title: The γ-Secretase Modulator, BMS-932481, Modulates Aβ Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers.
abstract: The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Aβ; in CSF, modest decreases in total Aβ were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF Aβ42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aβ lowering in Alzheimer's disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer's disease and other indications.
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.) holly.soares@bms.com.
authors.forename: Holly D
authors.initials: HD
authors.lastname: Soares
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Maciej
authors.initials: M
authors.lastname: Gasior
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Flora
authors.initials: F
authors.lastname: Berisha
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Michael T
authors.initials: MT
authors.lastname: Furlong
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Joseph
authors.initials: J
authors.lastname: Raybon
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Francis
authors.initials: F
authors.lastname: Sweeney
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Naiyu
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Billy
authors.initials: B
authors.lastname: Akinsanya
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Berman
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: John
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Dieter M
authors.initials: DM
authors.lastname: Drexler
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Charlie F
authors.initials: CF
authors.lastname: Albright
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ahlijanian
authors.affiliation: Bristol-Myers Squibb, Lawrence Township, New Jersey (H.D.S., J.R., K.A.L., N.Z., B.A., J.M., J.E.M., M.A.); Teva Pharmaceuticals, Frazer, Pennsylvania (M.G.); Bristol-Myers Squibb, Wallingford, Connecticut (J.H.T., L.A.T., R.E.O., D.M.D., C.F.A., M.K.A.); GSK Consumer Healthcare, Parsippany, New Jersey (J.-S.W.); Eisai, Woodcliff Lake, New Jersey (Q.H.); Kyowa Hakko Kirin Pharma, Princeton, New Jersey (F.B.); FORUM Pharmaceuticals, Waltham, Massachusetts (M.T.F.); Pfizer Worldwide Research and Development, Groton, Connecticut (F.S.); and Biohaven Medical Services, New Haven, Connecticut (R.M.B.).
authors.forename: Malaz
authors.initials: M
authors.lastname: AbuTarif
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid; D000814:Aniline Compounds / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C000619244:7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta(d)pyrimidine-2,4-diamine; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011743:Pyrimidines; D053829:Amyloid Precursor Protein Secretases