Phase 2 Safety Trial Targeting Amyloid β Production With a γ-Secretase Inhibitor in Alzheimer Disease

University of California, San Diego, La Jolla, CA 92037, USA.
Archives of neurology (Impact Factor: 7.42). 08/2008; 65(8):1031-8. DOI: 10.1001/archneur.65.8.1031
Source: PubMed


To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease.
Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial.
Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks.
Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale.
Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures.
LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration Identifier: NCT00244322.

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    • "During the last few years, various selective APP γ-secretase inhibitors have been developed (Basi et al., 2010; Fleisher et al., 2008; Probst et al., 2013) as strategic tools to reduce Aβ levels in Alzheimer's disease. So far, no study has explored the possibility to exploit γ-secretase inhibitors as a pharmacological tool to reduce the excessive levels of AICD that characterize the DS brain. "
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    ABSTRACT: Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalises AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 08/2015; 82. DOI:10.1016/j.nbd.2015.08.001 · 5.08 Impact Factor
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    • "In addition to its potential use for AD diagnosis, one possible application of measures of plasmatic Ab is the evaluation of target engagements for therapies modulating Ab synthesis. For example, treatments with gsecretase inhibitors are shown to reduce the level of Ab 40 in the plasma (Fleisher et al., 2008). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β peptide (Aβ) deposition in the brain is one of its hallmarks, and the measure of plasma Aβ is considered to be a biomarker for anti-amyloid drug efficacy in animal models of AD. However, age-associated plasmatic Aβ modulation in animal models is practically never addressed in the literature. Mouse lemur primates are used as a model of normal and AD-like cerebral aging. Here, we studied the effect of age on plasmatic Aβ in 58 mouse lemurs aged from 1 to 10 years. A subset of animals presented high plasmatic Aβ, and the proportion of animals with high plasmatic Aβ was higher in aged animals as compared with young ones. Histologic evaluation of the brain of some of these animals was carried out to assess extracellular and intracellular amyloid load. In aged lemurs, plasmatic Aβ was negatively correlated with the density of neurons accumulating deposits of Aβ.
    Neurobiology of Aging 07/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.017 · 5.01 Impact Factor
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    • "Recent reports of therapeutic strategies targeting Aβ, such as solanezumab and semagacestat, demonstrate that decreasing Aβ deposits or plasma Aβ levels after the appearance of symptoms does not improve cognitive dysfunction [6, 20]. In contrast, several reports have shown that tau is essential for Aβ-induced neuronal dysfunction in vitro and in vivo [21, 22]. "
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