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NON-AMYLOID APPROACHES TO DISEASE MODIFICATION FOR ALZHEIMER’S DISEASE: AN EU/US CTAD TASK FORCE REPORT

 

S. Gauthier1, P.S. Aisen2, J. Cummings3, M.J. Detke5, F.M. Longo6, R. Raman2, M. Sabbagh4, L. Schneider7, R. Tanzi8, P. Tariot9, M. Weiner10, J. Touchon11, B.Vellas12 and the EU/US CTAD Task Force*

 

* EU/US/CTAD TASK FORCE: Susan Abushakra (Framingham); John Alam (Boston); Sandrine Andrieu (Toulouse); Anu Bansal (Simsbury); Monika Baudler (Basel); Joanne Bell (Wilmington); Mickaël Beraud (Zaventem); Tobias Bittner (Basel); Samantha Budd Haeberlein (Cambridge); Szofia Bullain (Basel); Marc Cantillon (Gilbert); Maria Carrillo (Chicago); Carmen Castrillo-Viguera (Cambridge); Ivan Cheung (Woodcliff Lake); Julia Coelho (San Francisco); Daniel Di Giusto (Basel); Rachelle Doody (South San Francisco); John Dwyer (Washington); Michael Egan (North Wales); Colin Ewen (Slough); Charles Fisher (San Francisco); Michael Gold (North Chicago); Harald Hampel (Woodcliff Lake) ; Ping He (Cambridge) ; Suzanne Hendrix (Salt Lake City) ; David Henley (Titusville) ; Michael Irizarry (Woodcliff Lake); Atsushi Iwata (Tokyo); Takeshi Iwatsubo (Tokyo); Michael Keeley (South San Francisco); Geoffrey Kerchner (South San Francisco); Gene Kinney (San Francisco); Hartmuth Kolb (Titusville); Marie Kosco-Vilbois (Lausanne); Lynn Kramer (Westport); Ricky Kurzman (Woodcliff Lake); Lars Lannfelt (Uppsala); John Lawson (Malvern); Jinhe Li (Gilbert); Mark Mintun (Philadelphia); Vaidrius Navikas (Valby); Gerald Novak (Titusville); Gunilla Osswald (Stockholm); Susanne Ostrowitzki (South San Francisco); Anton Porsteinsson (Rochester); Ivana Rubino (Cambridge); Stephen Salloway (Providence); Rachel Schindler (New York); Hiroshi Sekiya (Malvern); Dennis Selkoe (Boston); Eric Siemers (Zionsville); John Sims (Indianapolis); Lisa Sipe (San Marcos); Olivier Sol (Lausanne); Reisa Sperling (Boston); Andrew Stephens (Berlin); Johannes Streffer (Braine-l’Alleud); Joyce Suhy (Newark); Chad Swanson (Woodcliff Lake); Gilles Tamagnan (New Haven); Edmond Teng (South San Francisco); Martin Tolar (Framingham); Martin Traber (Basel); Andrea Vergallo (Woodcliff Lake); Christian Von Hehn (Cambridge); George Vradenburg (Washington); Judy Walker (Singapore) ; Glen Wunderlich (Ridgefield); Roy Yaari (Indianapolis); Haichen Yang (North Wales); Wagner Zago (San Francisco); Thomas Zoda (Austin)

1. McGill Center for Studies in Aging, Verdun, QC, Canada; 2. Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA; 3. Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), USA; 4. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; 5. Cortexyme, South San Francisco, CA, USA; 6. Stanford University School of Medicine, Stanford CA USA; 7. University of Southern California Keck School of Medicine, Los Angeles, CA USA; 8. Harvard University, Boston, MA USA; 9. Banner Alzheimer’s Institute, Phoenix AZ USA; 10. University of California, San Francisco, CA USA; 11. Montpellier University, INSERM 1061, Montpellier, France; 12. Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France

Corresponding Author: Serge Gauthier, McGill Center for Studies in Aging, Verdun QC, Canada, serge.gauthier@mcgill.ca

J Prev Alz Dis 2020;3(7):152-157
Published online April 6, 2020, http://dx.doi.org/10.14283/jpad.2020.18

 


Abstract

While amyloid-targeting therapies continue to predominate in the Alzheimer’s disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.

Key words: Alzheimer’s disease, dementia, tau, tauopathy, neurotrophins, neuroinflammation, lifestyle intervention, photobiomodulation, neurostimulation, geroscience.


 

Introduction

Following a discussion on lessons learned from clinical trials of amyloid-based therapies for Alzheimer’s disease (AD) (1), on December 4, 2019, the EU/US CTAD Task Force turned their attention to alternative approaches for disease modification. These strategies do not negate the validity of the amyloid hypothesis; indeed, recently discovered genetic evidence continues to support the centrality of amyloid in the neurodegenerative processes that lead to AD (2–4). However, genetic and other studies point to additional mechanisms and pathways both upstream and downstream of amyloidogenesis, which may provide druggable therapeutic targets with potential for disease modification.
Neuropathological and imaging studies confirm the complexity and heterogeneity of AD (5) Mixed pathologies are evident in most individuals with a clinical diagnosis of AD (6), and in early clinical studies of amyloid-targeting drugs, a significant proportion of trial participants were shown to have no detectable amyloid. Nonetheless, among putative disease-modifying AD drugs in clinical trials, 40% target amyloid either with small molecules or immunotherapies. Another 18% target tau. Other mechanisms targeted for disease modification include neuroprotection, anti-inflammatory effects, growth factor promotion, and/or metabolic effects (7). Additional trials are underway assessing non-pharmacological approaches to treat AD, including lifestyle interventions and neurostimulation.

 

Anti-tau therapies

The microtubule-associated protein tau (MAPT, commonly referred to as tau) is the main constituent of the neurofibrillary tangles that are one of the two primary pathological hallmarks of AD. Its normal function is to stabilize microtubules and thus regulate intracellular trafficking, but in AD and other tauopathies, the protein undergoes post-translational modifications that lead to the development of a variety of oligomeric species, tangles, and neuropil threads that may be deposited as aggregates in specific brain regions, disrupting normal cytoskeletal function and protein degradation pathways (8). In the human brain, six isoforms of tau are present, which are classified as either 3R or 4R tau based on the number of repeat domains. Approximately equal levels of 3R and 4R tau are expressed in the normal brain; however, 3R:4R tau imbalances are seen in brains of individuals with tauopathies. In AD, isoform imbalances vary across brain regions and disease progression.
Unlike levels of amyloid beta protein (Aβ), which correlate poorly with cognition, tau levels are associated with both neurodegeneration and cognitive deficits (9). Tau pathology has been shown to follow a characteristic progression pathway in the brain, starting in areas responsible for learning and memory before spreading to cortical areas involved in other cognitive functions (10).
The complex progression of tau pathological events provides multiple potential opportunities for intervention. Anti-tau drugs in development target tau expression, aggregation, degradation, protein modifications (e.g. phosphatase modifiers, kinase inhibitors), microtubule stabilization, and extracellular tau inter-neuronal spread (8). As of February 2019, clinical trials were underway for 17 tau-targeting drugs – seven small molecules and 10 biologics (7). Only one drug, LMTX (TRx0237) – a reduced form of methylene blue, and a tau protein aggregation inhibitor — is currently being tested in a Phase 3 trial in early AD at 8 – 16 mg/day doses versus placebo (NCT03446001). This trial follows two Phase 3 trials in mild and mild to moderate AD (NCT01689246, NCT01689233) and a trial in behavioral variant FTD (NCT01626378) with higher doses, which showed negative results in the primary analysis of clinical efficacy. Biogen has a Phase 2 study underway of the anti-tau agent BIIB092 (gosuranemab) in participants with MCI due to AD or mild AD (NCT03352557). Phase 2 studies in biologically defined populations are also being conducted. For example, Roche/Genentech is conducting two Phase 2 studies of the anti-tau monoclonal antibody semorinemab in participants with prodromal or probable AD confirmed by amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) testing (NCT03828747). Clinical trials of anti-tau therapeutics have been conducted in other tauopathies, although two recent Phase 2 studies of anti-tau monoclonal antibody therapies (Abbvie’s AABV-8E12 and Biogen’s gosuranemab) in participants with progressive supranuclear palsy (PSP) were recently terminated for lack of efficacy (NCT2985879 and NCT03068468, respectively). Non-clinical studies of innovative anti-tau therapies are underway, such as a study that uses engineered tau-degrading intrabodies to target intracellular tau (11).
It is also theoretically possible that early anti-amyloid intervention may attenuate or even preclude downstream effects on tau. That is, non-tau-based treatments could have implications for tau and tangles.
Several challenges face developers of tau-based therapeutics. For tau reduction approaches, it is not known how much reduction is needed, how quickly and safely it can be accomplished, when different interventions might be effective during the course of the disease, and how long drug levels must be maintained to get an effect. Tau biology is complicated with numerous fragments and post-translational modifications associated with tauopathies, yet it remains unclear which tau species are toxic. Moreover, the targets, mechanisms and cellular locations through which such tau species promote degeneration remain to be identified. These issues make the design of clinical trials especially complicated and highlight the need for better tau biomarkers. Recent progress made in the development of tau ligands for PET may improve the efficiency of clinical trials, since tau-PET enables early diagnosis and tracking of disease progression, identifying individuals at risk for faster cognitive decline, and rapidly assessing pharmacodynamic effects of treatments (12). Plasma levels of total tau (t-tau) and neurofilament light (NfL) have been developed as biomarkers of neurodegeneration (13). Still needed are biomarkers that distinguish 3R from 4R tau and that quantify the many different tau species.

 

Neurotrophic strategies

The neurodegeneration that occurs in AD results from a complicated molecular and biochemical signaling network, likely triggered by Aβ and eventually leading to synaptic dysfunction, loss of dendritic spines, and neurite degeneration (14). Growth factors called neurotrophins regulate neuronal survival, development, and function by binding to cell surface receptors. The signaling networks regulated by these receptors have extensive overlap with those associated with neurodegeneration and modulation of neurotrophin receptors has thus been proposed as a potential therapeutic strategy (15). The Longo lab and others have zeroed in on the p75 neurotrophin receptor (p75NTR) as a therapeutic target for AD. Their working hypothesis, supported by human genomic and proteomic data, along with animal studies is that the p75NTR modulates the complex AD degenerative signaling network and that downregulating its signaling renders oligomeric Aβ unable to promote degeneration (16, 17).
Longo and colleagues have developed small molecule ligands that bind to p75NTR, activate survival-promoting signaling, and prevent Aβ-induced neurodegeneration and synaptic impairment (18). One molecule in particular, LM11A-31, has been shown to block Aβ-induced tau phosphorylation, misfolding, oligomerization and mislocalization; reverse late-stage spine degeneration; reverse synaptic impairment; prevent microglial dysfunction; and in wildtype mice suppress age-related basal forebrain cholinergic neuron degeneration (18–20). There is evidence that dendritic spine preservation is associated with cognitive resilience (21).
A Phase 2a pilot study sponsored by PharmatrophiX Inc. and funded in part by the National institute on Aging (NIA) and the Alzheimer Drug Discovery Foundation is underway, testing oral LM11A-31 in participants with mild-to-moderate AD and amyloid positivity assessed by CSF Aβ screening (NCT03069014). With an expected completion in the third quarter of 2020, the trial will assess safety and tolerability as well as cognitive, clinical, biomarker, and imaging exploratory endpoints. LM11A-31 may be effective in other disorders such as Huntington’s disease (22), diabetes-induced macular oedema (23), and traumatic brain injury (24).

 

Anti-microbial and anti-inflammatory strategies

Neuropathological studies of the AD brain show not only amyloid plaques and tau-based tangles but neuroinflammation as well. Indeed, according to the innate immune hypothesis, plaques, tangles, and neuroinflammation orchestrate an innate immune response that has evolved to protect the brain against microbial infection, with Aβ itself acting as an antimicrobial peptide (AMP) in the brain (25, 26). This hypothesis suggests that subclinical microbial infections in the brain rapidly ‘seed’ Aβ to trap microbes, and that this process drives Aβ neurotoxicity and opsonization (i.e, an ‘eat me’ signal for microglia to remove axons and synapses) (25). Tangles form in response to microbe invasion to block neurotropic microbe spread. AD risk genes are implicated in the innate immune protection hypothesis, which posits that AD-associated genetic risk variants were evolutionarily conserved to keep Aβ deposition, tangle formation, and gliosis/neuroinflammation on a ‘hair trigger’ as a means of protecting a subset of the human species in the advent of a major epidemic of brain infection.
The molecular pathways involved in these processes provide multiple potential therapeutic targets, including the use of anti-viral drugs, antibiotics, blockade of toxic microbial products, and immunization for prevention of subclinical infections; secretase inhibitors and immunotherapies to prevent Aβ seeding; kinase or phosphatase inhibitors to prevent the development of pathological forms of tau, and anti-inflammatories to suppress neuroinflammation. Gut microbiota may also play a role in AD pathogenesis by disrupting neuroinflammation and metabolic homeostasis, thus representing another potential intervention target (27).
One example of a bacterial hypothesis and associated strategy is based on the discovery of the bacterium Porphyromonas gingivalis (Pg), most commonly associated with periodontitis, in the brains of AD patients. Toxic virulence factors from the bacterium, proteases called gingipains, have been identified in AD brains, and gingipain levels correlated with tau and ubiquitin pathology. Oral infection of mice with Pg resulted in brain colonization, increased Aβ1-42, and loss of hippocampal neurons, effects that were blocked by COR388, a small-molecule irreversible lysine- gingipain inhibitor. COR388 significantly lowered markers of inflammation in plasma as well as AD-associated APOE fragments in CSF in a small Phase 1b study in mild-moderate AD patients (28), and a large Phase 2/3 study is underway with an interim readout expected in Q4 2020 and topline data in Q4 2021 (NCT03823404).
A retrospective cohort study showed that Herpes simplex virus (HSV)-infected subjects had a nearly 3-fold increased risk of AD but that treatment with anti-viral drugs such as acyclovir brought risk to non-infected levels (29). There is an ongoing phase 2 trial of valacyclovir for patients with mild AD and positive titers for HSV1 and HSV2 (NCT03282916). Trials in AD using doxycycline and minocycline did not show efficacy (30).
Anti-inflammatory strategies are also being pursued. A Phase 2 study underway in participants with late mild cognitive impairment (MCI) or early AD aims to protect neurons against oxidative stress using two small molecule drugs — tauroursodexycholic acid (TUDCA) and sodium phenylbutyrate — repurposed by Amylyx Pharmaceutical as AMX0035 (NCT03533257). Yet another Phase 3 study sponsored by AZTherapies, Inc. aims to reduce neuroinflammation by converting microglia from a proinflammatory to phagocytic state to promote clearance of Aβ by using a combination of two marketed drugs, cromolyn and ibuprofen, known as ALZT-OP1 (NCT02547818) (31).

 

Lifestyle intervention strategies and other non-pharmacological approaches

Multiple epidemiological studies in Europe, the United States, and Canada investigating an observed decline in the prevalence of dementia in recent years have suggested that dementia may be preventable by targeting lifestyle risk factors such as diabetes, hypertension, obesity, physical inactivity, smoking, depression, low education, and social isolation (32). Clinical studies are now beginning to support this assertion. The Systolic Blood Pressure Intervention Trial –Memory and Cognition in Decreased Hypertension (SPRINT MIND) study suggested that intensive blood pressure control may reduce the risk of probable dementia and mild cognitive impairment (MCI), although the results were not statistically significant, in part because the SPRINT trial was terminated early based on the significant benefits of blood pressure control on cardiovascular outcomes. The study may have been underpowered for cognitive endpoints (33). Further study is warranted given that a 10-year study in France showed that hypertension was associated with poorer cognition in middle-aged individuals (34).
Multi-domain strategies have focused on lifestyle factors. For example, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial demonstrated improved or stabilized cognitive function in participants that adhered to an intervention combining diet, physical exercise, cognitive training, and vascular risk monitoring (35). The Multidomain Alzheimer Prevention Trial (MAPT) tested an intervention combining cognitive and physical intervention along with omega-3 polyunsaturated fatty acid supplementation in frail, non-demented, community dwelling adults (36, 37). While MAPT failed to demonstrate significant slowing of cognitive decline, subgroup analyses suggested that individuals with low plasma levels of docosahexaenoic acid (DHA, an omega-3 fatty acid) have more cognitive decline, which appeared to be normalized with omega-3 supplementation(38). The benefits of omega-3 supplementation appeared to be greater in amyloid-positive individuals and in those with increased cardiovascular risk scores (39, 40). Based on the results from FINGER, MAPT, and other multidomain intervention studies, many additional studies are planned, including worldwide FINGERS studies (WW-FINGERS), a network of studies throughout the world that are adapting the multidomain strategies of the FINGER trial to different populations (41).
In addition to physical and cognitive activity, other non-pharmacological strategies are being investigated for their potential to slow cognitive decline and prevent dementia. For example, photobiomodulation (PBM) has been shown to be neuroprotective. In animal models PBM improved memory and normalized markers of AD, oxidative stress and neuroinflammation (42). A pilot study is now underway in participants with probable AD (NCT03405662).
Non-invasive neurostimulation with techniques such as repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for AD (43). Other technological approaches including assistive technologies, smart technologies, and telemedicine may improve the treatment and care of people with AD.

 

GeroSciences

Given that aging is the major risk factor for AD, therapeutic strategies aimed at the diseases of aging (e.g., frailty) may slow cognitive decline and the development of dementia (44) Considerable research is underway to investigate the relationship between biological aging and neurodegenerative disease. These efforts have coalesced in the emerging field of geroscience (44), which explores whether the physiological hallmarks of aging such as mitochondrial dysfunction, loss of proteostasis, increased cellular senescence, and stem cell exhaustion may contribute to the development of AD pathology and neurodegeneration (45). Identification of biomarkers of aging and elucidation of how the molecular pathways of aging and AD intersect could advance the identification of novel therapeutic targets and next-generation therapies, such as the use of mesenchymal stem cells (46). The links between aging and AD are being explored as one element of the INSPIRE Research Initiative (Barreto JFA in press).

 

Conclusions/moving forward

While the AD drug development pipeline continues to be dominated by Aβ-targeting therapies, there is increasing recognition that addressing the complexity of AD may require multiple agents and may need to start in early disease stage before pathology becomes irreversible. A “deep biology” view, such as that proposed by advocates of p75NTR modulation, posits that key ‘hub’ targets may enable modulation of multiple mechanisms (e.g. resilience to both Aβ and tau) and that key components of pathology could be reversible (e.g. spines, synaptic function). A single treatment could thus promote synaptic function and slow progression and prevent upstream tau aggregation and oligomer formation.
Given the importance of tau in the development of AD, and reflecting the recently proposed Research Framework (47), CTAD Task Force members advocated assessment of both Aβ and tau levels in all clinical trials. The A-T+N+ AD phenotype is common and should be targeted for anti-tau trials. A suggestion was made to name this phenotype Dementia Associated and Neurofibrillary tangle Neuroimaging Abnormality (DANNA). Tau imaging may provide a biological outcome, at least in Phase 2 studies, although the Task Force recognized that amyloid and/or tau PET imaging adds substantial subject and trial burden and cost. Other suggestions that could accelerate the development of anti-tau therapies include using basket designs that include participants with other tauopathies such as frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). While such trials would include participants with heterogeneous presentations, an outcome assessment such as Goal Attainment Scaling (GAS) could enable capture of clinically meaningful outcomes from diverse participants. This tool enables patients, caregivers, and clinicians, to set goals for treatment using a standardized guided interview, followed by an assessment of whether those goals have been attained (48, 49).
The Task Force suggested that combination therapy may be required to tackle such a complex disease as AD (50). They also advocated employing other innovative clinical trial methodologies to accelerate development of alternative approaches.
The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include:
• Increased partnerships in the pre-competitive space with increased sharing of granular level data, shared biomarkers, statistical approaches, information on site performance
• Innovative trial design
• More collaborative approaches to recruitment and retention of participants for clinical trials with a focus on participation of representative populations.

 

Acknowledgements: The authors thank Lisa J. Bain for assistance in the preparation of this manuscript.

Conflicts of interest: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Gauthier is a member of scientific advisory boards for Biogen, Boehringer-Ingelheim, and TauRx; and a member of the DSMB for ADCS, ATRI, and Banner Health; Dr. Aisen reports grants from Janssen, grants from NIA, grants from FNIH, grants from Alzheimer’s Association, grants from Eisai, personal fees from Merck, personal fees from Biogen, personal fees from Roche, personal fees from Lundbeck, personal fees from Proclara, personal fees from Immunobrain Checkpoint, outside the submitted work; Dr. Cummings is a consultant for Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP Pharma, Eisai, Foresight, Gemvax, Green Valley, Grifols, Karuna, Nutricia, Orion, Otsuka, Probiodrug, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, United Neuroscience pharmaceutical and assessment companies, and the Alzheimer Drug Discovery Foundation; and owns stock in ADAMAS, BioAsis, MedAvante, QR Pharma, and United Neuroscience. Dr. Detke reports personal fees, non-financial support and other from Cortexyme, during the conduct of the study; personal fees and other from Embera, personal fees and other from Evecxia, personal fees from NIH, outside the submitted work; Dr Kramer is an employee of Eisai Company, Ltd; Dr Longo has equity in and consults for PharmatrophiX, a company focused on the development of small molecule modulators for neurotrophin receptors. He is also a co-inventor on related patent applications. Dr. Raman reports grants from NIH, grants from Eli Lilly, grants from Eisai, outside the submitted work; Dr Sabbagh reports personal fees from Allergan, personal fees from Biogen, personnal fees from Grifols, personal fees from vTV Therapeutics, personal fees from Sanofi, personal fees from Neurotrope, personal fees from Cortexyme, other from Neurotrope, other from uMethod, other from Brain Health Inc, other from Versanum Inc, other from Optimal Cognitive Health Company, outside the submitted work; Dr. Schneider reports grants and personal fees from Eli Lilly, personal fees from Avraham, Ltd, personal fees from Boehringer Ingelheim, grants and personal fees from Merck, personal fees from Neurim, Ltd, personal fees from Neuronix, Ltd, personal fees from Cognition, personal fees from Eisai, personal fees from Takeda, personal fees from vTv, grants and personal fees from Roche/Genentech, grants from Biogen, grants from Novartis, personal fees from Abbott, grants from Biohaven, grants from Washington Univ/ NIA DIAN-TU, personal fees from Samus, outside the submitted work; Dr. Tanzi is a consultant and shareholder in AZTherapies, Amylyx, Promis, Neurogenetic Pharmaceuticals, Cerevance, and DRADS Capital; Dr. Tariot reports personal fees from Acadia , personal fees from AC Immune, personal fees from Axsome, personal fees from BioXcel, personal fees from Boehringer-Ingelheim, personal fees from Brain Test Inc., personal fees from Eisai, personal fees from eNOVA, personal fees from Gerontological Society of America, personal fees from Otuska & Astex, personal fees from Syneos, grants and personal fees from Abbvie, grants and personal fees from Avanir, grants and personal fees from Biogen, grants and personal fees from Cortexyme, grants and personal fees from Genentech, grants and personal fees from Lilly, grants and personal fees from Merck & Co, grants and personal fees from Roche, grants from Novartis, grants from Arizona Department of Health Services, grants from National Institute on Aging, other from Adamas, outside the submitted work; In addition, Dr. Tariot has a patent U.S. Patent # 11/632,747, “Biomarkers of Neurodegenerative disease.” issued; Dr. Weiner is the PI of The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Brain Health Registry. I am a Professor at University of California San Francisco; Dr. Touchon has received personnal fees from Regenlife and is JPAD associated Editor and part of the CTAD organizing committee; Dr. Vellas reports grants from Lilly, Merck, Roche, Lundbeck, Biogen, grants from Alzheimer’s Association, European Commission, personal fees from Lilly, Merck, Roche, Biogen, outside the submitted work

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ANTI-TAU TRIALS FOR ALZHEIMER’S DISEASE: A REPORT FROM THE EU/US/CTAD TASK FORCE

 

J. Cummings1, K. Blennow2, K. Johnson3, M. Keeley4, R.J. Bateman5, J.L. Molinuevo6, J. Touchon7, P. Aisen8, B. Vellas9 and the EU/US/CTAD Task Force*

 

* EU/US/CTAD TASK FORCE: EU/US/CTAD TASK FORCE: Bjorn Aaris Gronning (Valby); Paul Aisen (San Diego); John Alam (Cambridge); Sandrine Andrieu (Toulouse), Randall Bateman (St. Louis); Monika Baudler (Basel);  Joanne Bell (Wilmington); Kaj Blennow (Mölndal); Claudine Brisard (Blue Bell); Samantha Budd-Haeberlein (USA); Szofia Bullain (Basel) ; Marc Cantillon (Princeton) ; Maria Carrillo (Chicago);  Gemma Clark (Princeton); Jeffrey Cummings (Las Vegas); Daniel Di Giusto (Basel); Rachelle Doody (Basel); Sanjay Dubé (Aliso Viejo); Michael Egan (North Wales); Howard Fillit (New York); Adam Fleisher (Philadelphia); Mark Forman (North Wales); Cecilia Gabriel-Gracia (Suresnes); Serge Gauthier (Montreal); Jeffrey Harris (South San Francisco); Suzanne Hendrix (Salt Lake City); Dave Henley (Titusville); David Hewitt (Blue Bell); Mads Hvenekilde (Basel); Takeshi Iwatsubo (Tokyo); Keith Johnson (Boston); Michael Keeley (South San Francisco); Gene Kinney (South San Francisco); Ricky Kurzman (Woodcliffe Lake); Valérie Legrand (Nanterre); Stefan Lind (Valby); Hong Liu-Seifert (Indianapolis); Simon Lovestone (Oxford); Johan Luthman (Woodcliffe); Annette Merdes (Munich); David Michelson (Cambridge); Mark Mintun (Philadelphia); José Luis Molinuevo (Barcelona); Susanne Ostrowitzki (South San Francisco); Anton Porsteinsson (Rochester);  Martin Rabe (Woodcliffe Lake); Rema Raman (San Diego); Elena Ratti (Cambridge);  Larisa Reyderman (Woodcliffe Lake); Gary Romano (Titusville); Ivana Rubino (Cambridge); Marwan Noel Sabbagh (Las Vegas);  Stephen Salloway (Providence); Cristina Sampaio (Princeton); Rachel Schindler (USA); Peter Schüler (Langen); Dennis Selkoe (Boston); Eric Siemers (Indianapolis);  John Sims (Indianapolis); Heather Snyder (Chicago); Georgina Spence (Galashiels); Bjorn Sperling (Valby); Reisa Sperling (Boston); Andrew Stephens (Berlin); Joyce Suhy (Newark); Gilles Tamagnan (New Haven); Edmond Teng (South San Francisco); Gary Tong (Valby); Jan Torleif Pedersen (Valby); Jacques Touchon (Montpellier); Bruno Vellas (Toulouse ); Vissia Viglietta (Cambridge) ; Christian Von Hehn (Cambridge); Philipp Von Rosenstiel (Cambridge) ; Michael Weiner (San Francisco); Kathleen Welsh-Bohmer (Durham);  Iris Wiesel (Basel); Haichen Yang (North Wales);  Wagner Zago (South San Francisco); Beyhan Zaim (Woodcliffe Lake); Henrik Zetterberg (Mölndal)

1. University of Nevada Las Vegas, School of Allied Health Sciences and Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, USA; 2. Inst. of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden; 3. Massachusetts General Hospital, Harvard Medical School, Boston MA, USA; 4. Genentech Research and Early Development, So. San Francisco, CA, USA; 5. Washington University School of Medicine, St. Louis, MO, USA; 6. BarcelonaBeta Brain Research Center Pasqual Maragall Foundation, Barcelona, Spain; 7. Montpellier University, and INSERM U1061, Montpellier, France; 8. Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA; 9. Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France

Corresponding Author: Jeffrey Cummings, University of Nevada Las Vegas, School of Allied Health Sciences and Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, USA, cumminj@ccf.org

J Prev Alz Dis 2019;
Published online April 18, 2019, http://dx.doi.org/10.14283/jpad.2019.14

 


Abstract

Efforts to develop effective disease-modifying treatments for Alzheimer’s disease (AD) have mostly targeted the amyloid β (Aβ) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aβ protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.

Key words: Alzheimer’s disease, tau, tauopathy, therapeutics, biomarkers.


 

Introduction

No new drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease (AD) since 2003 (1) despite the fact that an estimated 5.7 million Americans and 50 million people worldwide have AD today, and the prevalence is expected to grow to 152 million worldwide by 2050 (2, 3).  AD clinical trials have failed at a very high rate: between 2002 and 2012, 99.6% of AD drugs tested failed to demonstrate clinical efficacy (1). Possible reasons for the high failure rate include targeting the wrong pathology or the wrong stage of disease (4, 5). Inappropriately designed trials and other methodological or unknown factors may have also contributed to treatment failures (6).
Despite the disappointments of the past 20 years, many experts in the Alzheimer’s community see reasons for optimism, including the emergence of novel drugs addressing a broader array of mechanisms than in the past (7). A recent report on the status of the AD drug development pipeline identified 112 agents: 26 in Phase 3 studies, 75 in Phase 2 studies, and 23 in Phase 1 studies (8). Moreover, whereas most of the negative studies in recent years targeted brain amyloidosis and amyloid β (Aβ), current studies are targeting a broader repertoire of mechanisms, including tau pathology. Of the 26 agents in Phase 3, only one targets tau, while 9 of the agents in Phase 2 (5 immunotherapies and 4 anti-aggregation agents) target tau (8).

 

Biology of tau and anti-tau therapeutics

The microtubule-associated protein tau, commonly referred to simply as tau, is found in a hyperphosphorylated form as insoluble, filamentous tangles and neuropil threads as well as dystrophic neurites in the AD brain (9). Along with plaques made up of aggregated Aβ protein, neurofibrillary tangles (NFTs) represent one of the hallmark pathologies of AD. Like Aβ, tau is found in several forms in the brain including monomers, oligomers, and fibrillary tangles (10).  Tau pathology also plays a central role in other neurodegenerative diseases known collectively as tauopathies, including the primary tauopathies frontotemporal lobar degeneration with tau inclusions (FTLD-tau), Pick’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), and chronic traumatic encephalopathy (CTE) (11).
Six isoforms of tau exist; it binds to several other proteins; and it undergoes many post-translational modifications, all of which contribute to its multiple functions in the brain. Tau protein plays important roles in cytoskeletal stability, cell signaling, synaptic plasticity, and neurogenesis (12, 13). In the AD brain, NFTs and neuropil threads composed of aggregated hyperphosphorylated tau are thought to be the primary drivers of neurodegeneration, although the mechanisms underlying the pathogenic process and the exact relationships of tau to Aβ remain unclear. Evidence also strongly suggests that tau propagates or spreads between cells (14) and that neuroinflammation triggered by microglial activation and astrogliosis contributes to tau-associated pathogenesis. Microglia may contribute to tau spreading (15). While postmortem and tau positron emission tomography (PET) studies indicate that tau spreading is associated with disease progression (16, 17), there are many unanswered questions regarding the rate of seeding or the effects of tau spreading on neuronal biology. If the spread of tau is driving clinical and cognitive changes, this would support intervening at the earliest stages of the tau-related disease process.
Neuropathological and imaging studies using PET suggest that tau aggregates are found in the entorhinal cortex and then the neocortex.  If and how this drives neurodegeneration, what forms of tau are toxic, and the relationship of tau to amyloid in terms of toxicity remain unanswered questions. Tau pathology correlates much more closely to cognitive decline than does amyloid pathology (18, 19), and a recent study suggests that tau aggregation is linked to neurodegeneration and clinical manifestations of AD (20).
The complexity of tau biology provides many potential therapeutic targets to prevent tau production, aggregation, or spread at the level of transcription, phosphorylation, depolymerization, and transport. For example, preclinical studies indicate that antibodies against tau can prevent the trans-synaptic transmission of tau between neurons (21). A Phase 1 study of the humanized monoclonal antibody ABBV-8E12 showed acceptable safety and tolerability, which provided the basis for initiating a Phase 3 study in PSP patients to assess dose-related efficacy (22). The antibody is intended to prevent the trans-neuronal spread of the tau protein. Other monoclonal antibodies being assessed in early phase studies and targeting aspects of the tau protein include BIIB092, LY3303560, and RO7105705 (Table 1).

Table 1. Phase 1 and 2 clinical Trials targeting tau in AD populations

Table 1. Phase 1 and 2 clinical Trials targeting tau in AD populations

ADAS-cog = Alzheimer’s Disease Assessment Scale, cognition subscale, ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory, AEs= adverse events, CDR-SB = Clinical Dementia Rating Scale Sum of Boxes, CGIC = Clinical Global Impressions Scale, FAQ = functional activities questionnaire, fMRI = functional magnetic resonance imaging, HAM-D = Hamilton Psychiatric Rating Scale for Depression, iADRS=integrated AD rating scale, MMSE = Mini-mental state examination, NPI = neuropsychiatric inventory, NPS battery = neuropsychiatric symptoms battery, RBANS= Repeatable Battery for the Assessment of Neuropsychological Status, TEAEs = treatment-emergent adverse events. UPSA=University of California Performance Based Skills Assessment, brief version

 

Current status of anti-tau therapies in the AD treatment pipeline

One putative anti-tau agent, TRx0237 was studied in a Phase 3 trial and failed to show a difference between different doses.  Studies in mouse models suggested that the agent functioned as an aggregation inhibitor and reduced the number of tau positive neurons (23); no target engagement biomarker was included in trial to determine if this was achieved in humans (24). Subgroup analyses suggest that some patients may have benefited from therapy and further studies of this compound are underway (24). Table 1 summarizes the anti-tau agents that are currently being tested in Phase 1 or Phase 2 clinical trials. These include both passive and active immunotherapies with monoclonal antibodies as well as drugs that affect the molecular structure of tau to modulate its function or prevent phosphorylation.
Other anti-tau drugs are also in development for AD including epigallocatechin-3 gallate (EGCG), a polyphenolic flavanoid extracted from green tea 25, and AC Immune’s tau morphomers, small molecules designed to inhibit aggregation and seeding and disaggregate already formed tau aggregates. Preclinical studies suggest that tau morphomers reduce pathological tau, improve cognition and function, and reduce microglia activation. Importantly, they are capable of crossing the blood-brain barrier.

 

Outcome measures and biomarkers

Tau PET imaging

Tau and Aβ aggregates in the brain have been investigated in several cohort studies, both neuropathologically at autopsy and in living people using PET (26-28). The overall picture emerging from these studies is that among cognitively normal individuals, about one-third have high amyloid, and among those with high amyloid about half also have high tau loads. A minority of cognitively normal individuals have sub-threshold levels of amyloid and high tau. The anatomic location of tau deposition may be important. These observations raise the possibility that quantifying progression of tau pathology may provide an early indicator of disease.
Johnson and colleagues have investigated the anatomical variability of amyloid and tau deposition in more than 400 individuals. These data indicate that distribution of tau in the rhinal cortex correlates with amyloid burden and that low amyloid individuals just starting to show elevations in tau are those most likely to be on the way to neocortical tauopathy. By the time tau levels have increased in the inferior temporal cortex, individuals may show significant impairments. These data support the hypothesis that amyloid is associated with tau spread.
Longitudinal data also provide support for these measures as useful for staging in order to establish a basis on which to measure change in serial imaging that could be useful in the clinical and clinical trial settings. Four stages were proposed:
Stage 0 – No signal exceeding background, consistent with Braak 0.
Stage 1 – Rhinal cortex signal emerging in a minority of low-amyloid clinically unimpaired individuals (allocortex, MTL) consistent with Braak I/II
Stage 2 – Inferior temporal signal emerging in the presence of high levels of fibrillar amyloid in clinically unimpaired individuals (corresponding to Braak stages III/VI)
Stage 3 – Additional neocortical binding in mild cognitive impairment (MCI) and AD patients (beyond inferior temporal; corresponding to Braak stages V/VI)
Figure 1 provides an example of images with high and low tau burden.

Figure 1. Flortaucipir images with low (Braak I/II) and high (Braak III/VI) levels of tau. The individual whose image is shown on the left had low amyloid levels; the one shown on the right had high amyloid levels (images courtesy of Keith Johnson)

Figure 1. Flortaucipir images with low (Braak I/II) and high (Braak III/VI) levels of tau. The individual whose image is shown on the left had low amyloid levels; the one shown on the right had high amyloid levels (images courtesy of Keith Johnson)

 

CSF and blood biomarkers of tau

A systematic review and meta-analysis of cerebrospinal fluid (CSF) and blood biomarkers showed that CSF levels of total tau (T-tau), phosphorylated tau (p-tau), Aβ42, and neurofilament light (NfL), and plasma levels of T-tau were associated with AD and MCI due to AD but with quite pronounced, assay-dependent variation between studies, and no or only weak correlation with CSF T-tau levels (29-31). With regard to P-tau, a semi-sensitive assay for tau phosphorylated at threonine 181 (similar to the most employed CSF test) with electrochemiluminescence detection has been developed (32). Using this assay, plasma P-tau concentration was higher in AD dementia patients than controls. Plasma P-tau concentration was associated with both Aβ and tau PET and more AD-associated than the corresponding plasma T-tau test, which are promising results in need of replication. While conventional plasma measures of Aβ42 and Aβ40 by ELISA do not show a consistent change in clinically diagnosed AD cases as compared with cognitively unimpaired elderly (29), recent studies of blood Aβ using single molecule array (Simoa) or mass spectrometry have shown a relationship between blood levels of Aβ 40/42 ratios and the brain burden of Aβ (33-35). NfL indicates axonal damage and can also be measured in blood (36). Blood NfL shows particular promise as a biomarker of neurodegeneration in AD (37, 38) but high levels are also found in many other disorders characterized by neurodegeneration (39, 40). Given that NfL is a general neurodegeneration marker and not specifically involved in AD pathophysiology, it may give more unbiased information than tau biomarkers in clinical trials. Furthermore, the correlation between CSF and blood levels of NfL is very high (36), which is not the case for blood measures of tau (30). Synaptic proteins, including dendritic protein neurogranin and the pre-synaptic growth-associated protein 43 (GAP-43), show marked increases in CSF and are seemingly specific for AD (41, 42). Emerging CSF biomarkers including neuron-specific enolase (NSE), visinin-like protein 1 (VLP-1), heart fatty acid binding protein (HFPAP), and YKL-40 (a marker of glial activation) show moderate associations with AD (29, 43).
CSF tau comprises many different tau fragments that reflect processing of secreted tau, and some of these fragments may prove to be useful diagnostically (44) or provide information about tau kinetics in neurons (45). New assays are being developed to measure additional endogenous tau fragments that may correlate with tau pathology. For example, one of these tau fragments, tau368, results from cleavage of tau by asparagine endopeptidase (AEP) at position 368. The result of this is tau hyperphosphorylation, impaired microtubule assembly, and aggregation of truncated tau in neurofibrillary tangles (46).  Inhibiting AEP may represent a novel therapeutic strategy for neurodegenerative disease (47).  Tau368 can be measured in CSF and a first small study shows an association with longitudinal increase in tau PET tracer retention (48). Further, mass spectrometry studies show that CSF tau is specifically cleaved to a mid-domain fragment between amino acids 222-225 (45). Using an assay based on an end-specific tau x-224 monoclonal antibody, increased CSF levels were found in AD, while tau224 levels were low in other tauopathies (49). Exosomal tau has been evaluated as a biomarker but the studies have not been replicated and it is presently not possible to draw any conclusion on whether or not exosomal tau is a biomarker for AD.
The varying measures of tau report on different aspects of AD biology. In the amyloid, tau, neurodegeneration (ATN) Framework for AD diagnosis (50), tau PET and CSF p-tau are viewed as reporters of the presence and spread of tau pathology, whereas CSF t-tau, fluorodeoxyglucose PET, and MRI atrophy are seen as reporters of neurodegeneration. Recent evidence suggests that the soluble forms of tau are increased in production with greater amyloid plaque burden (45), while aggregated forms of tau appear at later stages of AD pathophysiology, closer to symptom onset. Tau markers — tau PET, p-tau, t-tau — measure different aspects of AD from this perspective.
For use in clinical trials of anti-tau agents, CSF biomarkers of amyloid and tau are needed to provide evidence of target engagement, enable enrichment of trials with appropriate participants, and show downstream effects of treatment (51). Lowering of CSF p-tau may suggest an effect on tau phosphorylation; however, more studies are needed to evaluate how CSF p-tau relates to brain pathology. Biomarker studies in recent clinical trials of the anti-amyloid antibodies bapineuzumab, gantenerumab, and BAN-2401 suggest that declines in CSF p-tau, t-tau, neurogranin and NfL indicate a downstream effect of Aβ immunotherapy on neurodegeneration, tau pathology, and synaptic degeneration (52-54).
Fully automated CSF immunoassays of AD biomarkers are now available, and in a study comparing fully automated CSF immunoassay with amyloid PET imaging, a multinational group of investigators found that the CSF tau/Aβ ratio was as accurate as amyloid PET in predicting clinical progression among patients with MCI (55) .

 

Challenges and unanswered questions

While the development of tau-targeted therapies is seen by many in the AD research community as one of the highest priority efforts, the complexity of tau protein processing gives rise to many challenges that have slowed development of tau-based therapies (56). Among the questions raised by the Task Force were these:
•    What is known about the normal physiological function of tau, and are there potential negative/untoward consequences of reducing tau?
•    What is the effect of tau suppression on spatiotemporal deposition of tau?
•    What degree of tau lowering should be targeted to achieve an optimal therapeutic effect?
•    What other factors may contribute to tau-based neurodegeneration (e.g., inflammation, aging, or vascular factors?)
•    What is the relationship of amyloid-beta and tau?
•    What is the relationship of soluble forms of tau and aggregated tau deposits?
•    What is the role of microglia activation in the development of tau pathology?
•    Since most tau is intracellular, will targeting it extracellularly be sufficient; or is there a window of time during which limiting extracellular tau would show a treatment benefit?
•    What happens downstream when an antibody binds to tau? Is it sequestered or disposed of through cellular mechanisms or the glymphatic system 57 and does this result in downstream preservation of neurons?
•    What are the best tau epitopes or tau fragments to target?
•    Which tau fragments correlate best with AD-type neurodegeneration in CSF or in plasma?
•    Which p-tau variants in CSF or blood correlate best with tau pathology in AD, or can differentiate AD from other tauopathies?
•    Are there differential rates of change in tau deposition across the anatomy?
•    What regions should tau PET target to demonstrate target engagement, and how should tau PET be developed for use in clinical trials to predict treatment response or measure treatment effect?
•    What will be required to make tau PET useful clinically for diagnosis, prognosis, or prediction of treatment response?
•    Do trials for anti-tau agents require similar structures as for Aβ-targeting agents even though the dynamics of the protein are different?
•    What is the best population, taking into account the ATN stage, to target?
•    Should anti-tau clinical trials focus on subpopulations and if so, which subpopulations?
•    Would the best path forward for anti-tau agents be to test them in combination trials with Aβ-targeting agents or drugs that target other pathologies such as neuroinflammation?
•    How can tau-PET be used to stage AD?
•    What are the best tau-related outcomes for AD trials?

 

Conclusions

Anti-tau therapies are beginning to populate the AD drug development pipeline, mostly in Phase 1 and Phase 2 trials. However, anti-tau treatments have not yet shown evidence of a treatment effect in patients. The Task Force concluded that the development of anti-tau treatment will be determined by multiple trials and will require contributions from industry, academia, and advocacy groups.
The Task Force also called for incorporating CSF tau measures in all anti-tau trials. At a later date, tau PET may also be a viable option. For a biomarker to accurately assess target engagement and for pharmacodynamic studies, assays need to be designed specifically for the therapeutic antibody in addition to general tau-based assays. Such assays would enable exploration of whether a change in a specific tau species indicates that the therapeutic antibody binds tau in the brain parenchyma and if bound tau is secreted into the CSF.
Most Task Force members agreed that anti-tau trials are justified because AD symptoms are likely driven by the spread of tau and its degenerative effects, as well as by amyloid. However, most members also agreed that the specific tau-based mechanisms that will likely provide a treatment effect from anti-tau therapy are unclear and that significant observational and trial related studies will help better inform which tau targets will be most effective.

 

Acknowledgements: The authors thank Lisa J. Bain for assistance in the preparation of this manuscript.

Conflicts of interest: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Cummings is the Chief Scientific Officer of CNS Innovations. He acknowledges funding from the National Institute of General Medical Sciences (Grant: P20GM109025) and support from Keep Memory Alive; Consultation for Pharmaceutical Companies: Dr. Cummings has provided consultation to Acadia, Accera, Actinogen, AgeneBio, Alkahest, Allergan, Alzheon, Avanir, Axsome, Binomics, BiOasis Technologies, Biogen, Bracket, Denali, Diadem, EIP Pharma, Eisai, Genentech, Green Valley, Grifols, Hisun, Idorsia, Lundbeck, MedAvante, Merck, Otsuka, Pain Therapeutics, Probiodrug, Proclara, QR, Resverlogix, Roche, Samumed, Shinkei Therapeutics, Sunovion, Suven, Takeda, and United Neuroscience pharmaceutical and assessment companies. Consultation for Foundations: Dr. Cummings has provided consultation to Global Alzheimer Platform (GAP). Stock: Dr. Cummings owns stock in ADAMAS, BioAsis, Prana, MedAvante, Neurokos, and QR Pharma. Board member: None. Speaker/lecturer: None. Other: Dr. Cummings owns the copyright of the Neuropsychiatric Inventory (NPI). Dr. Cummings is the Chief Scientific Officer of CNS Innovations.Expert witness/legal consultation: None. NIH support: COBRE grant # P20GM109025; TRC-PAD # R01AG053798; DIAGNOSE CTE # U01NS093334.Research Support: None. Spousal ownership or significant financial interest in a relevant company: CNS Innovations. Dr. Johnson has consulted for Merck, Eli Lilly, Novartis, Biogen, Takeda, Roche, Eisai, Piramal, and GE. Dr. Keeley reports that he is an employee of Genentech. Dr. Bateman reports grants from BrightFocus Foundation, Pharma Consortium (Abbvie, AstraZeneca, Biogen, Eisai, Eli Lilly and Co., Hoffman La-Roche Inc., Janssen, Pfizer, Sanofi-Aventi),  the Tau SILK/PET Consortium (Biogen/Abbvie/Lilly), Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Anonymous Foundation, GHR Foundation, NIH, Alzheimer’s Association, Lilly, Rainwater Foundation Tau Consortium, and Cure Alzheimer’s Fund, grants, personal fees and non-financial support from Roche and Janssen, personal fees and non-financial support from Pfizer, Eisai, and Merck, and non-financial support from Avid Radiopharmaceuticals outside the submitted work. Washington University, Dr. Bateman, and David Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition”. Dr. Molinuevo reports personal fees from Alergan, from Oryzon, from Genentech, from Novartis, from Lundbeck, from Biogen, from Lilly, from Janssen, Green Valley, from MSD, from Eisai, from Alector and from Raman Health,  outside the submitted work. Dr. Touchon has nothing to disclose. Dr. Aisen reports grants from Lilly, personal fees from Proclara, other from Lilly, other from Janssen, other from Eisai, grants from Janssen, grants from NIA, grants from FNIH, grants from Alzheimer’s Association, personal fees from Merck, personal fees from Roche, personal fees from Lundbeck, personal fees from Biogen, personal fees from ImmunoBrain Checkpoint,  outside the submitted work. Dr. Vellas reports grants from Lilly, Merck, Roche, Lundbeck, Biogen, grants from Alzheimer’s Association, European Commission, personal fees from Lilly, Merck, Roche, Biogen,  outside the submitted work.

 

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AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

 

P. Novak1, N. Zilka2, M. Zilkova2, B. Kovacech2, R. Skrabana2, M. Ondrus1, L. Fialova2, E. Kontsekova2, M. Otto3, M. Novak4

 

1. AXON Neuroscience CRM Services SE, Dvorakovo nabrezie 10, 811 02 Bratislava, Slovakia; 2. AXON Neuroscience R&D Services SE, Dvorakovo nabrezie 10, 811 02 Bratislava, Slovakia; 3. Ulm University, Department of Neurology, Oberer Eselsberg 45, 89081 Ulm, Germany; 4. AXON Neuroscience SE, Arch. Makariou & Kalogreon 4, 6016 Larnaca, Cyprus

Corresponding Author: P. Novak, Axon Neuroscience CRM Services SE, Slovakia, +421911187237, petr.novak@axon-neuroscience.eu

J Prev Alz Dis 2019;1(6):63-69
Published online December 14, 2018, http://dx.doi.org/10.14283/jpad.2018.45


 

Abstract

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

Key words: tau, Alzheimer’s disease, tauopathy, immunotherapy, clinical trial.


 

Background

Neurofibrillary pathology, composed of misfolded tau protein, is a hallmark of Alzheimer’s disease (AD) and a range of non-AD tauopathies (1-4). Long neglected by a large portion of the AD field and seen as a by-product of amyloid β pathology, neurofibrillary tau pathology has been established as the closest correlate of cortical atrophy (5) and clinical progression in AD (6-8). Pathological changes on tau protein became a tempting target for disease-modifying therapy, with the first tau-targeted immunotherapy entering clinical development in 2013 (9). The steps taken along the way were recently summarised by Iqbal et al. (10) and the current state of drug development thoroughly reviewed by Li & Götz (11).
The function of microtubule-associated protein tau is regulated by alternative splicing, localisation, oligomerisation, phosphorylation and other posttranslational modifications, accompanied by conformational change (10). Tau is a vital component of the cytoskeleton and a multifunctional molecule involved in dynamics of neuronal microtubules, neuronal polarisation and synapse formation (12). Recent research indicates that it possesses diverse other functions, such as ribosomal DNA transcription, nucleolar transcriptional regulation, RNA metabolism and brain insulin signalling, morphological and synaptic maturation of new-born hippocampal granule neurons, and trafficking of cellular components (13, 14). In disease, tau protein undergoes a transformation that leads to the loss of vital functions and a toxic gain of function including microtubule mis-assembly, cytoskeleton disruption, mitochondrial impairment, oxidative stress, DNA damage, and neuroinflammation (11, 12, 15-18).
The post-translational modifications of tau protein are legion, with phosphorylation and truncation being specifically associated with pathogenesis of Alzheimer’s disease and other tauopathies (19-21). Specifically, it was shown that phosphorylation and truncation lead to enhancement of abnormal tau-tau interaction and tau oligomerisation in vitro and in vivo, generating precursors of oligomeric pathological tau (22-24). These modifications bestow novel conformations and epitope structure upon pathological moieties of tau (25, 26), which in turn make them immunologically distinguishable from healthy tau proteins, and thus an ideal target for immunotherapy. Tau epitopes in disease can arise due to aberrant phosphorylation (20), truncation (27), spontaneous conformational switch and/or template-assisted misfolding (28, 29). A crucial aspect is the distribution of these neo-epitopes among pathological tau species. As tau aggregation in AD takes place via the microtubule-binding repeat domain (30), this domain will be present in all pathological tau oligomers, and the neo-epitopes therein are likely to be conserved in the course of the disease. Since tau in the oligomers is frequently truncated in AD (21), neo-epitopes at the molecule’s termini are cleaved off in a subset of pathological tau forms. Such species become untargetable by therapies aimed at the termini (29). It is known that tau hyperphosphorylation at individual epitopes waxes and wanes over the course of the disease (31), making targeting of certain individual phospho-sites less effective.
Tau aggregates have the intriguing ability to spread from neurons affected by tau pathology to their healthy neighbours and perpetuate neurofibrillary degeneration therein, behaving in essence in a prion like fashion (32). These particles named «tauons», were first proposed in 1994 (33) and shown experimentally in 2009 (34). Locally, the spreading of tau aggregates can occur via diffusion based on proximity, while the spreading pattern to distant brain regions is based on neuronal connectivity (35, 36). The common immunological denominators of these propagating tau species are logical drug targets, and preventing the spread of tauons will halt neurofibrillary pathology and the progression of neurodegeneration in the patients’ brains.

 

Animal model design

An essential step in the development of disease-modifying therapies is the development of a suitable model that recapitulates biochemical features of human tau pathology faithfully. Only such a model has a high predictive value, making it more likely that an investigational medicinal product will perform as well in humans as it did in animals. The development of models for tau pathology has often taken a shortcut via using mutant tau (22, 37). However, no tau mutations have been identified in Alzheimer’s disease so far (4), and it is known that mutant tau filaments are conformationally different from healthy tau (28). In order to prepare a genuine model of Alzheimer tau pathology, we have instead opted for transgenes conferring expression of truncated 3R and 4R tau derived from sporadic Alzheimer’s disease (38). When expressed in brains of rats and mice, the truncated tau proteins induce extensive neurofibrillary degeneration that fulfils the criteria for human NFT pathology (thioflavin-S reactive, Congo-red birefringent, argyrophilic). Sarkosyl insoluble tau in these animals is composed of both endogenous and transgenic tau, and featuring both low- and high-molecular-weight filament and oligomeric tau species and multiple truncated forms. The pathology is accompanied by neuroinflammation, oxidative stress, synaptic abnormalities, and progressive neuronal dysfunction resulting in neurobehavioural impairment and death of the animals, with lifespan depending on transgene expression level (39-46).

Figure 1. Rat models expressing truncated tau 151-391/4R faithfully recapitulate human neurofibrillary tau pathology

Figure 1. Rat models expressing truncated tau 151-391/4R faithfully recapitulate human neurofibrillary tau pathology

Neurofibrillary tangles produced by transgenic animals were A) argyrophilic, B) Congo-red positive, C) thioflavin S reactive, and D) AT8-reactive, as one would expect of human NFTs. The animals displayed neuroinflammation, with increase in microglial numbers, altered morphology, and shift towards a phagocytic morphology (arrows) (E, F).

 

Preclinical development of AADvac1

In our efforts to identify a functionally important common denominator of pathological tau protein, we have initially generated a panel of anti-tau antibodies, including antibody DC8E8, which displayed a range of highly desirable traits. The DC8E8 antibody recognises three or four individual epitopes in the microtubule-binding region of 3R- and 4R-tau protein, respectively. The recognition is phosphorylation-independent. Importantly, the accessibility of the epitopes is highly increased in truncated tau, which translates into a pronounced preference of DC8E8 for the precursors of pathological tau over physiological tau. The antibody was able to recognise both early (pre tangle), intermediate (intracellular tangle) and late (ghost tangle) manifestations of tau pathology, with no off-target binding in a cross reactivity study in a range of normal human tissues. In Western blot, it recognised the entire ladder of pathological tau protein moieties extracted from AD brains (47). Functionally, DC8E8 was found to inhibit tau aggregation in vitro, probably by action of markedly flexible CDRH3 and CDRL1 loops (47). We studied in details the DC8E8 binding site topology by X-ray crystallography. DC8E8 possesses a 10 Å-deep binding pocket, extending over 18 × 14 Å of surface. The shape of this pocket indicates that the DC8E8 epitope on tau 299HVPGGG304 adopts a fold protruding into this space to bind in the DC8E8 combining site, creating a 180° turn on the tau chain (47).
It is worthy of note that several potential antibody candidates that, while highly specific for pathological, AD-derived forms of tau, have promoted tau aggregation instead of inhibiting it (47), highlighting the need to thoroughly evaluate the properties of any promising tau immunotherapy agents.
Subsequently, DC8E8 was used as a template to design an immunogen that would stimulate the production of antibodies with DC8E8-like properties. The peptide 294KDNIKHVPGGGS305, comprising one of the DC8E8 epitopes, was found to fulfil these requirements. Interestingly, an X-ray crystallography study (47) of the DC8E8 binding site suggests that the peptide forms a sharply protruding turn even in the unbound state in solution. Thus, AADvac1 contains the peptide hapten with a turn motif at the immunologically dominant residues, which promotes production of antibodies with DC8E8-like binding properties.
This peptide hapten was coupled to keyhole limpet haemocyanin (KLH) carrier and formulated with aluminium hydroxide adjuvant to yield the highly immunogenic vaccine AADvac1. The carrier serves to provide necessary T-cell epitopes without eliciting a T-cell response against tau, thus circumventing the problems seen with early anti-amyloid-β immunotherapy (i.e. the meningoencephalitis observed with AN1792) (48). Active anti-amyloid immunotherapies have similarly used hapten-carrier conjugates to address the same problem (49).
Similarly to what was observed with DC8E8 treatment in mice (22, 47), administration of AADvac1 to transgenic rats expressing truncated tau proved to be highly efficacious. The vaccine induced high IgG1-dominated antibody titres; no tau-directed T-cell response was observed. The amount of neurofibrillary tangles in the rodents’ brains was reduced (see Figure 2); sarcosyl-insoluble tau in the animals’ brains was reduced by ~70%, and pathological phospho-tau species by up to 95% (see Figure 3). This highlights the fact that while AADvac1 targets a conformational epitope, it also affects phospho-tau species. The proposed mechanism behind this is effect the antibody-mediated elimination of abnormal tau seeds that promote the spreading of tau pathology. Thus, the substrate for kinases – full length, truncated and oligomerised tau molecules – are removed, which results in reduced amount of hyperphosphorylated tau. Along with reduction of neurofibrillary pathology, the neurobehavioural phenotype of the animals was similarly improved (9).

Figure 2. Active vaccination reduced the number of transgenic rats developing extensive neurofibrillary pathology

Figure 2. Active vaccination reduced the number of transgenic rats developing extensive neurofibrillary pathology

Immunostaining with AT8, pT212 and pS214 shows low numbers of neurofibrillary tangles in the brainstem of treated transgenic rats (B), (E) and (H) compared with untreated transgenic rats (A), (D) and (G). Immunisation lowered the number of transgenic rats with extensive neurofibrillary degeneration by 55% (C) and (F) or by 77% (I). Modified from [9] originally published by BioMed Central, licensed under CC BY 4.0.

Figure 3. Immunisation with AADvac1 vaccine reduced tau oligomers and tau hyperphosphorylation

Figure 3. Immunisation with AADvac1 vaccine reduced tau oligomers and tau hyperphosphorylation

Western blot analysis with pan-tau monoclonal antibody DC25 showed reduction in oligomeric tau in the brain of transgenic rats treated with tau peptide vaccine (A). The monomeric endogenous rat tau proteins run between 43 and 68 kDa marker bands, whereas monomeric transgenic tau comprises multiple phospho-species between 29 and 43 kDa marker bands. In the vaccine-treated animals, there are only remnants of non phosphorylated transgene running just above the 29 kDa marker band. Western blot analysis revealed significant reduction of hyperphosphorylated tau species phosphorylated at Thr217 (monoclonal antibody (mAb) DC217) (B), pThr231 (mAb DC209) (C), pSer202/pThr205 (mAb AT8) (D) and pThr181 (mAb DC179) (E). (F) The graph represents the quantification and statistical evaluation of the difference between animals treated with vaccine and those treated with adjuvant only; *P < 0.05, **P < 0.01. Modified from (9) originally published by BioMed Central, licensed under CC BY 4.0.

 

Finally, GLP toxicology studies of AADvac1 were conducted in mice, rats, dogs, and rabbits, with the vaccine being well-tolerated at all administered dose levels in all tested species throughout the course of all studies. Single-dose toxicity studies were carried out in Wistar rats, with doses of up to 160 μg Axon Peptide 108 (coupled to KLH). Three individual chronic toxicity studies were conducted in rabbits, with doses of up to 200 μg Axon Peptide 108 (coupled to KLH) per dose, and up to 12 individual doses being administered over the course of 34 weeks. CNS safety pharmacology studies were carried out in mice (Irwin screen test); cardiorespiratory safety pharmacology studies were carried out in Beagle dogs.

 

Clinical development

Phase 1 (AD)

The first-in man clinical study of AADvac1 was initiated in 2013 and concluded in 2015 (50). As AADvac1 was the first tau-targeting immunotherapy investigated in humans, the enrolment of the initial 8 patients was performed in a stepwise manner. These patients were observed for at least 3 months before recruiting the remaining 22 patients. The trials’ primary purpose, safety assessment, provided encouraging results: the only adverse events clearly tied to treatment were (mostly mild) reversible injection site reactions.
The study’s duration was 24 weeks. Patients were administered 6 individual doses of AADvac1 (40 μg Axon Peptide 108 (coupled to KLH) with aluminium hydroxide (containing 0·5 mg Al³+) in a phosphate buffer volume of 0·3 mL) in 4 week intervals; patients allocated to placebo have received 3 doses of placebo, followed by a switch to AADvac1 treatment.
The study’s 18 month follow-up trial, conducted to assess the persistence of the antibody response, response to booster doses, and long-term effects of AADvac1 on safety, MRI volumetry, and cognition was concluded in 2016 (data are not published yet). Two booster doses of AADvac1 at 6-month intervals were administered over the course of the follow-up; including the initial vaccination regimen, patients have received a total of 8 AADvac1 doses over the course of 96 weeks.
One hurdle that any active immunotherapy for AD has to overcome is the generally reduced immune fitness of the elderly population (51). In this regard, the results were highly encouraging, since the peptide-KLH conjugate in AADvac1 was able to induce the desired IgG antibody response against the tau peptide in 29 out of 30 patients enrolled in the study. IgG titres continued to increase over the initial 6 dose regimen.
The antibodies generated by the patients’ immune systems were able to target also recombinant misdisordered truncated tau protein aa151-391/4R, and tau pathology in brain samples from AD patients, as shown by Western blotting).

Figure 4. IgG antibody response against the tau peptide component of AADvac1 continues to rise over the initial 6 dose regimen

Figure 4. IgG antibody response against the tau peptide component of AADvac1 continues to rise over the initial 6 dose regimen

The assay’s lower limit of quantification at a titre of 100 stands in for «no response». Upper limit of quantification at the titre of 204800. Non-responder indicated by red rectangle. Error bars denote geometric mean and 95% CI.

 

Following the initial 6-dose treatment regimen, the IgG titres in responders ranged from 1:4925 to >1:204800, as a function of the patients’ degree of immune competence (Figure 4). Patients with higher titres generally had high CD4+ lymphocyte counts, and low neutrophil counts. The sole non-responder displayed poor results in haematological assessments (low CD4+ T-helper cell counts, low absolute and relative lymphocyte counts, high absolute and relative neutrophil counts). This variability in the strength of the antibody response needs to be taken into account in any immunogenicity studies of active vaccines in seniors and should be reflected in adequate sample sizes.
Cognition, measured by the ADAS-Cog11, Letter fluency, and Category fluency tests, was stable over the initial 6 months of treatment. Due to the limited sample size of the study and the short duration of observation, this is no hard proof of efficacy, but is compatible with what would be observed with an efficacious compound.

Phase 2 (AD)

Based on the high immunogenicity, good safety profile, and cognitive trends observed in the phase 1 clinical trial, we have initiated the phase 2 study «ADAMANT» in mild Alzheimer’s disease (EudraCT 2015 000630-30, NCT 02579252). The trial is a double-blinded, randomised, placebo controlled, parallel group safety and efficacy study, enrolling patients with biomarker evidence of hippocampal atrophy and/or pathological tau protein and amyloid profiles in the CSF, in an MMSE range of 20-26.

Figure 5. : Sera of selected patients treated with AADvac1 detect high- and low-molecular-weight pathological tau species in all assessed brain extracts

Figure 5. : Sera of selected patients treated with AADvac1 detect high- and low-molecular-weight pathological tau species in all assessed brain extracts

(A) Sera from different AADvac1-treated patients detect the same AD brain extract. (B) Intensity of the staining is proportional to the antibody titre generated by the patients against pathological tau.

 

The patients will receive 11 vaccinations over the period of two years. In comparison to the phase 1 study and its follow up, the trial features an adapted treatment regimen, with booster doses administered at 3 month intervals (instead of 6 month intervals).
With 208 enrolled patients, the trial is powered to detect a 47% slowing of patient decline, as measured by the CDR-SB, as statistically significant. Beside the CDR-SB, we have implemented also a cognitive test battery that is tailored to the mild dementia population, avoiding issues like ceiling and floor effects that were seen in attempts to repurpose cognitive assessment tools initially intended mainly for moderate dementia for milder AD populations (52-54). The battery is composed of tests with proven utility in mild AD, measuring processing speed, verbal immediate and delayed recall and recognition, as well as visual memory via computerised Cogstate tests, verbal fluency and executive function via the letter fluency and category fluency tests, and finally executive function and working memory via the digit-symbol coding test. This composite is expected to be especially sensitive to cognitive decline at the mild dementia stage.
Extensive MRI measures (volumetry, diffusion tensor imaging, and fMRI) in all subjects, as well as CSF biomarker assessments and FDG-PET evaluation of a subset of study subjects were implemented to detect interaction between AADvac1 treatment and the AD pathophysiological process.
The study is expected to conclude in summer 2019.

Phase 1 (nfvPPA)

Non-fluent primary progressive aphasia (nfvPPA) is characterised by impairment in grammar and motor speech (apraxia of speech and dysarthria), along with predominant atrophy of the left posterior frontal lobe and insula (55). This phenotypic manifestation of the underlying neuronal degeneration is caused, in a majority of nfvPPA cases, by tau pathology, morphologically similar to AD, CBD or PSP (56-58). Therefore, patients with this well defined tauopathy are well suited for treatment with the AADvac1 vaccine.
The ongoing study “AIDA” A 24-month randomised parallel group single-blinded multi-centre phase 1 pilot study of AADvac1 in patients with non fluent primary progressive aphasia (EudraCT 2017-000643-41, NCT 03174886) is primarily a safety and immunogenicity trial, comparing two dosage strengths of AADvac1 in patients with mild-to-moderate nfvPPA. Efficacy is evaluated in an exploratory fashion, though some markers, e.g., neurofilament light chain protein (59, 60), appear to be very sensitive indicators of disease severity in frontotemporal dementias, and are thus potentially theragnostic. The cognitive and functional assessment were tailored to the population under study, seeking to capture impairment in language, behaviour, cognition, and possibly motor function. We have implemented a language-focused custom cognitive test battery (61). Additionally, the Addenbrooke’s Cognitive Examination test (ACE-III) was chosen as an established scale that assesses multiple cognitive domains, and is well-targeted to the patient population. The FTLD version of the Clinical Dementia Rating (Sum of Boxes) is used as a functional assessment; in comparison to the version used in AD, it incorporates also the domains «Language» and  «Behaviour, comportment and personality» (62); everyday functioning assessed by the Amsterdam instrumental activities of living scale (63). Behavioural pathology is assessed in greater depth by the frontal systems behaviour scale (FrSBe). Finally, to assess the entire spectrum of symptoms, the UPDRS Part III is used to evaluate Parkinson-like motor symptoms that can occur with the progression of the disease.
The thorough coverage of potential manifestations of nfvPPA clinical symptoms will allow the selection of most suitable endpoints for later studies.

 

Conclusions

AADvac1 targets a functionally and structurally outstanding epitope in the microtubule-binding region of tau protein, present once in each of the microtubule-binding repeats. The peptide hapten component of AADvac1 forms a conformational neo-epitope, identical to that present on truncated tau precursors of pathological oligomerised tau. This neo-epitope constitutes a common denominator of all analysed pathological tau species and is present in all assessed AD and non-AD tauopathy brains.
Using truncated tau as found in sporadic AD, we have generated transgenic rats and mice that faithfully replicate human tau pathology. Targeting the abovementioned epitope via passive or active immunisation resulted in reduction of neurofibrillary pathology, and improvement of the neurobehavioural phenotype of both transgenic mice and rats.
Treatment with AADvac1 induced IgG antibodies in 29 of 30 treated AD patients. These antibodies were able to target tau pathology in AD brain tissue slides. The encouraging safety profile observed in the phase 1 study marks AADvac1 as suitable for long term treatment, or even preventive application in the future.
The ADAMANT phase 2 double-blind safety and efficacy study is expected to conclude in mid-2019.
Meanwhile, the development of AADvac1 in non-AD tauopathies has begun with the phase 1 «AIDA» study in nfvPPA patients; results after 1 year of treatment are expected in 2019.
Should AADvac1 prove efficacious, its nature as an active vaccine will naturally lend itself both to the treatment of manifest AD, but especially also to the prevention of dementia, i.e. prevention of the accumulation of pathological tau proteins at the asymptomatic or early symptomatic stages of AD, as described in the FDA’s guidance for early Alzheimer’s disease (draft issued 2018), and in cases with family history of tau pathology (MAPT gene mutation carriers), as well as in carriers of mutations in the amyloid pathway (64).

 

Conflict of interest: Authors affiliated with AXON Neuroscience or one of its subsidiaries are employees of these companies. The employer of Markus Otto, Univeristy of Ulm, is receiving payments from AXON Neuroscience for the conduct of clinical studies on a per-patient per-visit basis.

Ethical standards: All experiments on animals were carried out according to institutional animal care guidelines conforming to international standards and were approved by the State Veterinary and Food Committee of the Slovak Republic. All human clinical trials are conducted according to the Declaration of Helsinki, and the ICH guidance on good clinical practice. All studies were approved by the responsible ethics committees and competent regulatory authorities. All patients have provided informed consent, and agreed to the publication of trial data.

 

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PRECLINICAL AND CLINICAL DEVELOPMENT OF ABBV-8E12, A HUMANIZED ANTI-TAU ANTIBODY, FOR TREATMENT OF ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES

 

T. West1, Y. Hu1, P.B. Verghese1, R.J. Bateman2, J.B. Braunstein1, I. Fogelman1, K. Budur3, H. Florian3, N. Mendonca4, D.M. Holtzman2

 

1. C2N Diagnostics LLC, Saint Louis, MO, USA; 2. Washington University, St. Louis, MO, USA; 3. AbbVie Inc., North Chicago, IL, USA; 4. AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany

Corresponding Author: Tim West, PhD, C2N Diagnostics, 20 S Sarah St, Saint Louis, MO 63108, Email: twest@c2ndiagnostics.com

J Prev Alz Dis 2017;4(4):236-241
Published online September 27, 2017, http://dx.doi.org/10.14283/jpad.2017.36

 


Abstract

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer’s disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer’s disease or PSP.

Key words: Tau, immunotherapy, Alzheimer’s disease, tauopathy, therapeutic.


 

Rationale

Tauopathies refer to a set of neurodegenerative disorders characterized by the pathological aggregation of microtubule-associated protein tau (MAPT) in neurons and glial cells in the human brain. The most common tauopathy is Alzheimer’s disease (AD), estimated to affect more than 5 million Americans and 46 million people worldwide. Less common tauopathies include progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), Pick’s disease and frontotemporal dementia with parkinsonism linked to chromosome 17, with the total number of tauopathies being greater than 20 (1). In some of these tauopathies (such as PSP, CBD, and Pick’s), aggregation of tau in the brain is the predominant form of brain pathology, while for other diseases (such as AD and Niemann Pick type C) other brain pathologies are involved in the disease alongside tau.
The human tau gene contains 16 exons and alternative spicing of exons 2, 3 and 10 results in six different tau protein isoform (2). Based on the number of inserts near the amino-terminal and the carboxy-terminal repeat domains, the isoforms are referred to as 0N3R, 1N3R, 2N3R, 0N4R, 1N4R and 2N4R. Under normal conditions, tau is predominantly localized within neurons and more specifically axons, although non-neuronal cells can have trace amounts (3). Tau was originally identified as a microtubule-associated protein that functions to promote assembly of microtubule protein subunit tubulin into microtubules and stabilize their structure (4). More recently, novel functions of tau have been discovered, such as iron transport, neurogenesis, synaptic plasticity and neuronal DNA protection (5).
Data from biochemical and animal studies of the tau protein suggest a working model that can serve as a basic framework for studying the pathophysiological functions of tau as well as for developing tau therapeutics. Tauopathy pathogenesis includes molecular events such as hyperphosphorylation and aggregation of tau. Hyperphosphorylation of tau can reduce its binding to microtubules, and thereby cause microtubule disassembly and axonal transport impairment and eventually synaptic dysfunction (6, 7). Hyperphosphorylation, as well as some other modifications of tau (such as truncation and O-glcNAcylation) also promote tau aggregation (5).
Aggregated tau can assume the form of either soluble oligomers, insoluble paired helical filaments (PHFs), or insoluble straight filaments. PHFs manifest as neurofibrillary tangles (NFT) in the brain and are one of the major histopathological hallmarks of tauopathies. While NFTs were originally assumed to be toxic and the main cause of neurodegeneration, growing evidence suggests that NFT are neither necessary nor sufficient to cause neurodegeneration (8–10).
Recent evidence suggests that of the various aggregated tau species, tau oligomers can be toxic to neurons (11–15) and that release of tau oligomers from neurons can lead to transmission of tau pathology between cells. The tau oligomers are taken up by synaptically connected neurons, causing the normal tau in the recipient neuron to aggregate – thus resulting in spreading of tau pathology from one neuron to the next through neuronal connectivity. Calvaguera et al. found that intracerebral injection of brain extract from mice with filamentous tau pathology induces the formation and spreading of aggregates made of hyperphosphorylated tau in mice expressing human wild-type tau (16). Subsequently, more studies have reported similar findings in vivo, confirming this “prion-like” property of pathological tau species isolated from human tissue or transgenic mice (17–21). This mode of transcellular propagation suggests that extracellular transfer of tau between cells may be a susceptible target for antibody-mediated therapies. In support of this hypothesis, tau immunotherapy has emerged as a promising therapeutic strategy for tauopathies and this approach has been shown to reduce tau pathology and improve behavioral deficits in animal models (22–27).

 

Preclinical data

The laboratory of Dr. Holtzman at Washington University School of Medicine generated a library of anti-human tau antibodies to test the hypothesis that propagation of aggregated tau between cells can be prevented by using anti-tau antibodies and to further assess the mechanisms of action of such antibodies (28). The library originated from mice immunized with full-length human tau protein (2N4R) and antibodies recognizing various epitopes of human tau were identified. Using an in vitro cell based assay, the anti-tau antibodies were found to specifically and dose dependently block uptake of misfolded tau from brain lysates into neuronal cells (19, 28).
To assess the in vivo activity of the antibodies, three of the anti-tau antibodies and one control antibody were administered intracerebroventricularly (ICV) into P301S tau transgenic mice. The P301S transgenic mouse carries a mutated human tau gene that causes early onset frontotemporal dementia in humans. These mice develop brain tau pathology as evidenced by presence of NFTs and phosphorylated tau as well as behavioral deficits consistent with human tau pathology (29). Antibodies were infused continuously starting just after the time when tau pathology starts to develop in these mice (6 months of age). At nine months, associative learning was assessed and the brains of the animals were assessed for a variety of histological and biochemical measures. Of the three antibodies tested in vivo, one antibody (HJ8.5) demonstrated a consistent effect on all of the outcome measures as compared to the control antibody. This antibody showed a reduction in phosphorylated tau by both biochemical and histopathological measures, and an improvement in associative learning (28).

In addition to evaluating central delivery of the antibody, the biological effects of administering HJ8.5 peripherally were assessed in a separate study. Here, six-month old P301S mice received weekly intraperitoneal (IP) doses of PBS, or 10 or 50 mg/kg of HJ8.5 for three months (30). After three months of treatment, there was a significant reduction of tau pathology in the hippocampus in both the 10 mg/kg and 50 mg/kg dose group compared with control (Figure 1A and B). This reduction in tau pathology was matched by a reduction in the formic acid insoluble tau measured in the cortex of P310S mice in the 50 mg/kg dose group (Figure 1C). Peripheral HJ8.5 administration also improved sensorimotor function in these mice as measured by inverted screen and ledge tests. Importantly, peripheral antibody administration significantly attenuated brain volume loss observed in P301S mice over the three-month timeframe. This finding is significant since brain atrophy in human tauopathies associates strongly with tau accumulation in the brain regions affected, and thus it appears that the reduction in tau pathology by the antibody treatment results in protection against brain atrophy.

Figure 1. Anti-tau antibody decreased phospho-tau staining in the hippocampal CA1 cell layer

Figure 1. Anti-tau antibody decreased phospho-tau staining in the hippocampal CA1 cell layer

 

(A) Representative coronal sections of biotinylated AT8 antibody staining of phosphorylated tau in the hippocampal CA1 cellular region of 9-month-old P301S mice treated for three months with vehicle and HJ8.5 at 50 mg/kg. The lower images are higher power views of the CA1 region in the uppers panels. Red arrows indicate the area magnified in the lower image. Black arrows indicate the hippocampal CA1 cell layer. (B) Quantification of biotinylated AT8 antibody staining of abnormally phosphorylated tau revealed a significant decrease in AT8 staining in mice treated with HJ8.5 at 50 mg/kg in the hippocampal CA1 cellular layer compared to vehicle-treated mice (P = 0.035). Values represent mean ± SEM. (C) Levels of formic acid soluble tau determined by ELISA. HJ8.5 treatment at 50 mg/kg significantly decreased insoluble human tau (P < 0.0001) compared to vehicle-treated mice. Values represent mean ± SEM. ****P < 0.0001. Figure is modified from (30) with permission.

 

At the end of the peripheral dosing study, the concentration of tau in the plasma of P310S mice was measured using a tau ELISA. The concentration of tau in plasma was significantly increased in P310S animals that had been injected with HJ8.5, and the increase was higher in the animals that received the higher dose of HJ8.5 (30). Further studies indicated that the antibody dependent increase of plasma tau resulted primarily from CNS derived tau and that plasma tau concentrations appeared to reflect soluble, extracellular tau in the brain (31).
Recent studies utilized adenoassociated virus (AAV) to express single chain fragment variable domains (scFv) derived from HJ8.5 directly in the brain of P301S transgenic mice (32). This treatment also decreased tau pathology, demonstrating that the Fc domain of the antibody is not required for a therapeutic effect.
In summary, these preclinical studies show that anti-tau antibodies have the potential to engage tau present in the brain’s extracellular space as well as in plasma. Administration of the anti-tau antibody HJ8.5 in these animal models via central (ICV) and peripheral (IP) routes markedly reduced tau pathology, neuronal loss, and brain atrophy, resulting in cognitive and sensorimotor preservation compared to control treated mice.

 

Clinical data

Based on the promising results from the transgenic mouse model studies, a variety of humanized anti-tau antibodies were generated to test the hypothesis that anti-tau antibodies can provide therapeutic benefits in human tauopathies. Following requisite cell line development and toxicology testing, clinical trials with the lead compound (C2N-8E12, now known as ABBV-8E12) were initiated during the summer of 2015. A phase 1 clinical trial (NCT02494024) was designed to test the safety and tolerability of a single dose of ABBV-8E12 in patients with PSP. Key inclusion and exclusion criteria for this study are listed in Table 1. Subjects were randomized in blocks of four in a double-blind manner to receive a single intravenous dose of ABBV-8E12 or placebo in a three to one ratio (drug:placebo). Using a continual reassessment method that pre-specified algorithms for dose escalation, each block of subjects was assigned to one of the five dose cohorts (2.5, 7.5, 15, 25, and 50 mg/kg) tested in the study. Dose escalation was implemented only after available safety data from lower doses had been reviewed by the data safety monitoring committee (DSMC). Safety was monitored for 84 days post-dosing and included AEs, laboratory analyses, MRI assessments, ECG evaluations, physical/neurological examinations, vital signs, mental health assessments and a brain MRI at two weeks after dosing.

Table 1. Key inclusion and exclusion criteria for the phase 1 clinical trial (NCT02494024)

Table 1. Key inclusion and exclusion criteria for the phase 1 clinical trial (NCT02494024)

 

A total of 38 subjects were screened for the phase 1 trial, with 30 subjects enrolling. Of the enrolled subjects, 7 were assigned to the placebo arm and 23 were assigned to one of the 5 dose arms (Table 2).The safety profile at all doses supported dose escalation to the maximum dose (50 mg/kg), which was administered to 10 subjects. Twenty-seven subjects completed the 84-day follow-up and one subject withdrew from the study due to an adverse event (AE). AEs occurred in 21 of the 30 (70%) study participants. Table 3 provides an overview of the AEs observed in the study. The majority of the AEs were rated by the blinded investigators as mild or moderate in severity. Only two AEs were rated as severe – one case of headache and one case of agitation. Treatment-relatedness of the AEs was also rated by the investigators, with the majority of the AEs being rated as unrelated to treatment.

Table 2. Patient demographics and disease characteristics at screening

Table 2. Patient demographics and disease characteristics at screening

 

Table 3. Adverse event summary

Table 3. Adverse event summary

Events are listed by MedDRA preferred term. Number of patients experiencing an event is shown in the table with the percent incidence in parentheses.

 

There were no clinically concerning trends observed in the number or severity of AEs between the placebo and ABBV-8E12 dose groups. Nearly half (44%) of the observed AEs resolved within the first two days of onset and 77% of AEs resolved within the first two weeks. At the day 14 MRI, no clinically significant radiographic abnormal findings were observed. Three serious adverse events (SAEs) were reported during the study. One subject, in the 15 mg/kg dose group, with a history of experiencing several falls at baseline, had subdural hematoma. One subject, in the 25 mg/kg dose group, with a history of anxiety and agitation around stressful events including medical procedures, reported an increase in anxiety, agitation and perseverative behaviors. One subject, in the 50 mg/kg dose group, with a history of hypertension had hypertensive cerebrovascular disease. These events did not indicate an emerging safety issue. Thus, ABBV-8E12, when administered in single doses of up to 50 mg/kg, appears to have an acceptable safety and tolerability profile.
While assessment of single-dose safety and tolerability were the primary objectives of this phase 1 study, both plasma and CSF samples were acquired for assessment of pharmacokinetics (PK) of ABBV-8E12 in plasma and penetration of drug into the brain. Figure 2 shows the average PK profiles for ABBV-8E12 in plasma for each dose cohort. Across the dose range of 2.5 mg/kg to 50 mg/kg IV, the ABBV-8E12 area under the curve (AUC) increased in a dose-proportional manner. The harmonic mean plasma half-life ranged from approximately 27 days to 37 days. This plasma half-life is consistent with what has been reported for other monoclonal antibodies.

Figure 2. Pharmacokinetic profiles of ABBV-8E12 in plasma. Plasma samples were collected for up to 84 days post dosing and drug concentrations measured using a validated PK assay

Figure 2. Pharmacokinetic profiles of ABBV-8E12 in plasma. Plasma samples were collected for up to 84 days post dosing and drug concentrations measured using a validated PK assay

Data shown as mean with error bars representing the standard deviation.

 

Cerebrospinal fluid (CSF) was sampled at screening and 14 days after drug administration. Measurement of ABBV-8E12 in CSF on day 14 revealed that CSF ABBV-8E12 concentrations increased with dose. Comparison of CSF concentrations to plasma concentrations of ABBV-8E12 on the same day showed that the CSF/plasma ratio ranged from 0.181% to 0.385%, consistent with what has been observed in other studies of monoclonal antibodies. Plasma samples collected out to day 84 were also assayed for the presence of anti-ABBV-8E12 antibodies using a validated anti-drug antibody assay. No anti-drug antibodies were detected in the post-dose plasma samples analyzed.

 

Future development plan/discussion

Based on the acceptable safety and tolerability profile of single doses up to 50 mg/kg in PSP patients, AbbVie is currently enrolling patients into two phase 2 clinical trials that assess the efficacy and safety of multiple doses of ABBV-8E12 in patients with early AD or PSP. In these studies, patients will be dosed for 96 weeks (early AD) or 52 weeks (PSP). The first cohort of 48 and 30 subjects each, in AD and PSP studies respectively, will undergo intensive safety monitoring.
The phase 2 AD study is a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of ABBV-8E12 in patients with early AD. For the purposes of this study, early AD is defined as a score of 22 or higher on the mini-mental state examination, a global score of 0.5 on clinical dementia rating, a score of 85 or lower on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)-delayed memory index, and a positive amyloid positron emission tomography (PET) scan.
The phase 2 AD study consists of a screening period of up to 8 weeks, a 96 week double-blind treatment period and a follow-up period of approximately 20 weeks following the last study drug administration. Approximately 400 subjects will be enrolled to meet the study objectives. Eligible subjects are between 55 to 85 years of age and have early AD in the absence of concurrent diseases that could confound safety or efficacy evaluations. Study participants are allowed to use concomitant medications to treat symptoms related to AD, if they are on a stable dose for at least 12 weeks prior to randomization. Upon completion of screening and baseline procedures, eligible subjects are randomized to one of the 3 ABBV-8E12 dose arms (low, medium and high dose) or placebo. Doses are administered every 4 weeks via IV infusion.
The primary efficacy measure for the AD study is the Clinical Dementia Rating scale – Sum of Boxes (CDR-SB). Secondary efficacy and exploratory outcomes include a variety of clinical measures, biologic markers, and neuroimaging measures. Safety will be monitored by adverse event reports, physical examination, laboratory tests, and imaging.
The phase 2 PSP study is a multiple dose, multicenter, multinational, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of ABBV-8E12 in patients with PSP. Eligible subjects are randomized to one of the two ABBV-8E12 dose arms (low and high dose) or placebo and ABBV-8E12 is administered every 4 weeks via IV infusion for a total of a 52-week treatment period. The study starts with a screening period of up to 8 weeks and ends with a follow-up period of approximately 20 weeks following the last study drug administration. Approximately 180 subjects will be enrolled to meet the study objectives. Eligible subjects are 40 years of age or older and meet PSP clinical criteria in the absence of concurrent diseases that could confound safety or efficacy evaluations. Study participants are required to have PSP symptoms for less than 5 years and to be able to walk 5 steps with minimal assistance.
The primary efficacy measure of this PSP phase 2 study is the PSP Rating Scale (PSPRS) (33). Secondary efficacy measures include a variety of biologic markers and clinical and neuroimaging outcome measures. Safety is assessed by adverse event reports, physical examination, laboratory tests and imaging.

 

Funding: This work was funded by C2N Diagnostics and AbbVie Inc., and supported by a grant from the Alzheimer’s Association (PCTR-15-330406) made possible by Part the Cloud™.

Acknowledgements: The team at C2N Diagnostics and AbbVie Inc. would like to sincerely thank the clinical investigators and the patients in the phase 1 clinical study for all their hard work and dedication to this clinical trial.

Conflict of interest: TW, IHH, PBV, and IF are full time employees and/or advisors of C2N Diagnostics, receiving stock and/or stock options. RJB is a co-founder of C2N Diagnostics. RJB and Washington University in St. Louis have equity ownership interest in C2N Diagnostics and may receive royalty income based on technology licensed by Washington University to C2N Diagnostics. RJB receives lab research funding from the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Co.), Eli Lilly and Co, Hoffman La-Roche, Janssen, Avid Radiopharmaceuticals, and the DIAN Pharma Consortium (Abbvie, Amgen, AstraZeneca, Biogen, Eisai, Eli Lilly and Co, Hoffman La-Roche, Janssen, Pfizer, and Sanofi). RJB has received honoraria from Janssen and Pfizer as a speaker and from Merck and Pfizer as an Advisory Board member. In addition, RJB receives income from C2N Diagnostics for serving on the Scientific Advisory Board. JBB is a co-founder and employee of C2N Diagnostics, receiving stock and/or stock options. KB, HF, and NM are employees of AbbVie, receiving stock and/or stock options. DMH co-founded and is on the scientific advisory board of C2N Diagnostics. DMH is an inventor on a submitted patent “Antibodies to Tau”, PCT/US2013/049333, that is licensed by Washington University to C2N Diagnostics. This patent was subsequently licensed to AbbVie. DMH receives research grants from the C2N Diagnostics, AbbVie, Eli Lilly, and Denali. DMH consults for Genentech, AbbVie, Eli Lilly, Proclara Biosciences, Glaxosmithkline, and Denali.

 

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