Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial

JAMA Neurology

Volumn 72, Issue 11, 2015, Pages 1324-1333

  Coric, Vladimir ^a   Salloway, Stephen ^b   Van Dyck, Christopher H ^c   Dubois, Bruno ^d   Andreasen, Niels ^e   Brody, Mark ^f   Curtis, Craig ^g   Soininen, Hilkka ^h   Thein, Stephen ⁱ   Shiovitz, Thomas ^j   Pilcher, Gary ^a   Ferris, Steven ^k   Colby, Susan ^a   Kerselaers, Wendy ^a   Dockens, Randy ^a   Soares, Holly ^a   Kaplita, Stephen ^a   Luo, Feng ^a   Pachai, Chahin ^l   Bracoud, Luc ^l   Mintun, Mark ^m   Grill, Joshua D ⁿ   Marek, Ken ^o   Seibyl, John ^o   Cedarbaum, Jesse M ^a   Albright, Charles ^a   Feldman, Howard H ^p   Berman, Robert M ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

^b BUTLER HOSPITAL   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d SORBONNE UNIVERSITÉ   (France)

^e KAROLINSKA INSTITUTE   (Sweden)

^f Brain Matters Research   (United States)

^g Central Florida Pain Centers   (United States)

^h UNIVERSITY OF EASTERN FINLAND   (Finland)

ⁱ Pacific Research Network Inc   (United States)

^j California Neuroscience Research Medical Group Inc   (United States)

^k NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^l BioClinica Inc   (United States)

^m AVID RADIOPHARMACEUTICALS   (United States)

ⁿ UNIVERSITY OF CALIFORNIA   (United States)

^o INSTITUTE FOR NEURODEGENERATIVE DISORDERS   (United States)

^p UNIVERSITY OF BRITISH COLUMBIA   (Canada)

more..

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AVAGACESTAT; CALCIUM; PLACEBO; TAU PROTEIN; URIC ACID; OXADIAZOLE DERIVATIVE; SULFONAMIDE;

ADULT; AGED; ALZHEIMER DISEASE; ANXIETY DISORDER; ARTICLE; BASAL CELL CARCINOMA; BRAIN ATROPHY; BRAIN HEMORRHAGE; CALCIUM BLOOD LEVEL; CEREBROSPINAL FLUID LEVEL; CLINICAL EFFECTIVENESS; COHORT ANALYSIS; CONTROLLED STUDY; DECREASED APPETITE; DEPRESSION; DIARRHEA; DISEASE COURSE; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG SAFETY; DRUG TOLERABILITY; EDEMA; FATIGUE; FEMALE; GASTROINTESTINAL DISEASE; GLUCOSURIA; HEART DISEASE; HUMAN; KIDNEY TUBULE DISORDER; MAJOR CLINICAL STUDY; MALE; MELANOMA; MILD COGNITIVE IMPAIRMENT; MULTICENTER STUDY; NAUSEA; NON MELANOMA SKIN CANCER; NUCLEAR MAGNETIC RESONANCE IMAGING; OBSERVATIONAL STUDY; PANCOLITIS; PARALLEL DESIGN; PHASE 2 CLINICAL TRIAL; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL; RASH; SIDE EFFECT; SQUAMOUS CELL CARCINOMA; TREATMENT DURATION; TREATMENT OUTCOME; URIC ACID BLOOD LEVEL; VERY ELDERLY; VOMITING; WEIGHT REDUCTION; ATROPHY; CEREBROSPINAL FLUID; CHEMICALLY INDUCED; CLINICAL TRIAL; COGNITIVE DYSFUNCTION; DIAGNOSTIC IMAGING; PATHOLOGY; PRODROMAL SYMPTOM; SCINTISCANNING; SKIN TUMOR; TREATMENT FAILURE;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; ATROPHY; COGNITIVE DYSFUNCTION; DISEASE PROGRESSION; FEMALE; HUMANS; MALE; OXADIAZOLES; PRODROMAL SYMPTOMS; RADIONUCLIDE IMAGING; SKIN NEOPLASMS; SULFONAMIDES; TREATMENT FAILURE;

EID: 84946709627     PISSN: 21686149     EISSN: 21686157     Source Type: Journal    
DOI: 10.1001/jamaneurol.2015.0607     Document Type: Article

References (42)

1. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010;9(11):1118-1127.
2. Grober E, Hall CB, Lipton RB, Zonderman AB, Resnick SM, Kawas C. Memory impairment, executive dysfunction, and intellectual decline in preclinical Alzheimer's disease. J Int Neuropsychol Soc. 2008;14(2):266-278.
3. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5(3):228-234.
4. Price JL, McKeel DW Jr, Buckles VD, et al. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009;30(7):1026-1036.
5. Bateman RJ, Xiong C, Benzinger TL, et al; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367(9):795-804.
6. Tong G, Wang JS, Sverdlov O, et al. 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. Clin Ther. 2012;34(3):654-667.
7. Tong G, Wang JS, Sverdlov O, et al. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol. 2013;75(1):136-145.
8. Jack CR Jr, Lowe VJ, Weigand SD, et al; Alzheimer's Disease Neuroimaging Initiative. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain. 2009;132(pt 5):1355-1365.
9. Jack CR Jr, Wiste HJ, Vemuri P, et al; Alzheimer's Disease Neuroimaging Initiative. Brain β-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression frommild cognitive impairment to Alzheimer's disease. Brain. 2010;133(11):3336-3348.
10. Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430-1440.
11. Martone RL, 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(2):598-608.
12. Meredith J, Barten D, Burton C, et al. Separation of Aβ Reduction from Notch Toxicity with Gamma Secretase Inhibitors in Rats. Alzheimers Dement. 2010;6(4)(suppl):S26.
13. Meredith J, Albright CF, Dockens R, et al. BMS-708163, a notch-sparing GSI, decreases central Aβ in rats, dogs, and humans with a therapeutic margin relative to notch toxicity [abstract]. Neurodegener Dis. 2011;8(1)(suppl):S1. doi:10.1159/000327701.
14. Tong G, Castaneda L, Wang JS, et al. A study to evaluate the effects of single oral doses of BMS-708163 in the cerebrospinal fluid of healthy young men. Alzheimers Dement. 2010;6(4)(suppl):S143. doi:10.1016/j.jalz.2010.05.441.
15. Wang JS, Castaneda L, Sverdlov A, et al. A placebo-controlled, ascending, multiple-dose study to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-708163 in healthy young and elderly subjects. Alzheimers Dement. 2010;6(4)(suppl):S540. doi:10.1016/j.jalz.2010.05.1804.
16. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH guidelines. http://www.ich.org/products/guidelines.html. Accessed April 12, 2014.
17. World Medical Association. Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed March 12, 2014.
18. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183-194.
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Text Revision. 4th ed. Arlington, VA: American Psychiatric Association; 2000.
20. Wechsler D. Wechsler Memory Scale-Revised. San Antonio, TX: NCS Pearson Inc; 1987.
21. Buschke H. Cued recall in amnesia. J Clin Neuropsychol. 1984;6(4):433-440.
22. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
23. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982;140(140):566-572.
24. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Clinical Gerontology: A Guide to Assessment and Intervention. New York, NY: Haworth Press; 1986:165-173.
25. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141(11):1356-1364.
26. Berg L, Miller JP, Baty J, Rubin EH, Morris JC, Figiel G. Mild senile dementia of the Alzheimer type 4: evaluation of intervention. Ann Neurol. 1992;31(3):242-249.
27. Galasko D, Bennett DA, Sano M, Marson D, Kaye J, Edland SD; Alzheimer's Disease Cooperative Study. ADCS Prevention Instrument Project: assessment of instrumental activities of daily living for community-dwelling elderly individuals in dementia prevention clinical trials. Alzheimer Dis Assoc Disord. 2006;20(4)(suppl 3):S152-S169.
28. Buschke H, Kuslansky G, Katz M, et al. Screening for dementia with the memory impairment screen. Neurology. 1999;52(2):231-238.
29. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDAWork Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34(7):939-944.
30. Bracoud L, Berman RM, Roche F, et al. Longitudinal volumetric changes in study CN156-018, as compared to ADNI-1 [abstract P27]. J Nutr Health Aging. 2013;17(9):829.
31. Istace A, Coric V, Roche F, et al. Comparison of boundary shift integral and tensor based morphometry to assess volume changes on whole brain and lateral ventricles-application to study CN156-018 [abstract P26]. J Nutr Health Aging. 2013;17(9):828.
32. Vercauteren T, Pennec X, Perchant A, Ayache N. Symmetric log-domain diffeomorphic registration: a demons-based approach. Med Image Comput Comput Assist Interv. 2008;11(pt 1):754-761.
33. Barnes J, Boyes RG, Lewis EB, et al. Automatic calculation of hippocampal atrophy rates using a hippocampal template and the boundary shift integral. Neurobiol Aging. 2007;28(11):1657-1663.
34. Clark CM, Schneider JA, Bedell BJ, et al; AV45-A07 Study Group. Use of florbetapir-PET for imaging β-amyloid pathology. JAMA. 2011;305(3):275-283.
35. Fleisher AS, Chen K, Liu X, et al. Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol. 2011;68(11):1404-1411.
36. Fox NC, Black RS, Gilman S, et al; AN1792 (QS-21)-201 Study. Effects of A-β immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005;64(9):1563-1572.
37. Salloway S, Sperling R, Fox NC, et al; Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):322-333.
38. Milano J, McKay J, Dagenais C, et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cellmetaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 2004;82(1):341-358.
39. Proweller A, Tu L, Lepore JJ, et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res. 2006;66(15):7438-7444.
40. Doody RS, Raman R, Farlow M, et al; Alzheimer's Disease Cooperative Study Steering Committee; Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369(4):341-350.
41. Dockens R, Wang JS, Castaneda L, et al. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012;51(10):681-693.
42. Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann Neurol. 2006;59(3):512-519.