TY - JOUR
T1 - Safety and biomarker effects of solanezumab in patients with Alzheimer's disease
AU - Farlow, Martin
AU - Arnold, Steven E.
AU - Van Dyck, Christopher H.
AU - Aisen, Paul S.
AU - Snider, B. Joy
AU - Porsteinsson, Anton P.
AU - Friedrich, Stuart
AU - Dean, Robert A.
AU - Gonzales, Celedon
AU - Sethuraman, Gopalan
AU - Demattos, Ronald B.
AU - Mohs, Richard
AU - Paul, Steven M.
AU - Siemers, Eric R.
N1 - Funding Information:
The authors thank Ms. Margaret Racke, Dr. John Hale, and Ms. Valentina Gelfanova (Eli Lilly and Company) for important technical contributions; Dr. Christopher Carlson (Eli Lilly and Company) for review of scientific content; Ms. Giedra Campbell and Ms. Karen Holdridge (Eli Lilly and Company) for assistance with manuscript preparation. This study was sponsored by Eli Lilly and Company ; M.F. receives research funds from Bristol-Myers Squibb, Danone, Elan, Eli Lilly, Forest, Janssen, Medivation, Pfizer, Novartis, Octapharma, and Sonexa ; is a consultant for Adamas, Accera, Adlyfe, Astra Zeneca, Astellas, BioRx, CoMentis, Cortex Pharm., Eisai, DS-Pharma Co. (Dainippon Sumitomo), Eli Lilly, GlaxoSmithKline, Medivation, Merck, Novartis, Noven, Octapharma, QR Pharm., Sanofi-Aventis, Schering-Plough, Suven Life Sciences Ltd., and Toyama Pharmaceuticals; is a speaker for Eisai, Forest, Janssen, Pfizer, and Novartis; and received royalty for intellectual property from Elan. S.E.A. received grant support and has been a consultant for Eli Lilly and Company and has also been supported by grants from the National Institutes of Health, Alzheimer’s Disease Cooperative Study, American College of Radiology Imaging Network, Elan Pharmaceuticals, Pfizer Incorporated, and the Ware Family Foundation . C.H.V.D. is a consultant for Bristol-Myers Squibb, GlaxoSmithKline, and Forest Laboratories. He serves as an editorial board member for Journal of Nuclear Medicine and Brain Imaging and Behavior . His research is funded by National Institutes of Health (NIH) grants #R01-AG030457-01A1, #R01-AG030457-01A1, and #UO1-AG024904 ; the Alzheimer’s Association ; and commercial support from Medivation, Abbott Laboratories, Eli Lilly and Company, Elan Pharmaceuticals, Wyeth Research, GlaxoSmithKline, Pfizer, Baxter Healthcare, Neurochem, and Bristol-Myers Squibb . Finally, he served as a legal consultant for Montstream and May, LLP. C.H.V.D.’s wife (Amy Arnsten) is a consultant for Shire Pharmaceuticals. She holds patents pertaining to guanfacine and lofexidine for behavioral disorders and receives royalty payments from Shire Pharmaceuticals for one of these. She also receives royalties from publication of the book The Neuropharmacology of Stimulant Drugs: Implications for AD/HD . Her research is funded by NIH grants #PO1-AG030004-01 and #U54RR024350-01 , NARSAD, and Shire Pharmaceuticals. P.S.A. serves on a scientific advisory board for NeuroPhage; serves as a consultant to Elan Corporation, Wyeth, Eisai Inc., Schering-Plough Corp., Bristol-Myers Squibb, Eli Lilly and Company, NeuroPhage, Merck & Co., Roche, Amgen, Genentech, Inc., Abbott, Pfizer Inc, Novartis, and Medivation, Inc.; receives research support from Pfizer Inc. , Baxter International Inc. , and the NIH (National Institute on Aging [NIA] U01-AG10483 [PI], NIA U01-AG024904 [Coordinating Center Director], NIA R01-AG030048 [PI], and R01-AG16381 [Co-I]); and has received stock options from Medivation, Inc. and NeuroPhage. B.J.S. has nothing to disclose. A.P.P. has received grant support from Baxter, Eisai, Elan, Eli Lilly and Company, Forest, Janssen, Medivation, Merck, Mitsubishi, Myriad Neurosciences, Neurochem, Ono Pharma, Pfizer, Toyama, and Wyeth ; serves as a consultant/on an advisory board for Elan, Janssen, Medivation, Transition Therapeutics, and Toyama; and serves on the speakers’ bureau for Forest. S.F., R.A.D., C.G., G.S., R.B.D., R.M., E.R.S. are employees and shareholders of Eli Lilly and Company. S.M.P. is a former employee and shareholder of Eli Lilly and Company.
PY - 2012/7
Y1 - 2012/7
N2 - Objectives: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer's disease. Cognitive measures were also obtained. Methods: In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale-cognitive portion was administered. Results: Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ 1-40 and Aβ 1-42 in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ 1-40 and Aβ 1-42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ 1-40 in CSF (P <.01), but increased unbound Aβ 1-42 in CSF in a dose-dependent manner. The Alzheimer's Disease Assessment Scale-cognitive portion was unchanged after the 12-week antibody administration. Conclusions: Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ 1-42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ 1-42 from amyloid plaques.
AB - Objectives: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer's disease. Cognitive measures were also obtained. Methods: In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale-cognitive portion was administered. Results: Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ 1-40 and Aβ 1-42 in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ 1-40 and Aβ 1-42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ 1-40 in CSF (P <.01), but increased unbound Aβ 1-42 in CSF in a dose-dependent manner. The Alzheimer's Disease Assessment Scale-cognitive portion was unchanged after the 12-week antibody administration. Conclusions: Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ 1-42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ 1-42 from amyloid plaques.
KW - Alzheimer's disease
KW - Aβ monoclonal antibody
KW - Cerebrospinal fluid immunotherapy
KW - LY2062430
KW - Solanezumab
KW - β-amyloid
UR - http://www.scopus.com/inward/record.url?scp=84863221661&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2011.09.224
DO - 10.1016/j.jalz.2011.09.224
M3 - Article
C2 - 22672770
AN - SCOPUS:84863221661
SN - 1552-5260
VL - 8
SP - 261
EP - 271
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 4
ER -