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Solanezumab

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https://www.readbyqxmd.com/read/28467878/the-failure-of-solanezumab-how-the-fda-saved-taxpayers-billions
#1
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
#2
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
#3
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])...
March 30, 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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/27025652/the-amyloid-hypothesis-of-alzheimer-s-disease-at-25%C3%A2-years
#16
REVIEW
Dennis J Selkoe, John Hardy
Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ...
2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27025080/-immunotherapy-for-alzheimer-s-disease-targeting-a%C3%AE
#17
Takeshi Tabira
Active and passive immunization of Alzheimer model mice with Aβ showed clearance of aggregated amyloid β deposits and improved memory and learning. Although human trial was halted because of autoimmune encephalitis, the trial revealed that immunization with Aβ also deleted amyloid deposits in humans without clinical benefit. On these proof of concept, several clinical trials using monoclonal antibodies are on-going. Although solanezumab which recognizes Aβ monomer turned out ineffective in the primary endpoint, it showed significant beneficial effect in mild AD cases in the secondary outcome...
March 2016: Nihon Rinsho. Japanese Journal of Clinical Medicine
https://www.readbyqxmd.com/read/27025079/-significance-and-progress-of-dian-a4-api
#18
Hiroyuki Shimada
The DIAN observational study compared the pathophysiological markers between mutation carriers and non-carriers for autosomal dominant Alzheimer's disease. It has revealed the biomarker changes in the mutation carrier's brain started as early as 20, even 25 years prior to symptoms. The researchers of DIAN started the prevention trial(DIAN-TU) with two monoclonal antibodies. The API study is the clinical trial of the anti-amyloid monoclonal antibody therapy to the kindred of early onset familial AD (EOAD) who carry the PSEN1 E280A mutation...
March 2016: Nihon Rinsho. Japanese Journal of Clinical Medicine
https://www.readbyqxmd.com/read/27019841/a-combined-measure-of-cognition-and-function-for-clinical-trials-the-integrated-alzheimer-s-disease-rating-scale-iadrs
#19
A M Wessels, E R Siemers, P Yu, S W Andersen, K C Holdridge, J R Sims, K Sundell, Y Stern, D M Rentz, B Dubois, R W Jones, J Cummings, P S Aisen
It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study...
December 1, 2015: Journal of Prevention of Alzheimer's Disease
https://www.readbyqxmd.com/read/26990863/a-retrospective-analysis-of-the-alzheimer-s-disease-vaccine-progress-the-critical-need-for-new-development-strategies
#20
REVIEW
Dante J Marciani
The promising results obtained with aducanumab and solanezumab against Alzheimer's disease (AD) strengthen the vaccine approach to prevent AD, despite of the many clinical setbacks. It has been problematic to use conjugated peptides with Th1/Th2 adjuvants to induce immune responses against conformational epitopes formed by Aβ oligomers, which is critical to induce protective antibodies. Hence, vaccination should mimic natural immunity by using whole or if possible conjugated antigens, but biasing the response to Th2 with anti-inflammatory adjuvants...
June 2016: Journal of Neurochemistry
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