Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): Tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers

Clinical Therapeutics

Volumn 34, Issue 3, 2012, Pages 654-667

  Tong, Gary ^a   Wang, Jun Sheng ^a   Sverdlov, Oleksandr ^a   Huang, Shu Pang ^a   Slemmon, Randy ^a   Croop, Robert ^a   Castaneda, Lorna ^a   Gu, Huidong ^a   Wong, Oi ^a   Li, Hewei ^a   Berman, Robert M ^b   Smith, Christina ^a   Albright, Charles F ^b   Dockens, Randy C ^a  

^a BRISTOL MYERS SQUIBB RESEARCH AND DEVELOPMENT   (United States)

^b BRISTOL MYERS SQUIBB   (United States)

Author keywords

A 1 40; Alzheimer's disease; Avagacestat; Gamma secretase inhibitor; Pharmacodynamic; Pharmacokinetic; Tolerability

Indexed keywords

AMYLOID BETA PROTEIN[1-40]; AVAGACESTAT; DUAL SPECIFICITY PHOSPHATASE 6; INTESTINAL TREFOIL FACTOR; PLACEBO; TRANSCRIPTION FACTOR HES 1; TREFOIL FACTOR FAMILY 3 PROTEIN; UNCLASSIFIED DRUG;

ADULT; ARTICLE; BLOOD SAMPLING; CONTROLLED STUDY; DISEASE SEVERITY; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG DETERMINATION; DRUG TOLERABILITY; HEADACHE; HUMAN; LIQUID CHROMATOGRAPHY; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NAUSEA; RANDOMIZED CONTROLLED TRIAL; RASH; SOMNOLENCE; TANDEM MASS SPECTROMETRY;

ADMINISTRATION, ORAL; ADOLESCENT; ADULT; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; BIOLOGICAL MARKERS; DOSE-RESPONSE RELATIONSHIP, DRUG; DUAL SPECIFICITY PHOSPHATASE 6; HOMEODOMAIN PROTEINS; HUMANS; MALE; OXADIAZOLES; PEPTIDE FRAGMENTS; PEPTIDES; SULFONAMIDES; YOUNG ADULT;

EID: 84863343191     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2012.01.022     Document Type: Article

References (37)

1. Grundman M., Petersen R.C., Ferris S.H., et al. Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 2004, 61:59-66.
2. Walsh S., Aisen P.S. Inflammatory processes and Alzheimer's disease. Expert Rev Neurother 2004, 4:793-798.
3. Selkoe D.J., Wolfe M.S. Presenilin: running with scissors in the membrane. Cell 2007, 131:215-221.
4. Haas C., Selkoe D.J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat Rev Mol Cell Biol 2007, 8:101-112.
5. Comery T.A., Martone R.L., Aschmies S., et al. Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 2005, 25:8898-8902.
6. Martone R.L., Zhou H., Atchison K., et al. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 2009, 331:598-608.
7. Mawuenyega K.G., Sigurdson W., Ovod V., et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010, 330:1774.
8. Pollack S.J., Lewis H. Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease. Curr Opin Investig Drugs 2005, 6:35-47.
9. Artavanis-Tsakonas S., Rand M.D., Lake R.J. Notch signaling: cell fate control and signal integration in development. Science 1999, 284:770-776.
10. Kadesch T. Notch signaling: a dance of proteins changing partners. Exp Cell Res 2000, 260:1-8.
11. Milano J., Dagenais C., Foster-Brown L., et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004, 82:341-358.
12. Wong G.T., Manfra D., Poulet F.M., et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004, 279:12876-12882.
13. Kumano K., Masuda S., Sata M., et al. Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis. Pigment Cell Melanoma Res 2008, 21:70-78.
14. Gillman K.W., Starrett J.E., Parker M.F., et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med Chem Lett 2010, 1:120-124.
15. Wright N.A., Hoffmann W., Otto W.R., et al. Rolling in the clover: trefoil factor family (TFF)-domain peptides, cell migration and cancer. FEBS Lett 1997, 408:121-123.
16. Denton R, Meredith JE, inventors. Gamma secretase Notch biomarkers. US patent US 7,989,208. August 2, 2011.
17. Weerkamp F., Luis T.C., Naber B.A., et al. Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program. Leukemia 2006, 20:1967-1977.
18. Meredith J Jr, Albright CF, Dockens RC, et al. BMS-708163, a Notchsparing GSI, decreases central Aβ in rats, dogs, and humans with a therapeutic margin relative to notch toxicity. Paper presented at: 10th International Conference on Alzheimer's and Parkinson's Diseases; March 9-13, 2011; Barcelona, Spain.
19. Siemers E., Skinner M., Dean R.A., et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005, 28:126-132.
20. Siemers E.R., Dean R.A., Friedrich S., et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 2007, 30:317-325.
21. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use International Conference on Harmonization, Accessed October 28, 2011. http://www.ich.org/products/guidelines.html.
22. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects World Medical Association General Assembly, Accessed September 30, 2011. http://www.wma.net/en/30publications/10policies/b3/index.html.
23. Gu H., Deng Y., Wang J., et al. Development and validation of sensitive and selective LC-MS/MS methods for the determination of BMS-708163, a gamma-secretase inhibitor, in plasma and cerebrospinal fluid using deprotonated or formate adduct ions as precursor ions. J Chromatogr B Analyt Technol Biomed Life Sci 2010, 878:2319-2326.
24. Hansson S.F., Andréasson U., Wall M., et al. Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients. J Alzheimers Dis 2009, 16:389-397.
25. Rainen L., Oelmueller U., Jurgensen S., et al. Stabilization of mRNA expression in whole blood samples. Clin Chem 2002, 48:1883.
26. iScript Products for Reverse Transcription Accessed November 2, 2011. http://www3.bio-rad.com/B2B/BioRad/promotional/iscript_product.jsp.
27. Lossos I.S., Czerwinski D.K., Alizadeh A.A., et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004, 29:1828-1837.
28. Lewis S.J., Heaton K.W. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997, 32:920-924.
29. Hemoccult II SENSA elite Accessed November 2, 2011. http://www.beckmancoulter.com/wsrportal/wsrportal.portal?_nfpb=true&_windowLabel=UCM_RENDERER&_urlType=render&wlpUCM_RENDERER_path=%2Fwsr%2Fdiagnostics%2Fclinical-products%2Frapid-diagnostics%2Fhemoccult-ii-sensa-elite%2Findex.htm.
30. SAS Statistical Software, Version 8.2 1999, Statistical Analysis Systems, SAS Institute Inc, Cary, NC.
31. Modern Applied Statistics with S-PLUS 1999, Springer, Berlin, Germany. 3rd ed. W.N. Venables, B.D. Ripley (Eds.).
32. Perrier D., Gibaldi M. General derivation of the equation for time to reach a certain fraction of steady state. J Pharm Sci 1982, 7:474-475.
33. Riegelman S., Collier P. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J Pharmacokinet Biopharm 1980, 8:509-534.
34. Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif.) 2001, 25:402-408.
35. Burton C.R., Meredith J.E., Barten D.M., et al. The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression. J Biol Chem 2008, 283:22992-30003.
36. Lanz T.A., Karmilowicz M.J., Wood K.M., et al. Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 2006, 319:924-933.
37. Bateman R.J., Siemers E.R., Mawuenyega K.G., et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 2009, 66:48-54.