Georges Imbert

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 β (Aβ) peptide is a potential strategy to slow the progression of Alzheimers disease. We aimed to assess the safety and tolerability of CAD106, a novel active Aβ immunotherapy for patients with Alzheimers disease, designed to induce N-terminal Aβ-specific antibodies without an Aβ-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 Alzheimers 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 μg or placebo, cohort two received CAD106 150 μg 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 Aβ-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 Aβ-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 Aβ antibody response meeting pre-specified responder threshold. One of 12 placebo-treated patients (8%) had Aβ-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 Alzheimers disease. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106. FUNDING Novartis Pharma AG.

Dose-dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship.

Examine the efficacy of a competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonist, selurampanel (BGG492), in the human photostimulation model.

Aβ-specific antibodies induced by active immunotherapy CAD106 engage Aβ in plasma in AD patients

contact with the interstitial fluid of the brain, allowing for the analysis of biochemical changes that may be related to the disease. The levels of soluble amyloid precursor protein (sAPP) alpha and beta in the CSF have both been investigated as potential biomarkers for AD. Some studies have suggested the levels of sAPPb are lower in subjects with AD, other reports have shown that both sAPPa and sAPPb are increased in AD subjects. Potentially the lack of consistency in these results could be due to fluctuations in the levels of sAPP in the CSF. Intrasubject CSF levels of Ab have been shown to significantly increase when sampling occurred frequently over 24 hours. To address this, we have examined CSF samples taken multiple times over a 24 hour period from subjects with AD or from age-matched controls.Methods: CSF samples were collected by lumbar drain with an indwelling catheter at 0h,1h,4h,8h,12h,18h and 24h during a 24-hour period from 15mild-to-moderate AD patients and 7 non-demented age matched control subjects (CT). sAPPa and sAPPb were measured usingMSD duplex electro chemiluminescence assays.Results:Both sAPPa and sAPPb were detectable in CSF from mild-to-moderate AD and CT subjects. sAPPa and sAPPb levels in AD CSF did not show significant diurnal fluctuations across the time points during a 24-hour period, however, far more variability was observed in CSF from age-matched controls. The CV across the time points was approximately 10% for AD subjects, and 40% for age-matched controls. On average, the levels of both sAPPa and sAPPb were lower in AD subjects relative to age-matched controls at all time points measured. Conclusions:Our results show levels of sAPPa and sAPPbwere consistent across multiple time points in subjects with AD, however they were variable in CSF of age-matched controls. The source of the variability in sAPP CSF levels in control subjects is not known, however, the results suggest caution should be used for employing these analytes as diagnostic biomarkers for determining the presence of Alzheimer’s disease.

Antibody immune response in cynomolgus monkeys following treatment with the active Aß immunotherapy CAD106

terms of their efficacy or to discover new ones. Methods: In pursuit of better caspase-3 inhibitors, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of caspase-3 inhibitors using molecular modeling software WIN CAChe 6.1 and statistical software STATISTICA. Results: The present study results in partition coefficient (log P), conformational energy (CME), and lowest unoccupied molecular orbital energy (ELUMO) as optimum physico-chemical properties which determine the caspase-3 inhibitory activity. Conclusions: On the basis of above study a new series of caspase-3 inhibitors has been designed with greater caspase-3 inhibitory activity. After synthesizing these compounds, it can be hypothesized that biological evaluation of these compounds would prove to be effective in addressing neurodegenerative disorders.