BACKGROUND: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms. OBJECTIVE: To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease. DESIGN: Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration. SETTING:Academic centers in the United States (Study 201) and England and Finland (Study 202). PATIENTS: Forty-six patients with mild to moderate Alzheimer disease. INTERVENTIONS: Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups. MAIN OUTCOME MEASURES: Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau). RESULTS: Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ. CONCLUSIONS: To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. TRIAL REGISTRATIONS clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.
RCT Entities:
BACKGROUND: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms. OBJECTIVE: To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease. DESIGN: Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration. SETTING: Academic centers in the United States (Study 201) and England and Finland (Study 202). PATIENTS: Forty-six patients with mild to moderate Alzheimer disease. INTERVENTIONS:Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups. MAIN OUTCOME MEASURES: Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau). RESULTS: Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ. CONCLUSIONS: To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. TRIAL REGISTRATIONS clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.
Authors: E Cavedo; S Lista; Z Khachaturian; P Aisen; P Amouyel; K Herholz; C R Jack; R Sperling; J Cummings; K Blennow; S O'Bryant; G B Frisoni; A Khachaturian; M Kivipelto; W Klunk; K Broich; S Andrieu; M Thiebaut de Schotten; J-F Mangin; A A Lammertsma; K Johnson; S Teipel; A Drzezga; A Bokde; O Colliot; H Bakardjian; H Zetterberg; B Dubois; B Vellas; L S Schneider; H Hampel Journal: J Prev Alzheimers Dis Date: 2014-12
Authors: S M Mills; J Mallmann; A M Santacruz; A Fuqua; M Carril; P S Aisen; M C Althage; S Belyew; T L Benzinger; W S Brooks; V D Buckles; N J Cairns; D Clifford; A Danek; A M Fagan; M Farlow; N Fox; B Ghetti; A M Goate; D Heinrichs; R Hornbeck; C Jack; M Jucker; W E Klunk; D S Marcus; R N Martins; C M Masters; R Mayeux; E McDade; J C Morris; A Oliver; J M Ringman; M N Rossor; S Salloway; P R Schofield; J Snider; P Snyder; R A Sperling; C Stewart; R G Thomas; C Xiong; R J Bateman Journal: Rev Neurol (Paris) Date: 2013-09-06 Impact factor: 2.607