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04/2017 journal articles

Editorials

CONTINUING PROGRESS IN ALZHEIMER’S DISEASE TRIALS: CAUSE FOR OPTIMISM

P.S. Aisen

J Prev Alz Dis 2017;4(4):211-212

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CITATION:
P.S. Aisen (2017): Continuing Progress in Alzheimer’s Disease Trials: Cause for Optimism. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.34

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RECRUITMENT OF AT-RISK PARTICIPANTS FOR CLINICAL TRIALS: A MAJOR PARADIGM SHIFT FOR ALZHEIMER’S DISEASE PREVENTION

J. Alber, A.K.W. Lee, W. Menard, D. Monast, S.P. Salloway

J Prev Alz Dis 2017;4(4):213-214

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CITATION:
J. Alber ; A.K.W. Lee ; W. Menard ; D. Monast ; S.P. Salloway (2017): Recruitment of At-Risk Participants for Clinical Trials: A Major Paradigm Shift for Alzheimer’s Disease Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.32

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PROSPECTS FOR EFFECTIVE TREATMENT OF THE DEMENTIA-ALZHEIMER SYNDROME: A RENEWED ODYSSEY IN SEARCH OF THE MAGIC ELIXIR

Z.S. Khachaturian

J Prev Alz Dis 2017;4(4):215-217

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CITATION:
Z.S. Khachaturian (2017): Prospects for Effective Treatment of the Dementia-Alzheimer Syndrome: A Renewed Odyssey in Search of the Magic Elixir. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.42

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Original Research

EPIGALLOCATECHIN 3-GALLATE AS AN INHIBITOR OF TAU PHOSPHORYLATION AND AGGREGATION: A MOLECULAR AND STRUCTURAL INSIGHT

M. Guéroux, C. Fleau, M. Slozeck, M. Laguerre, I. Pianet

J Prev Alz Dis 2017;4(4):218-225

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Polyphenols such as Epigallocatechin-3 gallate (EGCG) are currently bearer of hope to prevent or at least to slow down the deleterious effect of Tauopathies such as Alzheimer disease. One of the main effects of these neurodegenerative pathologies is the hyperphosphorylation and consequent aggregation of the Tau protein that leads to the irremediable neuronal cells death. In the present paper, we show how EGCG can play a crucial role to prevent Tau aggregation: (i) in binding Tau in its phosphorylation region with an affinity of the same order of magnitude than kinases (0.5 mM), hindering their access to the protein and (ii) in modifying the 3D-structure of Tau whose preferential conformation changes in the presence of EGCG. For this purpose, two peptides were synthesized, one of 20 residues long issued from the first Proline-rich region of Tau (171Ile-190Lys), the second of 50 residues long (171Ile-220Thr) corresponding to more than 50% of the Tau Proline rich domaine. The total attribution of all the 1H, 13C and 15N resonances of the two peptides has been achieved thanks to a “divide and conquer” strategy leading to their 3D structure preference and their affinity towards EGCG.

CITATION:
M. Guéroux ; C. Fleau ; M. Slozeck ; M. Laguerre ; I. Pianet (2017): Epigallocatechin 3-gallate as an Inhibitor of Tau Phosphorylation and Aggregation: A Molecular and Structural Insight . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.35

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VITAMIN E SUPPLEMENTATION REDUCES CELLULAR LOSS IN THE BRAIN OF A PREMATURE AGING MOUSE MODEL

G. La Fata, N. van Vliet, S. Barnhoorn, R.M.C. Brandt, S. Etheve, E. Chenal, C. Grunenwald, N. Seifert, P. Weber, J.H.J. Hoeijmakers, M.H. Mohajeri, W. P. Vermeij

J Prev Alz Dis 2017;4(4):226-235

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Background: Aging is a highly complex biological process driven by multiple factors. Its progression can partially be influenced by nutritional interventions. Vitamin E is a lipid-soluble anti-oxidant that is investigated as nutritional supplement for its ability to prevent or delay the onset of specific aging pathologies, including neurodegenerative disorders. Purpose: We aimed here to investigate the effect of vitamin E during aging progression in a well characterized mouse model for premature aging. Method: Xpg-/- animals received diets with low (~2.5 mg/kg feed), medium (75 mg/kg feed) or high (375 mg/kg feed) vitamin E concentration and their phenotype was monitored during aging progression. Vitamin E content was analyzed in the feed, for stability reasons, and in mouse plasma, brain, and liver, for effectiveness of the treatment. Subsequent age-related changes were monitored for improvement by increased vitamin E or worsening by depletion in both liver and nervous system, organs sensitive to oxidative stress. Results: Mice supplemented with high levels of vitamin E showed a delayed onset of age-related body weight decline and appearance of tremors when compared to mice with a low dietary vitamin E intake. DNA damage resulting in liver abnormalities such as changes in polyploidy, was considerably prevented by elevated amounts of vitamin E. Additionally, immunohistochemical analyses revealed that high intake of vitamin E, when compared with low and medium levels of vitamin E in the diet, reduces the number of p53-positive cells throughout the brain, indicative of a lower number of cells dying due to DNA damage accumulated over time. Conclusions: Our data underline a neuroprotective role of vitamin E in the premature aging animal model used in this study, likely via a reduction of oxidative stress, and implies the importance of improved nutrition to sustain health.

CITATION:
G. La Fata ; N. van Vliet ; S. Barnhoorn ; R.M.C. Brandt ; S. Etheve ; E. Chenal ; C. Grunenwald ; N. Seifert ; P. Weber ; J.H.J. Hoeijmakers ; M.H. Mohajeri ; W. P. Vermeij (2017): Vitamin E Supplementation Reduces Cellular Loss in the Brain of a Premature Aging Mouse Model . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.30

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Review Articles

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

T. West, Y. Hu, P.B. Verghese, R.J. Bateman, J.B. Braunstein, I. Fogelman, K. Budur, H. Florian, N. Mendonca, D.M. Holtzman

J Prev Alz Dis 2017;4(4):236-241

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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.

CITATION:
T. West ; Y. Hu ; P.B. Verghese ; R.J. Bateman ; J.B. Braunstein ; I. Fogelman ; K. Budur ; H. Florian ; N. Mendonca ; D.M. Holtzman (2017): Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer’s Disease and Other Tauopathies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.36

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THE ALZHEIMER’S PREVENTION INITIATIVE GENERATION PROGRAM: EVALUATING CNP520 EFFICACY IN THE PREVENTION OF ALZHEIMER’S DISEASE

C. Lopez Lopez, A. Caputo, F. Liu, M.E. Riviere, M.-L. Rouzade-Dominguez, R.G. Thomas, J.B. Langbaum, R. Lenz, E.M. Reiman, A. Graf, P.N. Tariot

J Prev Alz Dis 2017;4(4):242-246

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Alzheimer’s disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer’s disease under the Alzheimer’s Prevention Initiative Generation Program. The Alzheimer’s Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer’s disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer’s disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer’s disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

CITATION:
C. Lopez Lopez ; A. Caputo ; F. Liu ; M.E. Riviere ; M.-L. Rouzade-Dominguez ; R.G. Thomas ; J.B. Langbaum ; R. Lenz ; E.M. Reiman ; A. Graf ; P.N. Tariot (2017): The Alzheimer’s Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.37

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DEVELOPMENT REVIEW OF THE BACE1 INHIBITOR LANABECESTAT (AZD3293/LY3314814)

J.R. Sims, K.J. Selzler, A.M. Downing, B.A. Willis, C.D. Aluise, J. Zimmer, S. Bragg, S. Andersen, M. Ayan-Oshodi, E. Liffick, J. Eads, A.M. Wessels, S. Monk, J. Schumi, J. Mullen

J Prev Alz Dis 2017;4(4):247-254

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Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer’s disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aβ production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

CITATION:
J.R. Sims ; K.J. Selzler ; A.M. Downing ; B.A. Willis ; C.D. Aluise ; J. Zimmer ; S. Bragg ; S. Andersen ; M. Ayan-Oshodi ; E. Liffick ; J. Eads ; A.M. Wessels ; S. Monk ; J. Schumi ; J. Mullen (2017): Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.38

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CLINICAL DEVELOPMENT OF ADUCANUMAB, AN ANTI-A? HUMAN MONOCLONAL ANTIBODY BEING INVESTIGATED FOR THE TREATMENT OF EARLY ALZHEIMER’S DISEASE

S. Budd Haeberlein, J. O’Gorman, P. Chiao, T. Bussière, P. von Rosenstiel, Y. Tian, Y. Zhu, C. von Hehn, S. Gheuens, L. Skordos, T. Chen, A. Sandrock

J Prev Alz Dis 2017;4(4):255-263

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The amyloid hypothesis has been the dominant framework for Alzheimer’s disease (AD) research, including the development of anti-AD therapies. However, none of the phase III clinical trials conducted to date that targeted amyloid β (Aβ) production, aggregation, or clearance demonstrated a statistically significant treatment effect in patients with AD. This includes the approach of using monoclonal antibodies that recognize various Aβ epitopes and display different binding selectivity. While some monoclonal antibodies have failed in phase III trials, several are still in development. Aducanumab (BIIB037) is a human antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib trial (N=196 patients dosed), aducanumab was shown to reduce Aβ plaques and slow decline in clinical measures in patients with prodromal or mild AD, with acceptable safety and tolerability. The main safety finding was amyloid-related imaging abnormalities (ARIA), a side effect associated with removal of Aβ, which was dose-dependent and occurred more often in ApoE ε4 carriers than non-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase III trials of aducanumab in early AD, have been designed based on the outcomes of PRIME and on lessons from past clinical trials in patients with AD. Those study design features include patient selection with confirmed Aβ pathology, ensuring sufficient target engagement, and conducting clinical trials in patients at earlier symptomatic stages of AD.

CITATION:
S. Budd Haeberlein ; J. O’Gorman ; P. Chiao ; T. Bussière ; P. von Rosenstiel ; Y. Tian ; Y. Zhu ; C. von Hehn ; S. Gheuens ; L. Skordos ; T. Chen ; A. Sandrock (2017): Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.39

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DEVELOPING DISEASE-MODIFYING TREATMENTS IN ALZHEIMER’S DISEASE – A PERSPECTIVE FROM ROCHE AND GENENTECH

R. Doody

J Prev Alz Dis 2017;4(4):264-272

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease for which no preventative or disease-modifying treatments currently exist. Pathological hallmarks include amyloid plaques and neurofibrillary tangles composed of hyper-phosphorylated tau protein. Evidence suggests that both pathologies are self-propagating once established. However, the lag time between neuropathological changes in the brain and the onset of even subtle clinical symptomatology means that patients are often diagnosed late when pathology, and neurodegeneration secondary to these changes, may have been established for several years. Complex pathological pathways associated with susceptibility to AD and changes that occur downstream of the neuropathologic process further contribute to the challenging endeavour of developing novel disease-modifying therapy. Recognising this complexity, effective management of AD must include reliable screening and early diagnosis in combination with effective therapeutic management of the pathological processes. Roche and Genentech are committed to addressing these unmet needs through developing a comprehensive portfolio of diagnostics and novel therapies. Beginning with the most scientifically supported targets, this approach includes two targeted amyloid-β monoclonal antibody therapies, crenezumab and gantenerumab, and an anti-tau monoclonal antibody, RO7105705, as well as a robust biomarker platform to aid in the early identification of people at risk or in the early stages of AD. Identification and implementation of diagnostic tools will support the enrolment of patients into clinical trials; furthermore, these tools should also support evaluation of the clinical efficacy and safety profile of the novel therapeutic agents tested in these trials. This review discusses the therapeutic agents currently under clinical development.

CITATION:
R. Doody ; (2017): Developing Disease-Modifying Treatments in Alzheimer’s Disease – A Perspective from Roche and Genentech. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.40

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NEFLAMAPIMOD: CLINICAL PHASE 2B-READY ORAL SMALL MOLECULE INHIBITOR OF P38? TO REVERSE SYNAPTIC DYSFUNCTION IN EARLY ALZHEIMER’S DISEASE

J. Alam, K. Blackburn, D. Patrick

J Prev Alz Dis 2017;4(4):273-278

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Neflamapimod (previously code named VX-745) is a clinical phase 2b-ready highly specific inhibitor of the intra-cellular enzyme p38 mitogen activated protein kinase alpha (“p38α”) that is being developed as a disease-modifying drug for Alzheimer’s disease (AD) that acts via targeting synaptic dysfunction. Neflamapimod was discovered through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals, and developed previously by Vertex through to phase 2a in rheumatoid arthritis. EIP Pharma licensed the compound in 2014 for development and commercialization as a treatment of central nervous system (CNS) disorders. Neflamapimod is the most advanced in the clinic drug that targets specific molecular mechanisms within neurons that leads to synaptic dysfunction, the pathogenic process that is now considered to be a major driver of the development of memory deficits and disease progression in the early stages of AD. Based on the scientific rationale of targeting synaptic dysfunction and the preclinical data, neflamapimod has the potential to both reverse memory deficits and slow disease progression. Phase 2a clinical data in patients with early-stage AD (MMSE 20-28, biomarker positive) provides evidence that the preclinical science may be translatable to human Alzheimer’s, as 6- to 12-weeks of neflamapimod treatment led to significant improvement in episodic memory, the best clinical measure of synaptic dysfunction in AD. A phase 2b six-month placebo-controlled 150-patient clinical study is anticipated to start by end of 2017. This study is designed to definitively demonstrate that neflamapimod reverses memory deficits, and also to provide preliminary evidence that the drug slows disease progression.

CITATION:
J. Alam ; K. Blackburn ; D. Patrick (2017): Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.41

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Clinical Trials and Aging: 10th Conference Clinical Trials on Alzheimer’s Disease, November 1-4, 2017, Boston, USA

CTAD: SYMPOSIA, ORAL COMMUNICATIONS, POSTERS

Abstracts

J Prev Alz Dis 2017;4(4):282-428

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