Showing papers by "Eric Siemers published in 2014"

Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease

Abstract: BackgroundAlzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. MethodsIn two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary...

Cognitive and functional decline and their relationship in patients with mild Alzheimer's dementia.

Abstract: 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.

E.u./u.s. ctad task force on alzheimer\'s trial populations

Abstract: Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer's disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer's disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias.

Anti-Aβ antibody target engagement: commentary regarding Watt et al. Acta Neuropathol 127:803–810 (2014)

Abstract: denatured and treated with a detergent. The lack of sensitivity of the seLDI-TOF method was clearly demonstrated by the fact that it was barely able to detect the approximately 3,500 pM endogenous plasma Aβ1–40 found in the TG2576 App transgenic mice, which is approximately 70-fold greater than the levels present in human plasma [14]. secondly, the group performed seLDI-TOF on human brain extracts that were prepared under conditions that yielded primarily aggregated/oligomer Aβ, a structural form of Aβ to which solanezumab does not bind [17]. The abundance of oligomeric Aβ species in the human brain extracts is demonstrated in the bapineuzumab capture data. They showed that bapineuzumab captured more truncated forms of Aβ (5–42, 4–42, p3–42, 2–42) than full-length Aβ1–42 and since bapineuzumab does not recognize aminoterminally truncated forms, a likely way the truncated forms could be bound would be as part of an aggregate/ oligomer. The group did demonstrate that all the antibodies bound to multiple full-length forms of Aβ (1–42, 1–40, 1–39, 1–38) when similar extractions were performed on cortical tissue from 15-month-old TG2576 mice; however, prior studies have demonstrated that deposited Aβ from these transgenic mice is very easily solubilized as compared to Alzheimer’s disease tissue [13]. since solanezumab is selective for soluble monomeric forms of Aβ, the Watt et al. brain extraction experiments were not properly designed to detect target engagement for this antibody. Thirdly, the authors present no negative control experiments for their immunoprecipitation—mass spectrometry experiments using tagged Fab fragments of the antibodies. Appropriate controls would have been one or more tagged Fab fragments of unrelated antibodies and also omitting any primary antibody. Considering the very high amount of proteins in plasma (range 35–50 g/L), there is a very high risk of unspecific binding to the beads used for We read with interest the recent publication by Watt et al. [21] describing the properties of three anti-Aβ antibodies, bapineuzumab, solanezumab, and crenezumab in particular, with regard to target engagement. While the authors reported in vitro binding of the antibodies to synthetic Aβ, the ex vivo studies carried out on plasma and brain lysates led the authors to conclude that all three antibodies failed to engage the intended molecular targets. We believe the data represented do not justify the conclusions for the following reasons. First, surface-enhanced laser desorption/ionization timeof-flight mass spectrometry (seLDI-TOF Ms) used by Watt et al. to investigate this question does not possess a dynamic range sufficient to measure endogenous Aβ peptides in murine and human plasma. While the authors state that their method is capable of measuring 50 pM concentrations, detection at this level was demonstrated only after synthetic Aβ peptide was spiked into tissues that had already been

Delayed-start analyses of solanezumab phase 3 expedition studies in mild alzheimer's disease

Abstract: institutionalization, and high costs. Exercise studies in AD are just emerging and have produced conflicting findings on cognitive outcomes, largely due to low levels of exercise, poor delivery of aerobic exercise, and lack of controls. Methods: This randomized controlled trial (RCT) will investigate the effects of a novel 6-month, individualized, moderate-intensity stationarycycling intervention on cognition and hippocampal volume in communitydwelling older adults with mild-to-moderate AD. Ninety subjects will be randomized to the 6-month cycling intervention or attention control (sham exercise) groups using permuted blocks of 3 and 6 subjects randomly and a 2:1 allocation ratio, and followed for another 6months (see Figure 1). A combined heart rate reserve and perceived exertionmethod shown to be feasible and reliable in our preliminary studies will be used to prescribemoderate intensity exercise. Cognition will be measured by the AD Assessment Scale-Cognition (ADAS-Cog) at baseline, 3, 6, 9, and 12 months. Hippocampal volume will be measured by magnetic resonance imaging (MRI) at baseline, 6, and 12 months. The sample size will give us 80% power to detect at least a 2.5-point difference in within-group changes in ADAS-Cog at 6 months for the intervention group. Results: This study is funded by the National Institutes of Health’s National Institute on Aging (NIA) from 8/1/2013 to 7/31/2018, and is currently enrolling. Findings from the study will determine the immediate and long-term effects of the cycling intervention on cognition and hippocampal volume in AD over 1 year. Conclusions: This study is testing a rigorously-designed and delivered moderate-intensity of aerobic exercise intervention in a clinical AD population. Findings will provide important data to address the critical gap in knowledge of the therapeutic effects of aerobic exercise in AD and offer a potentially effective treatment for AD.