Safety and biomarker effects of solanezumab in patients with Alzheimer's disease.
OBJECTIVE
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.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
Martin
M
Farlow
Steven E
SE
Arnold
Christopher H
CH
van Dyck
Paul S
PS
Aisen
B Joy
BJ
Snider
Anton P
AP
Porsteinsson
Stuart
S
Friedrich
Robert A
RA
Dean
Celedon
C
Gonzales
Gopalan
G
Sethuraman
Ronald B
RB
DeMattos
Richard
R
Mohs
Steven M
SM
Paul
Eric R
ER
Siemers
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D011569:Psychiatric Status Rating Scales; D011725:Pyridines; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome
C473191:6-iodo-2-(4'-dimethylamino-)phenyl-imidazo(1,2-a)pyridine; D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D010446:Peptide Fragments; D011725:Pyridines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C550616:solanezumab