Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study

Background Immunotherapy targeting the amyloid beta (A beta) peptide is a potential strategy to slow the progression of Alzheimer's disease. We aimed to assess the safety and tolerability of CAD106, a novel active A beta immunotherapy for patients with Alzheimer's disease, designed to induce N-terminal A beta-specific antibodies without an A beta-specific T-cell response. Methods We did a phase 1, double-blind, placebo-controlled, 52-week study in two centres in Sweden. Participants, aged 50-80 years, with mild-to-moderate Alzheimer's disease were entered into one of two cohorts according to time of study entry and then randomly allocated (by use of a computer-generated randomisation sequence) to receive either CAD106 or placebo (4:1; cohort one received CAD106 50 mu g or placebo, cohort two received CAD106 150 mu g or placebo). Each patient received three subcutaneous injections. All patients, caregivers, and investigators were masked to treatment allocation throughout the study. Primary objectives were to assess the safety and tolerability of CAD106 and to identify the A beta-specific antibody response. Safety assessment was done by recording of all adverse events, assessment of MRI scans, physical and neurological examinations, vital signs, electrocardiography, electroencephalography, and laboratory analysis of blood and CSF. Patients with A beta-IgG serum titres higher than 16 units at least once during the study were classified as responders. This study is registered with ClinicalTrials.gov, number NCT00411580. Findings Between August, 2005, and March, 2007, we randomly allocated 31 patients into cohort one (24 patients to CAD106 treatment and seven to placebo) and 27 patients into cohort two (22 patients to CAD106 treatment and five to placebo). 56 of 58 patients reported adverse events. In cohort one, nasopharyngitis was the most commonly reported adverse event (10 of 24 CAD106-treated patients). In cohort two, injection site erythema was the most commonly reported adverse event (14 of 22 CAD106-treated patients). Overall, nine patients reported serious adverse events-none was thought to be related to the study drug. We recorded no clinical or subclinical cases of meningoencephalitis. 16 of 24 (67%) CAD106-treated patients in cohort one and 18 of 22 (82%) in cohort two developed A beta antibody response meeting pre-specified responder threshold. One of 12 placebo-treated patients (8%) had A beta-IgG concentrations that qualified them as a responder. Interpretation Our findings suggest that CAD106 has a favourable safety profile and acceptable antibody response in patients with Alzheimer's disease. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106. Funding Novartis Pharma AG.