NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 458-467 - 2019
Maria Z. Kounnas1, Murat S. Durakoglugil2, Joachim Herz2, William T. Comer3
1Department of Pathology, University of California, San Diego, La Jolla, CA
2Department of Molecular Genetics, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX
3NeuroGenetic Pharmaceuticals, Inc., Rancho Santa Fe, CA

Tóm tắt

AbstractIntroductionCurrently, there is no cure for Alzheimer's disease (AD), and it is widely accepted that AD is a complex disease with multiple approaches necessary to prevent and treat the disease.MethodsUsing amyloid biomarkers in human cerebrospinal fluid, pharmacokinetic, safety, and metabolism studies, we investigate the properties of NGP 555, γ‐secretase modulator, for the first time in human clinical trials.ResultsOur preclinical and clinical studies combined show beneficial effects with NGP 555 on synaptic response and amyloid cerebrospinal fluid biomarkers while avoiding negative side effects. Importantly, pharmacokinetic and pharmacodynamic parameters combined with safety outcomes indicate that NGP 555 penetrates the blood‐brain barrier and increases the ratio of amyloid‐β peptide Aβ37 and Aβ38 compared with that of Aβ42, establishing a proof of target engagement in humans in a 14 day, once‐daily oral dosing trial.DiscussionIn humans, NGP 555 has demonstrated a beneficial shift in the production of Aβ37 and Aβ38 versus Aβ42 biomarker levels in the cerebrospinal fluid while maintaining an adequate safety profile. The overall clinical goal is to achieve an optimal balance of efficacy for altering amyloid‐β peptide (Aβ) biomarkers while maintaining a safe profile so that NGP 555 can be given early in AD to prevent production of Aβ42 and accumulation of amyloid plaques, in an effort to prevent aggregation of tau and destruction of neurons and synapses resulting in cognitive decline.

Tài liệu tham khảo

Alzheimer A., 1995, An English translation of Alzheimer's 1907 paper, Uber eine eigenartige Erkankung der Hirnrinde, 90, 429 10.1038/197192b0 Terry R., 1964, Ultrastructural studies in Alzheimer's presenile studies, Am J Pathol, 44, 269 10.1016/S0928-4257(98)80035-1 10.1002/ana.21610 10.1212/WNL.0b013e3182918ca6 10.1373/clinchem.2013.202937 10.1016/j.pharmthera.2018.11.006 10.1523/JNEUROSCI.3501-06.2007 10.2174/1567205016666190301111120 10.1186/s40478-019-0664-z 10.3233/JAD-160488 10.1515/revneuro-2017-0063 10.1126/science.1072994 Golde T., 2009, Targeting Aβ and tau in Alzheimer's disease, an early interim report, Exp Neurol, 223, 252, 10.1016/j.expneurol.2009.07.035 10.2183/pjab.93.048 Lao K., 2018, Drug development for Alzheimer's disease: review, J Drug Target, 20, 1 10.1007/s40263-019-00613-7 10.2174/156802611795860942 10.1586/ern.09.24 10.1016/B978-0-12-394816-8.00004-0 10.1016/j.neulet.2019.02.011 Evin G., 2008, γ‐secretase modulators: hopes and setbacks for the future of Alzheimer's treatment, Expert Rev Neurother, 8, 1611, 10.1586/14737175.8.11.1611 10.1021/bi400377p Gijsen J., 2012, Secretase inhibitors and modulators as a disease modifying approach against Alzheimer's disease, Annu Rep Med Chem, 47, 55 10.1074/jbc.M111.305227 10.1038/nature07055 Tamayev R., 2012, Inhibition of gamma‐secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia, Mol Neurodegener, 7, 1, 10.1186/1750-1326-7-19 10.1093/toxsci/kfh254 10.1038/nature03659 Green R., 2009, Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial, JAMA, 16, 2557, 10.1001/jama.2009.1866 10.1002/jcph.249 10.1093/toxsci/kft224 10.1124/jpet.116.232256 10.1021/acs.jmedchem.5b01960 Xie L., 2019, Synthesis of pyridopyrazine‐1,6‐dione γ‐secretase modulators via selective 4‐methylimidazole N1‐ Buchwald arylation, J Org Chem, 84, 4921, 10.1021/acs.joc.8b02953 10.1016/j.bmc.2018.04.053 10.1016/j.bmc.2017.11.049 10.1021/acsmedchemlett.7b00178 10.1186/s13195-016-0199-5 10.1124/jpet.117.240861 10.1016/j.neuron.2010.08.018 Kounnas M., 2017, NGP 555, a γ‐secretase modulator, lowers the amyloid biomarker, Aβ42, in cerebrospinal fluid while preventing Alzheimer's disease amyloid pathology and cognitive decline in Rodents, Alzheimers Dement, 3, 65, 10.1016/j.trci.2016.09.003 10.1001/jamaneurol.2014.2482 10.1523/JNEUROSCI.5161-07.2008 Wang Z., 2017, Human brain‐derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP, J Neurosci, 37, 11947, 10.1523/JNEUROSCI.2009-17.2017 10.1523/JNEUROSCI.3850-04.2005 10.1074/jbc.C300239200 10.3390/ijms19061621 10.3233/JAD-2011-101065
Thông tin
Thông tin xuất bản

Alzheimer's and Dementia: Translational Research and Clinical Interventions

Tập 5

458-467

Thông tin tác giả