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  • Title: Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease.
    Author: Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E, AAB-001 201/202 Investigators.
    Journal: Arch Neurol; 2012 Aug; 69(8):1002-10. PubMed ID: 22473769.
    Abstract:
    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.
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