Browsing by Author "Graf, Ana"

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    Active Aβ immunotherapy CAD106 in Alzheimer's disease: A phase 2b study
    (Elsevier, 2017-01) Vandenberghe, Rik; Riviere, Marie-Emmanuelle; Caputo, Angelika; Sovago, Judit; Maguire, R. Paul; Farlow, Martin; Marotta, Giovanni; Sanchez-Valle, Raquel; Scheltens, Philip; Ryan, J. Michael; Graf, Ana; Department of Neurology, School of Medicine
    Introduction This randomized, double-blind, placebo-controlled, 90-week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer's disease. Methods One hundred twenty-one patients received up to seven intramuscular injections of CAD106 (150 μg or 450 μg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. Results CAD106 induced strong serological responses (amyloid-beta [Aβ]–Immunoglobuline G[IgG]) in 55.1% (150 μg) and 81.1% (450 μg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7–33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2–31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid-related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aβ-IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD106-treated patients (r = −0.84, P = .0004). Decrease in cortical gray-matter volume from baseline to week 78 was larger in SSRs than in controls (P = .0077). Discussion Repeated CAD106 administration was generally well tolerated. CAD106 450 μg with alum adjuvant demonstrated the best balance between antibody response and tolerability.
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    Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease
    (BioMed Central, 2015) Farlow, Martin R.; Andreasen, Niels; Riviere, Marie-Emmanuelle; Vostiar, Igor; Vitaliti, Alessandra; Sovago, Judit; Caputo, Angelika; Winblad, Bengt; Graf, Ana; Department of Neurology, IU School of Medicine
    Introduction: CAD106 is designed to stimulate amyloid-β (Aβ)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. Methods: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer’s disease (AD) aged 40 to 85 years. Patients were randomized to receive 150μg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 μg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aβ-specific antibody response in serum and Aβ-specific T-cell response (core only). Comparable Aβ-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. Results: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aβ-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aβ1–6 nor Aβ1–42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. Conclusions: No unexpected safety findings or Aβ-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aβ-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD.