment, within the Dominantly Inher-


ited Alzheimer’s Disease Network (DIAN), for those at genetic risk of early onset AD, and in the AntiAmyloid Treatment of Asymptomatic Alzheimer’s disease (A4) trial, for those with evidence of brain amyloidopathy but clinically asymptomatic.14 Although a confirmatory test that mild patients are effectively treated by solanezumab is needed, the solanezumab data are noteworthy because they provide the first clinical evidence that targeting ␤-amyloid may improve AD, albeit only in the early stages of dementia. It has been suggested that greater reductions in amyloid burden may be necessary to impede disease progression in patients with early disease symptoms.12,13,15 Alternatively, it has been proposed that anti-amyloid therapies will be of greatest benefit before the effects of ␤-amyloid accumulation have caused downstream effects on the disease cascade and widespread irreversible neuronal degeneration, possibly years before the onset of dementia.10,15,16 Along this line, it is worth noting that as many as one-third of subjects diagnosed clinically as having probable AD and referred for clinical trials (often those evaluating amyloid-reducing agents) have negative amyloid imaging.17,18 This has recently prompted Jack et al.19 to propose the category of “amyloid-first” disease for those subjects who follow the traditional amyloid cascade pathway and a new category of “neurodegeneration-first”

Figure 2. Change in cognition as measured by the 11-item Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog 11) over 78 weeks—all subjects, compared to those with mild AD (pooled 302/301 data, modified intent-to-treat population). Bap, bapineuzumab; MMSE, Mini Mental State Examination.11


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disease in whom symptoms or biomarker changes precede evidence of amyloidosis. This newly proposed categorization, if validated, has significant implications that span from the formulation of molecular pathogenesis to the design of clinical trials. The topline results for the ADCS-Baxter GAP R Alzheimer’s Partnership) of intrial (Gammagard travenous immunoglobulin (IVIg; IGIV; Gammagard) were also negative. However, a pre-specified stratification by APOE genotype revealed evidence for benefit in stabilizing some neuropsychological test scores among APOE ε4 carriers.20 This is the opposite of what was observed with bapineuzumab, where APOE ε4 carriers showed the least benefit.21 IVIg has been proposed to have anti-inflammatory, anti-A␤ oligomer, and/or immunomodulatory activities.22–24 APOE ε4 AD is reported to be more proinflammatory than nonAPOE ε4 AD,25 and one or more of these potential inflammation-linked mechanisms of action (and perhaps others) underlie the apparent benefits observed among APOE ε4 carriers. Still, since the neuropsychological benefits for APOE ε4 carriers in the GAP study were not clinically meaningful, there is not an obvious pathway to regulatory approval for an AD indication for IVIg.

A call to action On the basis of insights gained from recent late-stage drug failures, it is clear that the challenges of developing and testing disease-modifying treatments for AD and dementia will require radically different approaches to therapeutic target identification and clinical trial design. Efforts must galvanize stakeholders across academia, industry, government, and patient advocacy to enable pooling of knowledge and resources and to drive collective action to avert a public health crisis that is already on the horizon. The National Alzheimer’s Project Act (NAPA) released its first National Plan to Address AD in 2012.26 This plan established five ambitious goals, including the prevention and effective treatment of AD by 2025. Additionally, 13 countries are developing or have implemented national Alzheimer’s disease plans, adding further political imperative. To support the goals of the NAPA, other countries globally, and other AD and dementia organizations, the New York Academy of Sciences and One Mind for Research collaboratively established 4

the Alzheimer’s Disease and Dementia Leadership Council (ADDLC).a The ADDLC provides a forum from which leading healthcare industry partners, renowned academic researchers, government, and advocacy groups can collectively develop recommendations aimed at transforming the productivity of biomedical research and accelerating the development of new diagnostics and therapeutics. The ADDLC’s foremost mission is to identify the critical bottlenecks in dementia research and drug development, and to seek innovative and collaborative means to eliminate them. In recognition of the need to speed the path, the ADDLC has focused on solutions that minimize duplication, enhance collaborations, and foster public/private co-investment. To this end, the ADDLC established four working groups: (1) basic research, (2) early development/translational research, (3) prevention trials, and (4) public/private interface. Each group was charged with identifying the bottlenecks impeding advances in these areas, proposing solutions, and establishing a 2020 vision of success. The following sections of this report present their findings. Basic research working group In basic research, the overarching need is to develop a deep, disease-level mechanistic understanding of AD. If this need were addressed, it would improve researchers’ abilities to identify therapeutic targets with a higher probability of clinical success, allow for the development of effective translational cellular and animal models of human disease, and ultimately reduce the risk and cost of clinical development. Therefore, the goal of the basic science working group is identifying challenges to obtain the needed level of mechanistic understanding of dementia and providing proposed solutions to advance basic research efforts by 2020.

2020 vision of success The basic science working group envisions a transparent, alliance-driven research landscape that comprises public/private sectors and drives progress collaboratively (Table 1). Within this landscape, future laboratory resources would be centrally networked, standardized, and openly accessible.

a

A complete list of ADDLC members can be found in the Acknowledgments.


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Table 1. Characteristics of the future landscape

Precompetitive information would be freely shared among academia, industry and government while research findings, whether positive or negative, would be shared and integrated. Academia, industry, and government would jointly contribute to funding, implementing, and participating in initiatives such as the proposed “crossroads program” and the collaborative research network.

Critical challenges and recommended solutions To achieve their 2020 vision of success the basic science working group identifies critical challenges in basic science research and provides recommendations to overcome them. Lack of communication and collaboration. Communication and collaboration within and between key stakeholders in academia and industry must be improved to facilitate dissemination of novel findings, form cooperative partnerships, and set a research agenda that will speed basic understanding of disease mechanisms. To that end, the basic science working group has proposed a crossroads program to establish direct and continuous interactions between experts from industry and academia. Participants in this program would collectively determine the state-of-thescience, identify knowledge gaps, determine the resource gaps, and establish priorities for funding the science, platforms, and tools needed to accelerate advancement. This program is envisioned as a series of direct, in-person conferences that would convene three or four times per year.

It is essential that this effort be further galvanized by the infusion of knowledge from the basic neuroscience community and other fields of basic science research. A model for this approach is the Allen Institute (www.alleninstitute.org), whose interdisciplinary team of scientists, in genomics, neuroscience, informatics, computer science, and engineering, creates vast, multimodal datasets that expedite research.

Lack of a core set of research tools and best practices. A core set of research tools and best practices will help eliminate discrepant findings and redundant efforts. For example, numerous groups have independently developed and validated transgenic mouse models of disease, each believing their own model to be the most relevant. Therefore, there is no standard upon which to compare the results of trials on the basis of these different models. In addition, glimpses of an understanding of AD based on reprogrammed neurons are emerging.18,19 Such observations need to be shared, reproduced, extended, and validated as common and accessible cellular pathophysiological models for the community of researchers. The working group proposes the creation of a formal collaborative research network (CRN) that would operate in a precompetitive environment and collectively determine a core set of research tools and best practices. Animal and cellular models, protocols, and other experimental methods that stem from this evaluation would be made freely available to all groups. Further, the CRN would take a lead


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role in the evaluation, incorporation and dissemination of new technologies as they arise. Perhaps the most significant effort of the CRN would be to establish a framework for data sharing and creation of integrated disease models that could be replicated and validated. The network could leverage existing information technology infrastructure to encourage data sharing between different research domains and work with grant and policy leaders to incentivize collaboration. Such efforts would be a key bridge between basic science and translational research. Lack of organization/ready accessibility of widely available large, diverse, and high-quality biorepositories. Biobanks that are openly accessible to all researchers and contain diverse, high-quality biospecimens need to organized to optimally facilitate genomic, proteomic, cellular, and other molecular-based research. While there are largescale initiatives directed at biorepositories (e.g., NCRAD) and also brain tissue (ADC network), the route to information around the resources, their access and organization, needs to be better developed. To complement dementia biorepositories, a general aging registry should be established so that data can be captured and brain tissue obtained at death for comparative purposes. The basic research working group has developed a preliminary plan (Table 2) for meeting its 2020 vision of success, including meetings to develop the CRN and collaborating with the public/private interface working group to discuss the current information technology infrastructure and its future directions. There is a major sequencing effort underway funded by the National Institute on Aging and the National Human Genome Research Institute to whole sequence 111 late onset AD multiplex families (600 individuals) and to perform whole exome sequencing of 11,000 within a case control design. The family data was ready for analysis in January 2014, and case control data will be ready in the summer/fall of 2014. This will feed into basic research models to examine function and identify new targets. Early development/translational working group Early development/translational research will critically help ensure that data from translational an6

imal models and early human phase I and phase II trials are sufficiently informative to allow a determination of a compound’s potential clinical efficacy and safety, such that the investment and use of the large-scale trial resources and patients in phase III are justified relative to the chances of success. The underlying science and hypothesis that is being elucidated in early trials should be robust enough that it drives further validation into the late stages as well. The ultimate goal is that all patient trials should generate results that inform the field in ways that validate or invalidate the underlying mechanistic hypothesis. This iterative process in translational studies would allow for elimination of certain hypotheses and areas of investigation, and create increased focus on the most promising science and targets for intervention. Early-phase testing must therefore address and robustly target underlying disease mechanisms, give evidence of pharmacological target engagement, and affect biomarkers related to efficacy; data from preliminary studies must achieve definitive benchmarks in each stage before compounds progress to later developmental phases. This will serve to expedite and de-risk drug development, which would help to remove some of the barriers to continued investment in dementia clinical trials that have arisen as a result of the many costly late-stage failures.

2020 vision of success In the early development/translational working group’s vision of success, the future research stream would involve a model or a network of models that integrated the kinetics of the disease with individual mechanistic pathways. By 2020, an aspiration might be that disease models would be well understood and largely validated, fostering experiments that would entail reasonable risk and promise for drug discovery. The risks or uncertainties within the model would be described and made transparent to the international community. Experiments would be designed and implemented in accordance with an established drug discovery workflow. Collaborations (and underlying infrastructure) would allow for true synergy: basic data on understanding human disease and use of preclinical models would inform the target validation process and clinical development, and vice versa, in a continuous feedback loop. By 2020, the working group anticipates that:


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Table 2. Basic research working group Recommendations Collaborative research network

Tasks

r r r r r

Crossroads program

r

r r r

Platforms to support interdisciplinary science Liaison with public/ private interface working group to develop IT infrastructure

r

r

r r

r

r

Conduct a landscape analysis to understand state of the science Determine a core set of research tools and best practices Develop a plan for a precompetitive environment Open source exchange of animal models, protocols, and reagents Evaluation and dissemination of new technologies

Proposed output

r r r r

Standardized, validated disease models Biobanks Biorepositories Framework for data sharing

Assess how to utilize IT infrastructure (e.g., data sharing, access to DNA or tissue banks)

r r

r

Establish forum for collaborative interactions between industry and academia Identify knowledge gaps Determine resource gaps Establish priorities for funding research and tools that will accelerate advancements in AD Infuse knowledge and expertise from other basic research platforms, e.g., Allen Institute

Proposed deliverables

r

r r

Global scoping report (draft completed Jan. 2014) Workshop to be held once annually

Workshops held three to four times annually

Create comprehensive datasets that will expedite research Identification of desired IT capabilities Development of proposal for IT infrastructure

the amyloid hypothesis will be proven or disproven; but regardless, the assumption is that there will be a need for either new therapeutic approaches or refinements of existing ones; there will be a better understanding of tau pathology in driving disease, along with new approaches to target it, as well as addressing the relationships among pathologies that lead to or cause disease; genetic information will continue to be used to identify potential new targets and to further inform existing ones in ways that may help to stratify patients; models that better mimic the course of the disease will be available, allowing for therapies to be tested in the most suitable patient

r r r r


r

Workshop includes public/private interface working group

Resource needs

r r

Funding Location

r r

Funding Location

r

Funding

r

Funding

populations, from presymptomatic disease, to prodromal stages, to dementia; there will be a basic understanding of the relationship between animal and human biomarkers, allowing for better translations across preclinical and clinical stages; disease progression biomarkers that predict clinical outcomes will advance, such that long, expensive trials with a large patient population will no longer be needed; personal diagnostics and biomarkers will exist that predict individual risk for AD and provide guidance for treatment selection; and pharmacogenetic markers will be routinely applied to advance understanding of treatment response and the most appropriate development pathways for a given therapy.

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Critical challenges and recommended solutions In order to achieve their 2020 vision of success, the early development/translational working group pinpointed several challenges and provided recommendations to improve early development of translational research.

biosignatures that identify individuals who will/will not develop dementia must be identified. These can be useful tools for supporting the development of personalized diagnostics able to predict individual risk, inform preventive treatment, and select mechanisms and interventions most promising for that patient.

There are critical gaps in both the understanding of underlying disease mechanisms and the use of model systems for target identification. Improved translational animal models that more fully mimic hypothesized disease pathways (both amyloid and non-amyloid-focused) must be developed in order to close the gap between the mechanistic understanding of disease pathology and potential clinical application. Whereas evidence suggests that ␤-amyloid is important in human pathology, other potentially significant mechanisms (e.g., immune/inflammatory) are not as well understood. Further, current models do not incorporate multiple pathologies; for example, there are few animal models that show key pathological features of the disease, such as amyloid pathology alongside of (or actually driving) tau pathology, synaptic loss, neuronal death and brain atrophy, or the activation of microglia and complement factors. Indeed, tau-based pathologies and mechanisms that drive the spreading and toxicity associated with tau pathology generally need more elucidation. Although these features of pathology are prominent in Alzheimer’s disease, there are currently very few drug intervention targets and a few animal models for testing and translation into humans. A network of improved animal models that include areas such as tau and immune mechanisms will be critical for bringing candidate compounds into testing.

Lack of transparency in terms of best practices and sharing of data, biospecimens, and reference standards. Drug discovery and development could also be de-risked by establishing a precompetitive space wherein researchers could share preclinical and clinical trial data, establish cooperative academic/industry networks, and create mechanisms for sharing biospecimens, including clinical samples such as CSF and tissue samples, with reference samples. This sharing of resources would support the development of standardized best practices that would speed early discovery for all stakeholders.

Lack of tools to support target validation in earlyphase studies and that assess individualized risk. Proof-of-concept studies in early-stage trials require development of highly sensitive biomarkers and cognitive assessment tools able to detect changes reflecting disease progression in a relatively shorter time frame, possibly before overt symptoms of dementia emerge. Such tools will dramatically shorten trial time frames and decrease the number of patients required for enrollment, thereby further derisking clinical development. As Alzheimer’s disease appears to arise from environmental, metabolic, and genetic risk factors, 8

Incentives/catalysts to ensure continued drug development are lacking. The working group supports the proposals of the public/private interface working group to establish greater incentives for industry (see below) so that research and development of drugs for AD and dementia will continue. It is also recommended that, as validated surrogate measures of disease progression emerge, the traditional structures of clinical trials be changed. Such efforts, conducted collaboratively with governing bodies, such as the FDA, would expedite and streamline approval processes. Furthermore, political leadership, such as the UK government that convened the December 2013 G8 Dementia Summit, would set the stage for hastening the collaborative imperatives and national planning priorities that would be needed to more urgently catalyze and advance the field. The early development/translational working group has developed a preliminary plan (Table 3) for meeting its 2020 vision of success. This includes assessing the AD and dementia landscape at the translational interface, initiating novel approaches for evaluating new biomarkers for disease progression, and planning a symposium to bring together stakeholders and encourage new collaborations with these goals in mind. Prevention trials working group The overall goal of the prevention trials working group is to facilitate development of tools and the


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Table 3. Early development/translational working group Recommendations Biomarkers

Tasks Predict clinical outcome

r

r

Conduct a landscape analysis at the translation interface to identify gaps r Identify early readout, sensitive markers r Host a symposium with multisector stakeholders to brainstorm around new approaches (e.g., synaptic biomarkers, transport in interstitial fluids) Personal diagnostics r Identify biomarkers that will predict risk of AD r Develop biomarkers that can provide guidance for treatment Pharmacogenetic r Identify biomarkers that will advance understanding of treatment response Improved translational animal models

r r

r

Target validation in earlyphase studies

r

r

Data sharing

r

r

Drug development opportunities/incentives

r r r

Improved models that mimic disease hypotheses (amyloid, tau) Close the gap between disease pathophysiology and potential clinical applications Models that translate multimodal pathologies (amyloid plus tau) Develop proof-of-concept studies with highly sensitive biomarkers and cognitive assessment tools Assess changes rapidly before onset of symptoms

Establish a precompetitive space where researchers share preclinical and clinical trial data Establish cooperative academic/industry networks Develop data standard Ensure that research and development of AD therapeutics will continue Consider improvements to existing patent law that will overcome challenges of the development cycle

r

r r r

r

r r

Proposed output Novel candidate biomarkers that can be validated and qualified by existing consortia

r r

Proposed deliverables Global scoping report (draft completed Jan. 2014) Symposium

Network of improved animal models for testing candidate compounds

Shorten trial times Reduce the number of patients required for trial enrollment De-risk clinical development

Accelerate drug discovery

r

r

Workshops (Prevention of Alzheimer’s, held June 10–11, 2013, www.nyas. org/ADWorkshop2013eB; Global Alzheimer’s Platform, held Feb. 19–20, 2014) Workshops (described directly above)

r r

Resource needs Funding Location

r

Funding

r r

Funding Infrastructure

r r r

Funding Intellectual property Academic/industry precompetitive collaborations

Evenly distribute risk of developing AD drugs Expedite and streamline FDA approval process


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infrastructure necessary to enable efficient, largescale primary and secondary prevention trials in AD and dementia. It follows on the hypothesis that early intervention for prevention is needed given the imperative to intercede before there is irreversible neurodegenerative injury and a cascade of neuropathological events. In advancing preventive approaches, whom to treat, when to intervene, how to measure treatment effects, and how to predict long-term clinical outcomes must be ascertained.

2020 vision of success Successful implementation of the working group’s recommendations would see a 2020 with wide sponsorship of harmonized primary and secondary prevention trials, including those sponsored by the Veterans Administration and Department of Defense. Secondary prevention trials would be succeeding, and primary prevention trials would be in progress. Selection of patients would be appropriately targeted with primary prevention trials, including subjects with no evidence of dementia. A systematic, international approach would drive rapid patient enrollment in clinical trials; such populations would be appropriately diverse. Biomarkers that predict clinical outcomes and sensitive cognitive measures to detect early clinical response would be available. These efforts would be supported by open-access, structured databases for biosamples, imaging, and other trial data, made freely available to all academic, industry, and government groups.

als must be established, with harmonized protocols, outcome assessments, and data collection. Continuous adaptive trial designs that explore candidate medicines from multiple sources, prioritize or deprioritize medicines based on their interim performance, and that remain open for patients to enroll or re-enroll should be advanced to allow testing of multiple mechanisms implicated in AD. This methodology based on the design of the I-SPY 2 trials used in the oncology field could result from public/private partnerships and ultimately test many candidate medicines and qualify one or more for further phase IIb work, or even pivotal trials. Prevention trial databases and biosamples (for at least placebo data) should be freely accessible. It will be necessary to fund the infrastructure to collect and distribute data and samples in a manner similar to the Alzheimer’s Disease Cooperative Study (ADCS). All patient consents must allow broad sharing of de-identified data and samples. Preparations should be made now to facilitate eventual primary prevention trials, such as capturing data from existing and future cohorts, funding biomarker collection on “screen-fails” from prevention trials (e.g., repeat amyloid imaging on amyloid negative individuals), and planning large natural history studies in mid-life high-risk cohorts. All of these efforts can be conducted in a precompetitive, collaborative partnership among all stakeholders.

Critical challenges and recommended solutions The working group identified a number of important challenges to their vision of success and provided the following recommendations to address them.

A mechanism for facilitating rapid enrollment in planned secondary prevention trials is lacking. It will be crucial to develop educational outreach programs to help recruit diverse populations that are at the greatest risk for cognitive decline, but that may be least likely to enroll in trials. Registries of such populations for current and future prevention initiatives should be constructed.

Collaborative efforts are needed to design ideal preventive studies with an aim toward protocol harmonization and mechanisms for collecting and sharing data. Researchers must determine how to structure short, compelling, biomarker-driven phase II studies that can best support the probability of success in phase III. In this regard, knowledge from other prevention efforts can be leveraged, such as those by the Dominantly Inherited Alzheimer Network (DIAN), the Alzheimer Prevention Initiative (API), and the A4. Furthermore, common definitions for primary and secondary prevention tri-

Additional sensitive cognitive and behavioral assessments, and more validated biomarkers, are needed. In addition to the lack of biological measures of efficacy mentioned above, there are few validated, sensitive, and predictive cognitive tools and patient-reported outcomes for assessing treatment response and other outcomes for phase II and III prevention studies. A clear priority would be to develop and validate cognitive composite measures that can track decline at an early stage from normal cognitive function to subtly abnormal function with a high degree of sensitivity and specificity. Such

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Table 4. Prevention trials working group Recommendations Infrastructure for patient enrollment/registry: call for a global platform

Innovative designs

r r r r

r r r

Development of cognitive outcome measures

r r

Validation of biomarkers and cognitive markers for prevention studies

r

Tasks Survey of existing trials/recruitment efforts (contact ADEAR/API) Assess utility of registry concept Assemble and coordinate with the 2ADAPT working group Build a trial-ready cohort with run-in data acquisition and develop infrastructure to support the cohort Develop a roadmap to implement adaptive design for AD clinical trials Secure public and private funding and support Establish an international collaboration to advance adaptive trials in preclinical to early AD

Interrogate data from past and current trials: cognitive modeling Facilitate the establishment of a harmonized system for measuring and documenting cognitive assessments Develop protocols for comparison of treatment to screen-fail groups (natural history)

r

r

r r

Proposed output Recommendations of best practices for prevention trial recruitment Adaptive design framework that will facilitate treatment agent assessment Well-characterized trial-ready cohort Global alliance, which will reduce duplication and coordinate efforts


r

r r

r

r

Proposed composite model

Validated cognitive markers and biomarkers (data and tools in public domain)

r r

r r

Roadmap (completed Oct. 2013 led to the IMI 11th call for proposals in Dec. 2013 for EPOC-AD: page 23: http://www. imi.europa.eu/sites/ default/files/uploads/ documents/11th_ Call/11thCallText_ updated20122013. pdf); AD Summit (held Nov. 6–7, 2013; www. nyas.org/pathto2025) Workshops (Prevention of Alzheimer’s, held June 10–11, 2013, www. nyas.org/ADWorkshop 2013-eB; Global Alzheimer’s Platform, held Feb. 19–20, 2014) Analyze existing data by end of 2015 Establish harmonization system by end of 2015

Protocol development by end of 2014 Validation by 2019

r

r r

r

r r

r r

Resource needs Funding (estimated cost, $25K, for market research support and consulting) Funding Potential partners (IMI EPOC-AD and existing prevention studies; existing registries, and cohorts) Global infrastructure

Funding Potential partners (C-Path; FDA)

Funding Potential partners (IMI EPOC-AD; AA; FNIH; AMP; ADDF)

IMI EPOC-AD, Innovative Medicines Initiative European Platform For Proof of Concept for Prevention in Alzheimer’s Disease; AA, Alzheimer’s Association; FNIH, Foundation for the National Institutes of Health; ADDF, Alzheimer’s Drug Discovery Foundation.

measures should be developed for diverse populations, across the range of age and education, and build on work in cognitive neuroscience that uses fMRI tasks to engage neural systems vulnerable to AD. These tools could enhance our understanding of when the disease would be likely to emerge in at-risk individuals, as well as whom should be treated, and when. It will become imperative to know which atrisk individuals do not progress to dementia despite having Alzheimer pathology and how to capitalize on this knowledge in designing successful trials.

The assessment of benefit risk and how to integrate this consideration into decisions around prevention trials will be required as this initiative advances to 2020. On the basis of identified challenges and proposed solutions, the prevention trials working group established a preliminary plan to build toward its 2020 vision of success (Table 4). The preliminary plan includes determining best practices for recruiting patients to prevention trials, developing a system for modeling cognitive outcomes, and developing


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Table 5. Public/private interface working group Recommendations Describe relevant collaborative structures that will facilitate implementation of the research proposals developed by the three other working groups

Closed-session symposium with IT and tech transfer experts Datamine FDA proposal

Develop a scorecard (content from early development and translational working group)

Tasks

r

Landscape analysis of funding models that support research on: - PK-PD - Animal models - Early-stage product development - Proof of concept studies

r

r r r r r

Schedule a date, agenda, and attendee list

Proposed output

r r r r

r

Innovative funding models Data aggregation and sharing IP ownership Harmonize, not standardize

As above

r r r

r

Economic analysis of AD R&D29 AD Summit (held Nov. 6–7, 2013; www.nyas. org/pathto2025) Workshops (Prevention of Alzheimer’s, held June 10–11, 2013, www.nyas.org/ ADWorkshop2013-eB; Global Alzheimer’s Platform, held Feb. 19–20, 2014; Innovative Models of Funding for Alzheimer’s Disease, scheduled for Dec. 2014) Symposium

Resource needs

r r

r r r

Align resources to draft an AD proposal Engage FDA representatives Draft and submit a proposal Hold a workshop with the intended outcome of developing a scorecard Research existing frameworks in other disease areas

r

protocols for validating cognitive assessment tools and biomarkers. Public/private interface working group The public/private interface working group was created for the purpose of coordinating and fostering the interface with governmental agencies, public funders, charities, advocacy groups, and of engaging the multiple industrial partners in supporting the direction of the council and the ideas of the other three working groups so that the ADDLC would be able to carry out its initiatives. This working group provides the context needed to interface at the global level and ensure successful implementation of key initiatives, by coordinating with existing initiatives and leveraging innovative sources of funding.

2020 vision of success The working group’s ideal public/private interface environment would have several key features. 12


Workshop

r r

Funding Potential collaborators (FDA and other government entities, including NAPA; public and private sources of funding)

Funding Location

Potential partner (FDA)

Funding Location

First, novel, precompetitive clinical trials would test drugs and diagnostics collaboratively, and such trials would reduce risk because they would be funded by all shareholders. Risk would be further reduced through incentivized development and adoption of biomarkers and standardized end points. Platforms would exist to facilitate sharing of clinical trial results, including negative clinical data. All stakeholders would have access to centralized data repositories, and data mining efforts would be precompetitive and incentivized, with mechanisms in place for protecting intellectual property. Here, governmental agencies such as the FDA would be a proactive partner in data mining, with third parties managing the data-sharing process. In addition, the patient community would be fully engaged in the drug development and clinical trial process, and would understand the value of their participation in clinical studies. In turn, closer interactions between the patient advocacy


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dards to facilitate data mining. One solution would be to develop a standardized score card to track progress and validate biomarkers.

Figure 3. Shared output among the four working groups. Increased likelihood of success occurs when overlap is maximized.

community and research/drug development would ensure that patient’s needs are identified and studied in clinical trials. In addition to traditional sources, public/private partnerships would facilitate project funding through other channels, including activation of the advocacy community of patients, payers, caregivers, and charities. Further, there would be increased funding oversight and direction from non-industry stakeholders, such as venture philanthropists and federal agencies. By 2020, the working group anticipates that:

r

r

precompetitive, incentivized collaborations, and public/private consortia will exist in which private entities are rewarded for research efforts, yet the public interest will be served in the broadest way; and a comprehensive business model, with all partners (including payers), will be designed.

Critical challenges and recommended solutions Current contractual and intellectual property rules de-incentivize potential collaborations. One step toward changing the current environment would be to host a symposium that explores options in technology transfer/contracting models that would help incentivize novel partnerships. Incentives that drive academic/industry/government partnerships should be offered, with the goal of more evenly distributing development risks. With regard to patent law, consideration should be given to extending patent protections so that industry can capture a return on investment, given the prolonged duration of the development cycle. Organizations historically have not shared data from trials or collectively established data stan-

The public is poorly informed about the real costs and challenges of developing treatments for AD and dementia. The working group proposes development of a communications agenda to create urgency, drive public fundraising, and educate the public, patients, and academia on the costs and challenges of AD and dementia research and development. The FDA continues its engagement with industry to drive advances in the field. The FDA has issued new draft guidance entitled “Draft Guidance for Industry on Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease” to allow more innovative trial designs, including using a single primary cognitive outcome as part of the approval process for a preventive treatment. Organizations suffer from initiative fatigue. Rather than creating additional new initiatives that would lead to redundant efforts, the working group proposes to collaborate with other global initiatives to achieve shared goals and develop action plans. In order to overcome challenges to its vision of success, the public/private interface working group has identified four key efforts: (1) to create an applied AD and dementia institute that would be managed precompetitively and staffed by both industry and academia; (2) to create a plan to make primary prevention studies both affordable and viable through mechanisms such as common registries and continuous adaptive trials (I-SPY 2); (3) to foster public/private funding of these partnerships in AD and dementia research, capturing the motivation of advocacy groups, philanthropies, government, academic groups, and industry; and (4) to define how to accelerate the development of translational tools that could reduce the risk/benefit ratio for moving a compound from the laboratory to the clinic. The public/private interface working group’s preliminary plans for moving forward are summarized in Table 5. Conclusions The ADDLC convened with a clear mission in mind: to examine current challenges and recommend solutions that would transform the


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productivity of biomedical research and accelerate development of new diagnostics and therapeutics. Each of the four working groups—basic research, early development/translational research, prevention trials, and public/private interface— were tasked to seek innovative solutions to key challenges within their domains. Notably, several common areas of focus for advancement of AD and dementia research and drug development emerged across the groups (Fig. 3). On the basis of this convergence of concepts across the working groups, the ADDLC believes that these are key areas to focus efforts to successfully drive forward AD and dementia research and drug development. The ADDLC fully recognizes that there will be no single effort or partnership that will be individually responsible for taking on this twenty-first century public health challenge. It foresees it will contribute unique value and also support the efforts of partners with whom its broad goals are shared to improve care and opportunity for those suffering from AD, or for those at risk. The framework presented in this paper is the first pass at a roadmap, with the anticipation that it will grow and transform organically if it is to succeed. Acknowledgments The authors gratefully acknowledge the contributions of the medical writing agency Percolation Communications LLC, who produced the first draft of this paper. They were funded by One Mind for Research and the New York Academy of Sciences to integrate all the historical notes, minutes, and interviews from the workshops conducted in 2011–12, sponsored by One Mind for Research. The subsequent drafts were advanced to final form by the lead and co-authors. The authors also acknowledge inkind support from PricewaterhouseCoopers. The contributions of the members of the ADDLC are also gratefully acknowledged. Its members include: Ger Brophy, GE Healthcare; Samantha L. Budd, AstraZeneca Pharmaceuticals, LP; Harry Calhoun, IBM Research. Andrea Califano, Columbia University; Alan J. Cross, AstraZeneca Pharmaceuticals, LP; Susan De Santi, GE Healthcare; Michael Ehlers, Pfizer Inc; Howard H. Feldman, (co-chair), University of British Columbia; Howard Fillit, Alzheimer’s Drug Discovery Foundation; Sam Gandy, Icahn School of Medicine and James J. Peters VA Medical Center; Christo14

pher Henderson, Columbia University; David M. Holtzman, Washington University School of Medicine; Richard Huganir, Johns Hopkins University School of Medicine; Jackie Hunter, OI Pharma Partners; Michael Krams, Janssen Pharmaceuticals, Inc; Story C. Landis, National Institute of Neurological Disorders and Stroke; Virginia Lee, University of Pennsylvania School of Medicine; Husseini K. Manji, Johnson & Johnson Pharmaceuticals Group; Tetsuyuki Maruyama, Takeda Pharmaceuticals; Richard Mayeux, Columbia University College of Physicians and Surgeons and NY-Presbyterian Hospital/Columbia University Medical Center; Richard C. Mohs, Eli Lilly and Company; Jeffrey S. Nye, (co-chair), Janssen R&D, LLC, Johnson and Johnson Innovation; Menelas N. Pangalos, AstraZeneca Pharmaceuticals, LP; Steven M. Paul, Weill Cornell Medical College; Gregory A. Petsko, Weill Cornell Medical College; Ajay Royyuru, IBM Research; Thomas Rooney, Sanofi; Ellis Rubinstein (co-chair), The New York Academy of Sciences; Mary C. Sano, Mount Sinai School of Medicine; Darryle D. Schoepp, Merck and Company, Inc; Dennis J. Selkoe, Harvard Medical School and Brigham and Women’s Hospital; Morgan Sheng, Genentech; Reisa A. Sperling, Harvard Medical School; Rudolph E. Tanzi, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease; Marc Tessier-Lavigne, The Rockefeller University; John Q. Trojanowski, University of Pennsylvania School of Medicine; Marc Walton, US Food and Drug Administration; Michael W. Weiner, University of California, San Francisco; Pascale Witz, GE Healthcare; and Janet Woodcock, US Food and Drug Administration. Conflicts of interest H. Feldman was a full-time paid employee of BristolMyers Squibb on leave from the University of British Columbia (UBC) from 2009–2011. He also received stocks and stock options from Bristol-Myers Squibb while in this role. In 2012, he returned to the UBC where he undertook this paper and his role on the ADDLC as co-chair. He has performed service contract agreements with Lilly Pharmaceuticals, Kyowa Hakko Kirin, and Biogen Idec, for which UBC has received payments. He has received honorarium for lecturing from Danone Nutricia (2012). He has received travel grant or travel support from One Mind for Research for meeting attendance in 2013, and


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the New York Academy of Sciences’ Alzheimer Disease Leadership Council Meetings in 2012 and 2013. He holds the Fisher Family and Alzheimer Society of British Columbia Endowed Professorship in Alzheimer’s Disease Research. M. Haas was a full-time employee of One Mind for Research and is the founder and CEO of Orion Bionetworks. S. Gandy is a member of the DSMB for the Pfizer/J&J Alzheimer’s Immunotherapy Alliance. He has received research support from Amicus Pharmaceuticals for evaluation of GM1-reducing drugs in animal models of A␤ oligomer accumulation and currently receives research support from Baxter Pharmaceuticals for evaluation of IVIg in animal models of A␤ oligomer accumulation. D. Schoepp is a full-time employee of Merck and Company, Inc., and is a shareholder. A.J. Cross is a full-time employee of AstraZeneca Neuroscience Innovative Medicines, 141 Portland Street, Cambridge, MA 02139, and is a shareholder. R. Mayeux has no conflicts. R.A. Sperling has served as a trial investigator for Janssen, Pfizer, Bristol-Myers-Squibb, Eli Lilly, and Avid. She has served as a paid consultant to Roche, Merck, Lundbeck, and Boehringer-Ingelheim. She is the project leader for the ADCS A4 trial, which receives financial support from Eli Lilly and Avid Radiopharmaceuticals. H. Fillit has no conflicts. D. van de Hoef has no conflicts. S. Dougal was a paid employee of the New York Academy of Sciences. J.S. Nye is a full-time employee of Janssen R&D, a subsidiary of Johnson and Johnson, and is a shareholder. References 1. Plassman, B.L., K.M. Langa, G.G. Fisher, et al. 2007. Prevalence of dementia in the United States: The aging, demographics, and memory study. Neuroepidemiology 29 (1–2): 125–132. 2. International statistical classification of diseases and related health problems, 10th revision, edition 2010. Geneva, World Health Organization. 3. Schneider, J.A., Z. Arvanitakis, S.E. Leurgans & D.A. Bennett. 2009. The Neuropathology of Probable Alzheimer Disease and Mild Cognitive Impairment. Ann. Neurol. 66(2): 200– 208. 4. Woodward, M., I.R.A. Mackenzie, G.Y.R. Hsiung, et al. 2010. Multiple Brain Pathologies in Dementia are Common. Eur. Geriatr. Med. 1(5): 259–265.


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21. Kaufer, D. & S. Gandy. 2009. APOE {epsilon}4 and bapineuzumab: Infusing pharmacogenomics into Alzheimer disease therapeutics. Neurology 73(24): 2052–2053. 22. Sudduth, T.L., A. Greenstein & D.M. Wilcock. 2013. Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers A␤ in APP/PS1 mice along a different time course than anti-A␤ antibodies. J. Neurosci. 33(23): 9684–9692. 23. Gong, B., Y. Pan, W. Zhao, et al. 2013. IVIG immunotherapy protects against synaptic dysfunction in Alzheimer’s disease through complement anaphylatoxin C5a-mediated AMPACREB-C/EBP signaling pathway. Mol. Immunol. 56(4): 619– 629. 24. Cattepoel, S., A. Schaub, M. Ender, et al. 2013. Intravenous immunglobulin binds beta amyloid and modifies its aggregation, neurotoxicity and microglial phagocytosis in vitro. PLoS One 8(5): e63162.

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