Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials.

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.

Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients.

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.

Amyloid status imputed from a multimodal classifier including structural MRI distinguishes progressors from nonprogressors in a mild Alzheimer's disease clinical trial cohort.

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.

Adverse events and dropouts in Alzheimer's disease studies: what can we learn?

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.

Safety profile of Alzheimer's disease populations in Alzheimer's Disease Neuroimaging Initiative and other 18-month studies.

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.

Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease.

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.

Function and clinical meaningfulness of treatments for mild Alzheimer's disease.

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.

Expression levels of protein kinase C-alpha in non-small-cell lung cancer.

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.

The role of protein kinase C-alpha in malignancies of the nervous system and implications for the clinical development of the specific PKC-alpha inhibitor aprinocarsen (Review).

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.

The role of protein kinase C-alpha (PKC-alpha) in melanoma.

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.

Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings.

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.