PMID- 25918556 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20150428 LR - 20220408 IS - 1758-9193 (Print) IS - 1758-9193 (Electronic) VI - 7 IP - 1 DP - 2015 TI - Long-term treatment with active Abeta immunotherapy with CAD106 in mild Alzheimer's disease. PG - 23 LID - 10.1186/s13195-015-0108-3 [doi] LID - 23 AB - INTRODUCTION: CAD106 is designed to stimulate amyloid-beta (Abeta)-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 150mug CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 mug 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 Abeta-specific antibody response in serum and Abeta-specific T-cell response (core only). Comparable Abeta-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 Abeta-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Abeta1-6 nor Abeta1-42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. CONCLUSIONS: No unexpected safety findings or Abeta-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Abeta-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. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00733863, registered 8 August 2008; NCT00795418, registered 10 November 2008; NCT00956410, registered 10 August 2009; NCT01023685, registered 1 December 2009. FAU - Farlow, Martin R AU - Farlow MR AD - Department of Neurology, Indiana University School of Medicine, 355 West 16th Street, Suite 4700, Indianapolis, IN 46202 USA. FAU - Andreasen, Niels AU - Andreasen N AD - Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, Novum, Huddinge, SE-141 57 Stockholm Sweden ; Karolinska University Hospital Huddinge, Geriatric Clinic, Clinical Trial Unit, SE-141 86 Stockholm, Sweden. FAU - Riviere, Marie-Emmanuelle AU - Riviere ME AD - Novartis Pharma AG, Basel, CH-4002 Switzerland. FAU - Vostiar, Igor AU - Vostiar I AD - Novartis Pharma AG, Basel, CH-4002 Switzerland. FAU - Vitaliti, Alessandra AU - Vitaliti A AD - Novartis Pharma AG, Basel, CH-4002 Switzerland. FAU - Sovago, Judit AU - Sovago J AD - Novartis Pharma AG, Basel, CH-4002 Switzerland. FAU - Caputo, Angelika AU - Caputo A AD - Novartis Pharma AG, Basel, CH-4002 Switzerland. FAU - Winblad, Bengt AU - Winblad B AD - Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, Novum, Huddinge, SE-141 57 Stockholm Sweden ; Karolinska University Hospital Huddinge, Geriatric Clinic, Clinical Trial Unit, SE-141 86 Stockholm, Sweden. FAU - Graf, Ana AU - Graf A AD - Novartis Pharma AG, Basel, CH-4002 Switzerland. LA - eng SI - ClinicalTrials.gov/NCT00733863 SI - ClinicalTrials.gov/NCT00795418 SI - ClinicalTrials.gov/NCT00956410 SI - ClinicalTrials.gov/NCT01023685 PT - Journal Article DEP - 20150427 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 PMC - PMC4410460 EDAT- 2015/04/29 06:00 MHDA- 2015/04/29 06:01 PMCR- 2015/04/27 CRDT- 2015/04/29 06:00 PHST- 2014/07/07 00:00 [received] PHST- 2015/02/19 00:00 [accepted] PHST- 2015/04/29 06:00 [entrez] PHST- 2015/04/29 06:00 [pubmed] PHST- 2015/04/29 06:01 [medline] PHST- 2015/04/27 00:00 [pmc-release] AID - 108 [pii] AID - 10.1186/s13195-015-0108-3 [doi] PST - epublish SO - Alzheimers Res Ther. 2015 Apr 27;7(1):23. doi: 10.1186/s13195-015-0108-3. eCollection 2015.