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INTRODUCTION: Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid ß and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). METHODS: In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. RESULTS: Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3-6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. DISCUSSION: In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.
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INTRODUCTION: Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid ß (Aß)1-40 and Aß1-42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aß isoforms and their relationship with solanezumab exposure. METHODS: CSF Aß isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3. RESULTS: Solanezumab produced statistically significant increases in CSF total Aß isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aß isoforms were observed. Solanezumab penetration into the central nervous system was low. DISCUSSION: Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aß concentrations.
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BACKGROUND: Alzheimer's disease is characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aß, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aß1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS: A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).
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Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores/líquido cefalorraquidiano , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Placa Amiloide/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Falha de TratamentoRESUMO
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]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. RESULTS: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. DISCUSSION: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.
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Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Compostos de Anilina/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Etilenoglicóis/metabolismo , Fatores Imunológicos/uso terapêutico , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Substância Branca/efeitos dos fármacosRESUMO
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. RESULTS: Seven publications provided MCI/mild AD functional outcomes, one of which reported a significant functional treatment effect. Secondary analyses of EXPEDITION studies suggested a smaller functional effect of solanezumab relative to cognition. An increasing effect of solanezumab over 18 months was shown for cognition and function. DISCUSSION: Function as the sole measure to demonstrate clinical meaningfulness of cognitive effects in mild AD may have limitations. For disease-modifying treatments, point differences on cognitive and functional scales should be qualified with duration of treatment.
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INTRODUCTION: Mild-Alzheimer's disease (AD) subjects without significant Aß pathology represent a confounding finding for clinical trials because they may not progress clinically on the expected trajectory, adding variance into analyses where slowing of progression is being measured. METHODS: A prediction model based on structural magnetic resonance imaging (MRI) in combination with baseline demographics and clinical measurements was used to impute Aß status of a placebo-treated mild-AD sub-cohort (N = 385) of patients participating in global phase 3 trials. The clinical trajectories of this cohort were evaluated over 18 months duration of the trial, stratified by imputed Aß status within a mixed-model repeated measures statistical framework. RESULTS: In the imputed Aß-positive cohort, both cognitive (ADAS-Cog14 and MMSE) and functional (ADCS-iADL) measures declined more rapidly than in the undifferentiated population. DISCUSSION: Our results demonstrate imputing Aß status from MRI scans in mild-AD subjects may be a useful screening tool in global clinical trials if amyloid measurement is not available.
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Doença de Alzheimer/classificação , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Imagem Multimodal , Idoso , Doença de Alzheimer/terapia , Compostos de Anilina , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-ß peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. METHODS: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. RESULTS: In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. DISCUSSION: These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.
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Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Cognição/efeitos dos fármacos , Testes Neuropsicológicos/estatística & dados numéricos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Método Duplo-Cego , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
INTRODUCTION: In two solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status. METHODS: Quantile regression was used to examine solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively. RESULTS: In mild patients, solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, solanezumab did not show effects across most percentiles. DISCUSSION: Results are compatible with design of the ongoing solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.
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BACKGROUND: The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. OBJECTIVE: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. METHODS: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. RESULTS: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. CONCLUSIONS: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.
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Doença de Alzheimer/complicações , Doença de Alzheimer/psicologia , Transtornos Cognitivos/etiologia , Idoso , Idoso de 80 Anos ou mais , Alanina/análogos & derivados , Alanina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antipsicóticos/uso terapêutico , Azepinas/uso terapêutico , Transtornos Cognitivos/diagnóstico , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Interpreting Alzheimer's disease (AD) clinical trial (CT) outcomes is complicated by treatment dropouts and adverse events (AEs). In elderly participants, AE rates, dropouts, and deaths are important considerations as they may undermine the validity of clinical trials. Published discontinuation and safety data are limited. METHODS: Safety data from 1054 placebo-treated participants in IDENTITY and IDENTITY-2, 76-week, Phase 3 AD studies conducted in 31 countries, were pooled, annualized, and summarized overall, by country and age group. RESULTS: Median age was 74.2 (interquartile range 67.9-79.5) years; 57.4% were female; and median observation time was 63.2 (interquartile range 41.6-77.4) weeks when study drug dosing was halted. Overall annualized rates for discontinuations, discontinuations due to AEs, serious adverse events (SAEs), and deaths were 21.6% (range 19.6%-24.0%), 8.2% (range 8.1%-8.3%), 12.0%, and 1.7%, respectively. AE and discontinuation rates varied by country and age groups. Fall, pneumonia, and atrial fibrillation AEs were more frequent in the oldest age group. CONCLUSIONS: These annualized placebo safety data provide insight into the course of enrolled patients with mild-to-moderate AD, and are useful in planning longer term trials and in monitoring safety.
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Alanina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Azepinas/efeitos adversos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Acidentes por Quedas/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Alanina/efeitos adversos , Fibrilação Atrial/epidemiologia , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Placebos , Pneumonia/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: In patients with Alzheimer's disease (AD), the relationship between cognitive and functional progression is not fully understood; however, functional decline has been postulated to follow cognitive decline. OBJECTIVE: To assess the relationship between cognitive and functional treatment effects in mild AD dementia patients. METHODS: Data of patients with mild AD were pooled from two multicenter, double-blind, Phase 3 studies. Patients were randomized to infusions of 400-mg solanezumab (n = 654), or placebo (n = 660) every 4 weeks for 18 months. Cognitive and functional outcome measures were assessed using the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL), respectively. Analyses included comparisons among normalized scales, correlations between outcome measures, and path analyses to model the relationship of treatment effect on cognition and function. RESULTS: Normalized ADAS-Cog and ADCS-ADL scales showed cognitive impairment was more evident than functional impairment in mild AD. The correlation between cognition and function increased over time. Path analyses demonstrated that 87% of the treatment effect on function was driven by the treatment effect on cognition, with the remaining 13% due to direct treatment effect. CONCLUSION: Findings from this study are consistent with the hypothesis that functional impairment is primarily driven by and follows cognitive decline in mild AD dementia. The cognitive treatment effect appeared to explain the majority of the functional treatment effect. It is possible that a cognitive treatment effect may be considered as a leading indicator for functional outcomes in an 18-month clinical trial for milder stages of AD.
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Atividades Cotidianas/psicologia , Doença de Alzheimer/psicologia , Transtornos Cognitivos/psicologia , Cognição/fisiologia , Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Cognição/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Progressão da Doença , Humanos , Testes NeuropsicológicosRESUMO
OBJECTIVE: Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable risk-benefit profile in a Phase 3 study of patients with Alzheimer's disease (IDENTITY trials), and clinical development was halted. To assist in future development of γ-secretase inhibitors, we report detailed safety findings from the IDENTITY study, with emphasis on those that might be mechanistically linked to γ-secretase inhibition. RESEARCH DESIGN AND METHODS: The IDENTITY trial was a double-blind, placebo-controlled trial of semagacestat (100 mg and 140 mg), in which 1537 patients age 55 years and older with probable Alzheimer's disease were randomized. Treatment-emergent adverse events (TEAEs) are reported by body system along with pertinent laboratory, vital sign, and ECG findings. RESULTS: Semagacestat treatment was associated with increased reporting of suspected Notch-related adverse events (gastrointestinal, infection, and skin cancer related). Other relevant safety findings associated with semagacestat treatment included cognitive and functional worsening, skin-related TEAEs, renal and hepatic changes, increased QT interval, and weight loss. With few exceptions, differences between semagacestat and placebo treatment groups were no longer significant after cessation of treatment with active drug. CONCLUSIONS: Many of these safety findings can be attributed to γ-secretase inhibition, and may be valuable to researchers developing γ-secretase inhibitors.
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Alanina/análogos & derivados , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Azepinas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Idoso , Alanina/administração & dosagem , Alanina/efeitos adversos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nootrópicos/administração & dosagem , Nootrópicos/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Medição de RiscoRESUMO
Clinical diagnosis of Alzheimer's disease (AD) is challenging, with 20% or more of patients misdiagnosed, even by expert clinicians. The authors conducted a retrospective, cross-sectional analysis comparing baseline neuropsychiatric and other clinical characteristics in 199 expert-diagnosed mild and moderate AD dementia patients participating in industry-sponsored clinical trials of an investigational therapy, where 18% lacked florbetapir positron emission tomography (PET) evidence of AD neuropathology. Significant differences were found only for cognition and ApoE ε4 status, but the large degree of score overlap would preclude using these measures to predict AD misdiagnosis. This study highlights the value of amyloid PET when evaluating patients with seemingly typical AD.
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Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Etilenoglicóis , Tomografia por Emissão de Pósitrons , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Análise de Variância , Encéfalo/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos RetrospectivosRESUMO
BACKGROUND: Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer's disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials. METHODS: We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer's Disease Neuroimaging Initiative study. RESULTS: AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%-5.8% of patients), headache (4.0%-5.5%), constipation (4.3%-4.7%), nausea (2.0%-5.8%), joint swelling (3.6%-3.7%), vomiting (3.6%-3.7%), and anxiety (3.2%-3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%-33.0% vs 8.2%-21.0%) and greater discontinuations due to AEs (9.5%-11.6% vs 2.7%-3.2%). Rates of death (1.8%-2.4%) and SAEs (19.9%-21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%-4.0%) where SAEs were reported. CONCLUSIONS: In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer's Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.
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Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/efeitos adversos , Neuroimagem , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Placebos/efeitos adversos , Estudos Retrospectivos , Fatores de TempoRESUMO
In recent years advances in histopathological and molecular understanding of hematologic malignancies have led to the development of drugs which selectively target proteins associated with hematologic tumorigenesis. One such targeted agent is the antisense oligonucleotide aprinocarsen, which specifically inhibits the signaling protein, protein kinase C-alpha (PKC-alpha). Although PKC-alpha has been associated with tumorigenesis, its role and expression levels in patients with hematologic malignancies are not well understood. We here review studies investigating the expression and role of PKC-alpha in hematologic malignancies. Such a review may offer new insights on how to develop strategies in identifying patients that might best benefit from PKC-alpha inhibition.
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Neoplasias Hematológicas/enzimologia , Linfoma não Hodgkin/enzimologia , Proteínas de Neoplasias/metabolismo , Proteína Quinase C-alfa/metabolismo , Animais , Antineoplásicos/uso terapêutico , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Fosforotioatos , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/genéticaRESUMO
Current treatments of non-small-cell lung cancer (NSCLC) are inadequate and new therapies are being developed that target specific cellular signaling proteins associated with tumor growth. One potential target is protein kinase C (PKC)-alpha, a signaling molecule with an important role in cell regulation and proliferation. The present study examines the expression levels of PKC-alpha in NSCLC to better understand the distribution of PKC-alpha in NSCLC. We analyzed tumor specimens from an independent tumor tissue bank to determine PKC-alpha protein and messenger RNA gene expression in NSCLC. In addition, we used publicly available gene expression array data to further understand PKC-a-associated gene expression profiles in NSCLC. We found that PKC-alpha is highly expressed in < or = 20% of patients with NSCLC. We also found that PKC-alpha was preferentially expressed in adenocarcinoma compared with squamous cell carcinoma of the lung.
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Carcinoma Pulmonar de Células não Pequenas/genética , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Proteína Quinase C/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Quinase C-alfa , RNA Mensageiro/metabolismoRESUMO
In recent years research has focused on the development of specific, targeted drugs to treat cancer. One approach has been to block intracellular signaling proteins, such as protein kinase C alpha (PKC-alpha). To help support the rationale for clinical studies of a PKC-alpha-targeted therapy in breast and ovarian cancers, we reviewed publications studying PKC-alpha expression in these tumors. Since these investigations were mostly performed in cell lines, we supplemented this review with some preliminary findings from studies examining PKC-alpha expression in tumor tissue biopsies obtained from patients with breast and ovarian cancer. Based on the reviewed publications using representative cell lines and our preliminary findings on tumor tissue of patients with breast cancer, we infer that PKC-alpha levels may especially be increased in breast cancer patients with low or negative estrogen receptor (ER) levels. Thus, clinical studies determining efficacy of selective or specific inhibitors of PKC-alpha should include determination of ER status in order to help answer whether blocking PKC-alpha in patients with low or absent ER can result in clinical benefit.
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Neoplasias da Mama/enzimologia , Neoplasias Ovarianas/enzimologia , Proteína Quinase C/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/uso terapêutico , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Oligonucleotídeos Fosforotioatos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteína Quinase C-alfa , Receptores de Estrogênio/metabolismoRESUMO
As our understanding of tumorigenesis increases, interference with the various signaling pathways of tumor cells has become an attractive approach to arresting tumor cell growth and overcoming chemoresistance. Among many intracellular signaling proteins, protein kinase C (PKC) isoenzymes have been identified as possible targets to render tumor cells more susceptible to apoptosis and growth arrest. We review the known biology of the alpha-isoenzyme of PKC in different cancers to provide a rational approach for developing targeted therapies using PKC modulators, including aprinocarsen, an antisense oligonucleotide (ASO) against PKC-alpha.
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Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/fisiologia , Tionucleotídeos/uso terapêutico , Animais , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/enzimologia , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Proteína Quinase C-alfa , Tionucleotídeos/farmacologiaRESUMO
In the 1980s, protein kinase C (PKC) was identified as a contributing factor in skin tumorigenesis. As drugs targeting specifically PKC have become available, the intent of this review was to assess the role of PKC, in particular of PKC-alpha in melanoma or other skin cancers. We reviewed and summarized published studies examining the role of PKC-alpha in the development of melanoma or other skin cancers. Most studies to date have been cell-culture based. In models of melanoma, PKC-alpha activation is typically associated with increased tumour cell proliferation, invasiveness and decreased differentiation, suggesting that PKC-alpha inhibitors, such as aprinocarsen, an antisense oligonucleotide directed against PKC-alpha, may be appropriate in the treatment of skin malignancies. Because of the recent developments on selective or specific PKC-alpha inhibitors, including aprinocarsen, there is a growing need to conduct further translational research, especially in melanoma patients, to identify the patient population that might benefit most from PKC-alpha targeted therapy.
Assuntos
Melanoma/enzimologia , Proteína Quinase C/metabolismo , Neoplasias Cutâneas/enzimologia , Animais , Humanos , Melanoma/epidemiologia , Melanoma/genética , Melanoma/terapia , Proteína Quinase C/química , Proteína Quinase C/genética , Proteína Quinase C-alfa , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapiaRESUMO
Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein. This understanding is expected to improve the identification of patients who most likely will benefit from treatment with a specific inhibitor, such as aprinocarsen. In order to better understand the role of PKC-alpha in nervous system malignancies we here review the published literature on PKC-alpha expression in nervous system tumors, including glioblastoma multiforme. In pre-clinical experiments aprinocarsen had demonstrated anti-tumor activity, in particular in animal models of glioblastoma. Thus, clinical study CS10 with aprinocarsen was undertaken in patients with central nervous system (CNS) malignancies. The results of this study and considerations for future clinical studies in CNS tumors are reviewed.