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Solanezumab

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https://www.readbyqxmd.com/read/29067346/phase-ii-clinical-trials-of-anti-amyloid-%C3%AE-antibodies-when-is-enough-enough
#1
REVIEW
Michael Gold
Efforts to develop new therapies to combat Alzheimer's disease suffer from extraordinarily high failure rates that make it difficult to justify continued investment in the field. Although there are a number of plausible explanations for this extremely high attrition rate, one of the explanations that has received little attention is the lack of compelling data from Phase II studies for compounds that have been pushed into Phase III trials and then have failed. An analysis of publicly available data from the Phase II studies for bapineuzumab and solanezumab indicates that neither compound produced compelling evidence of drug-like behavior that would justify their progression into pivotal trials...
September 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://www.readbyqxmd.com/read/29037101/the-potential-of-solanezumab-and-gantenerumab-to-prevent-alzheimer-s-disease-in-people-with-inherited-mutations-that-cause-its-early-onset
#2
Francesco Panza, Davide Seripa, Madia Lozupone, Vincenzo Solfrizzi, Bruno P Imbimbo, Maria Rosaria Barulli, Rosanna Tortelli, Rosa Capozzo, Paola Bisceglia, Andrea Dimitri, Roberta Stallone, Vittorio Dibello, Nicola Quaranta, Antonio Daniele, Antonello Bellomo, Antonio Greco, Giancarlo Logroscino
The recent failure of several clinical trials on anti-β-amyloid (Aβ) drugs in Alzheimer's disease (AD) suggested earlier intervention in the disease course. Secondary prevention trials have been started in autosomal-dominant AD (ADAD) individuals without cognitive dysfunction and in cognitively healthy subjects at risk of developing sporadic AD (SAD). Areas covered: Herein, the authors discuss prevention trials in ADAD and SAD, with a focus on the anti-Aβ monoclonal antibodies solanezumab and gantenerumab presently in Phase III clinical development...
October 16, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28924036/mechanisms-of-recognition-of-amyloid-%C3%AE-a%C3%AE-monomer-oligomer-and-fibril-by-homologous-antibodies
#3
Jun Zhao, Ruth Nussinov, Buyong Ma
Alzheimer's disease is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapy is a promising approach, but amyloid antibody structural information is limited. Here we simulate the recognition of monomeric, oligomeric, and fibril amyloid-β (Aβ) by three homologous antibodies (solanezumab, crenezumab, and their chimera, CreneFab). Solanezumab only binds the monomer, whereas crenezumab and CreneFab can recognize different oligomerization states; however, the structural basis for this observation is not understood...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28649604/combined-immunotherapy-with-anti-insulin-resistance-therapy-as-a-novel-therapeutic-strategy-against-neurodegenerative-diseases
#4
Yoshiki Takamatsu, Gilbert Ho, Wakako Koike, Shuei Sugama, Takato Takenouchi, Masaaki Waragai, Jianshe Wei, Kazunari Sekiyama, Makoto Hashimoto
Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of α-synuclein in Parkinson's disease...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28593105/photobiomodulation-with-near-infrared-light-helmet-in-a-pilot-placebo-controlled-clinical-trial-in-dementia-patients-testing-memory-and-cognition
#5
Marvin H Berman, James P Halper, Trent W Nichols, H Jarrett, Alan Lundy, Jason H Huang
Alzheimer's disease (AD) is a common, chronic expensive debilitating neurodegenerative disease with no current treatments to prevent the physical deterioration of the brain and the consequent cognitive deficits. The current pathophysiology of Alzheimer's disease is the accumulation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein and amyloid-beta (Aβ) plaques. Antibody therapy of Tau and Amyloid beta, vaccines and other methods to decrease Tau and or Amyloid have not been successful after considerable pharmaceutical and biotech efforts...
2017: Journal of neurology and neuroscience
https://www.readbyqxmd.com/read/28467878/the-failure-of-solanezumab-how-the-fda-saved-taxpayers-billions
#6
Chana A Sacks, Jerry Avorn, Aaron S Kesselheim
The November 2016 announcement that Eli Lilly’s investigational drug solanezumab failed in a phase 3 clinical trial dashed hopes that it would be a long-anticipated disease-modifying treatment for Alzheimer’s disease. For people living with Alzheimer’s — along with their relatives and caregivers,..
May 4, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28402165/statistical-properties-of-continuous-composite-scales-and-implications-for-drug-development
#7
Hong Liu-Seifert, Scott Andersen, Michael Case, JonDavid Sparks, Karen C Holdridge, Alette M Wessels, Suzanne Hendrix, Paul Aisen, Eric Siemers
Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite...
April 12, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28365320/use-of-white-matter-reference-regions-for-detection-of-change-in-florbetapir-positron-emission-tomography-from-completed-phase-3-solanezumab-trials
#8
Adam S Fleisher, Abhinay D Joshi, Karen L Sundell, Yun-Fei Chen, Sara Kollack-Walker, Ming Lu, Sherry Chen, Michael D Devous, John Seibyl, Kenneth Marek, Eric R Siemers, Mark A Mintun
INTRODUCTION: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. METHODS: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr])...
October 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/28229126/assessing-quality-of-life-in-alzheimer-s-disease-implications-for-clinical%C3%A2-trials
#9
Kristin Kahle-Wrobleski, Wenyu Ye, David Henley, Ann Marie Hake, Eric Siemers, Yun-Fei Chen, Hong Liu-Seifert
INTRODUCTION: Characterization of the quality of life (QOL) in Alzheimer's disease (AD) scale within the context of a clinical trial may inform its applicability in future trials. METHODS: Using data from 1322 patients enrolled in two phase-III studies (EXPEDITION 1 [NCT00905372] and 2 [NCT00904683]) of intravenous solanezumab in outpatients with mild AD dementia, correlations between patient- and caregiver-assessed QOL and between QOL and clinical outcome measures were examined...
2017: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/28219449/ex-vivo-18-o-labeling-mass-spectrometry-identifies-a-peripheral-amyloid-%C3%AE-clearance-pathway
#10
Erik Portelius, Niklas Mattsson, Josef Pannee, Henrik Zetterberg, Magnus Gisslén, Hugo Vanderstichele, Eleni Gkanatsiou, Gabriela A N Crespi, Michael W Parker, Luke A Miles, Johan Gobom, Kaj Blennow
BACKGROUND: Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer's disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis...
February 20, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28102152/solanezumab-too-late-in-mild-alzheimer-s-disease
#11
EDITORIAL
The Lancet Neurology
No abstract text is available yet for this article.
February 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28066098/novel-strategies-for-alzheimer-s-disease-treatment-an-overview-of-anti-amyloid-beta-monoclonal-antibodies
#12
REVIEW
Katarzyna Rygiel
Alzheimer's disease (AD) is a multifactorial, progressive neurodegenerative disorder with a poor prognosis, and thus, novel therapies for AD are certainly needed in a growing population of elderly patients or asymptomatic individuals, who are at risk for AD, worldwide. It has been established that some AD biomarkers such as amyloid-beta load in the brain, precede the onset of the disease, by approximately 20 years. Therefore, the therapy to prevent or effectively treat AD has to be initiated before the emergence of symptoms...
November 2016: Indian Journal of Pharmacology
https://www.readbyqxmd.com/read/28034844/solanezumab-and-the-amyloid-hypothesis-for-alzheimer-s-disease
#13
EDITORIAL
David G Le Couteur, Sally Hunter, Carol Brayne
No abstract text is available yet for this article.
December 29, 2016: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/27899350/sixty-seconds-on-solanezumab
#14
Nigel Hawkes
No abstract text is available yet for this article.
November 29, 2016: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/27725918/chemical-and-neuropathological-analyses-of-an-alzheimer-s-disease-patient-treated-with-solanezumab
#15
Alex E Roher, Chera L Maarouf, Tyler A Kokjohn, Christine Belden, Geidy Serrano, Marwan S Sabbagh, Thomas G Beach
INTRODUCTION: Based on the amyloid cascade hypothesis of Alzheimer's disease (AD) pathogenesis, a series of clinical trials involving immunotherapies have been undertaken including infusion with the IgG1 monoclonal anti-Aβ antibody solanezumab directed against the middle of the soluble Aβ peptide. In this report, we give an account of the clinical history, psychometric testing, gross and microscopic neuropathology as well as immunochemical quantitation of soluble and insoluble Aβ peptides and other proteins of interest related to AD pathophysiology in a patient treated with solanezumab...
2016: American Journal of Neurodegenerative Disease
https://www.readbyqxmd.com/read/27678025/emerging-drugs-to-reduce-abnormal-%C3%AE-amyloid-protein-in-alzheimer-s-disease-patients
#16
REVIEW
Francesco Panza, Davide Seripa, Vincenzo Solfrizzi, Bruno P Imbimbo, Madia Lozupone, Antonio Leo, Rodolfo Sardone, Gaetano Gagliardi, Lucia Lofano, Bianca C Creanza, Paola Bisceglia, Antonio Daniele, Antonello Bellomo, Antonio Greco, Giancarlo Logroscino
Currently available drugs against Alzheimer's disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016...
December 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27266343/conformational-selection-in-amyloid-based-immunotherapy-survey-of-crystal-structures-of-antibody-amyloid-complexes
#17
REVIEW
Buyong Ma, Jun Zhao, Ruth Nussinov
BACKGROUND: The dominant feature in neurodegenerative diseases is protein aggregations that lead to neuronal loss. Immunotherapies using antibodies or antibody fragments to target the aggregations are a highly perused approach. The molecular mechanisms underlying the amyloid-based immunotherapy are complex. Deciphering the properties of amyloidogenic proteins responsible for these diseases is essential to obtain insights into antibody recognition of the amyloid antigens. SCOPE OF REVIEW: We systematically explore all available crystal structures of antibody-amyloid complexes related to neurodegenerative diseases, including antibodies that recognize the Aβ peptide, tau protein, prion protein, alpha-synuclein, huntingtin protein (mHTT), and polyglutamine...
November 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27239541/function-and-clinical-meaningfulness-of-treatments-for-mild-alzheimer-s%C3%A2-disease
#18
Eric Siemers, Karen Chilcott Holdridge, Karen L Sundell, Hong Liu-Seifert
INTRODUCTION: Effectiveness of Alzheimer's disease (AD) treatments is commonly evaluated with coprimary outcomes; cognition with function to ensure clinical meaningfulness of a cognitive effect. METHODS: We reviewed the literature for functional outcomes in mild AD or mild cognitive impairment (MCI) patients (distinct from combined mild-moderate/severe AD) treated with approved AD drugs. Cognitive and functional treatment differences in mild AD patients in solanezumab EXPEDITION/EXPEDITION2 studies were compared across time...
2016: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/27239538/amyloid-related-imaging-abnormalities-from-trials-of-solanezumab-for-alzheimer-s-disease
#19
Christopher Carlson, Eric Siemers, Ann Hake, Michael Case, Roza Hayduk, Joyce Suhy, Joonmi Oh, Jerome Barakos
INTRODUCTION: Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). METHODS: Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition...
2016: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/27223100/analysis-of-recent-failures-of-disease-modifying-therapies-in-alzheimer-s-disease-suggesting-a-new-methodology-for-future-studies
#20
REVIEW
Hamid Reza Amanatkar, Bill Papagiannopoulos, George Thomas Grossberg
Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer's disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer's disease...
January 2017: Expert Review of Neurotherapeutics
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