O4‐11‐04: ACTIVE Aβ IMMUNOTHERAPY CAD106 PHASE II DOSE‐ADJUVANT FINDING STUDY: SAFETY AND CNS BIOMARKERS
Ana Graf, Marie‐Emmanuelle Riviere, Angelika Caputo, Martin Rhys Farlow, Giovanni Marotta, Raquel Sánchez‐Valle, Philip Scheltens, J. Michael Ryan, Rik R. Vandenberghe · Alzheimer s & Dementia · 2014
CAD106 is an active Aβ immunotherapy in development for the treatment of Alzheimer's disease (AD). Previous studies showed that doses up to 150μg CAD106 induced consistent Aβ-antibody response with no major safety concerns. However, CNS biomarkers were not comprehensively assessed so far. Safety, tolerability and biomarker effects of CAD106 were assessed at doses of 150μg or 450μg in a 90-weeks dose-adjuvant finding study. Mild AD patients (MMSE 20-26) received up to 7injections of CAD106 or placebo (7:1 ratio) over 60 weeks with a full evaluation at week 78. Safety and antibody response compared CAD106 overall vs placebo; while biomarker analyses compared CAD106 strong serological responders (SSRs) vs non-responders + placebo (controls). 121 patients were enrolled to receive CAD106 (n=106) or placebo (n=15) and 8.5% vs 6.7% discontinued the study for a safety related reason, respectively. Two-thirds of CAD106-treated patients (150μg: 54%, 450μg: 76%) met the criteria for SSRs. Three SAEs were assessed as related to study medication by the investigator: acute psychosis, allergic dermatitis and atrial fibrillation. A total of five patients, all SSRs, had amyloid-related imaging abnormalities (ARIA), 4 with ARIA-H and 1 with ARIA-E, and all remained asymptomatic. Brief and self-limited injection-related reactions were observed in the majority of patients on active treatment. Within CAD106 group, signal with 18 F-florbetapir amyloid PET (SUVR of the global cortical region) correlated strongly (r= -0.8) with the AUC of Aβ-IgG titers over 78 weeks. Amyloid load decreased over time in SSRs (n=11) but not in controls (n=4) with a group difference of -3.46% (95%CI: -31.04%, 24.12%). P-tau levels decreased in SSRs (n=20) vs controls (n=8), with a group difference of -5.13pg/mL (95%CI: -12.25, 1.99). Reduction in brain volume was more pronounced in SSRs (n=54) over controls (n=22) with a group difference for whole brain of -0.58% change from baseline (95%CI: -1.72, 0.55). No treatment effect was detected on the clinical scales for SSRs (n=51) vs controls (n=14). There were no unexpected safety findings related to the long-term exposure to CAD106-induced antibodies over 90 weeks. The pattern of biomarker data is consistent with the CNS activity of CAD106-induced antibodies in humans.