Michio Kanekiyo, United States of America
Eisai Inc NBGAuthor Of 3 Presentations
PRELIMINARY AMYLOID PET ANALYSIS IN BAN2401 PHASE 2 OPEN-LABEL EXTENSION IN SUBJECTS WHO PARTICIPATED IN THE CORE IMAGING SUBGROUP
Abstract
Aims
To evaluate preliminary findings for BAN2401, a humanized IgG1 monoclonal antibody that selectively binds Aβ protofibrils, to evaluate the longitudinal amyloid positron emission tomography (PET) findings in subjects who participated in the Core amyloid imaging subgroup.
Methods
A total of 39 subjects who participated in the Core imaging subgroup are evaluated in the Open Label Extension (OLE) imaging subgroup (Core allocation: placebo:10; 10 mg/kg monthly:19; 10 mg/kg biweekly:10). All subjects received 10 mg/kg biweekly for up to 12 months in the OLE. All subjects were amyloid positive at baseline in the core study based on PET visual read. Piecewise regression analyses were conducted on amyloid PET standard uptake value ratio (SUVr) over the 18-month core period, at baseline of the OLE, and over 12 months during the OLE.
Results
Reductions were dependent on Core treatment assignment and PET SUVr at OLE baseline, with model-estimated slope for change from baseline SUVr of -0.026 in Core placebo-treated subjects, compared to -0.004 in Core 10 mg/kg biweekly-treated subjects over the 12-month OLE. Change from core baseline point estimate SUVr values for Core placebo-treated subjects were 0.05022, -0.027, -0.104, and -257 at OLE baseline, 3, 6, and 12 months, respectively, in the OLE. Point estimate SUVr values for Core BAN2401-treated subjects changed less relative to OLE baseline over the 12-month OLE.
Conclusions
Results from this preliminary analysis suggest that 10 mg/kg biweekly BAN2401 elicits rapid reduction of brain amyloid that is apparent as early as 3 months of treatment.
A FULLY AUTOMATED PLASMA ABETA ASSAY INCORPORATING APOE4 STATUS PREDICTS AMYLOID POSITIVITY DETERMINED BY A CENTILOID THRESHOLD OF AMYLOID PET
Abstract
Aims
Amyloid pathology is a defining feature of Alzheimer’s disease (AD). Amyloid positron emission tomography (PET) is used to assess amyloid pathology, but its use may be limited by cost and accessibility. Recently, we developed plasma Aβ1-40 and Aβ1-42 immunoassays on our fully automated system (HISCLTM series). Here, we evaluated the performance of our plasma immunoassay to predict amyloid positivity defined by a centiloid threshold.
Methods
149 samples were assessed from the Eisai Elenbecestat Phase 3 program who underwent amyloid PET. The centiloid cut point of 32.20 was determined by predicting amyloid positivity defined by visual read and maximizing the Youden index. To assess the overall performance of plasma Aβ1-42/Aβ1-40 ratio, area under the curve (AUC) was obtained by performing receiver operating characteristic (ROC) analysis using logistic regression. The model incorporating APOE4 status was also evaluated. Furthermore, correlation between plasma Aβ1-42/Aβ1-40 ratio and centiloids was assessed.
Results
The plasma Aβ1-42/Aβ1-40 ratio predicted amyloid PET positivity with an AUC of 0.82 and a sensitivity and specificity equal to 78%. Including APOE4 status as a predictor increased the overall performance (AUC = 0.87), and the sensitivity and specificity were 94% and 71%, respectively. The plasma Aβ1-42/Aβ1-40 ratio was also found to correlate with centiloids values (Spearman rank correlation coefficient = -0.57).
Conclusions
We have observed plasma Aβ1-42/Aβ1-40 ratio can predict amyloid pathology. Incorporating APOE4 status in addition to plasma Aβ1-42/Aβ1-40 ratio achieved high predictive performance, with a high sensitivity. To further assess clinical utility of our assay system, additional sample sets will be evaluated.
EFFICACY AND SAFETY OF ELENBECESTAT IN SUBJECTS WITH EARLY ALZHEIMER'S DISEASE: RESULTS FROM THE MISSIONAD PHASE 3 PROGRAM
Abstract
Aims
To evaluate the BACE inhibitor elenbecestat in early Alzheimer’s Disease (EAD).
Methods
The MissionAD program comprised two randomized, placebo-controlled phase 3 studies. Patients with EAD were randomized 1:1 to either once-daily elenbecestat (50 mg) or placebo for 24 months. The primary endpoint was CDR-SB at 24 months in the combined studies. Key secondary endpoints included AD Composite Score (ADCOMS) and amyloid PET.
Results
Following recommendation of the elenbecestat DSMB, the studies were terminated early due to an unfavourable risk-benefit ratio. 2209 patients were treated (elenbecestat:1101;placebo:1108) and 189 had a 24-month CDR assessment. No differences were observed in least squares (LS) mean [SE] change from baseline in CDR-SB at 24 months (elenbecestat: 1.99 [0.146]; placebo: 2.17 [0.142]; LS mean difference [95% CI]: -0.17 [-0.57, 0.22]). For ADCOMS at 24 months, no differences were observed in LS Mean (SE) change from baseline (elenbecestat: 0.23 [0.015]; placebo: 0.24 [0.014]; LS mean difference [95% CI]: -0.02 [-0.06, 0.02]). LS mean (SE) change from baseline in amyloid PET centiloids at 24 months was -5.02 (2.046) for elenbecestat and 7.81 (2.500) for placebo (LS mean differences [95% CI] was –12.83 [-18.79, -6.88], nominal p<0.001). Incidence of adverse events were similar between groups with lymphopenia, rash, dizziness, weight loss, and abnormal dreams occurring more frequently with elenbecestat.
Conclusions
There was no evidence of a treatment effect on CDR-SB or ADCOMS for elenbecestat in the early terminated MissionAD studies.