Persistence of BAN2401-Mediated Amyloid Reductions Post-Treatment: A Preliminary Comparison of Amyloid Status Between the Core Phase of BAN2401-G000-201 and Baseline of the Open-Label Extension Phase in Subjects with Early Alzheimer’s Disease Chad J. Swanson, Yong Zhang, Shobha Dhadda, Jinping Wang, June Kaplow, Heather Bradley, Martin Rabe, Keiichiro Totsuka, Robert Lai, Robert Gordon, Lynn D. Kramer Dataset updated since abstract submission 1
Declaration of Interests / Disclosures Presenter: Chad J. Swanson, PhD Dr. Swanson is an employee of Eisai Inc. 2
BAN2401-G000-201: Global* Phase 2b Population Design Endpoints • Early AD: Duration and Size: 18 months and approximately Primary Endpoint (12 months Using Bayesian 800 subjects Statistics) MCI due to AD (MCI) or • Treatment: 6 arms (as well as IAs) Mild Alzheimer’s dementia ( mAD) (1 Pbo, 5 dose arms, 2 regimens) • ADCOMS as clinical outcome assessment (NIA-AA Criteria) – All subjects received biweekly infusions to maintain the blind • Amyloid pathology confirmed by amyloid PET or CSF Secondary Endpoints – All subjects remained on the same randomized dose throughout dosing (18-month Final Analysis Using Conventional • MMSE range: 22-30 Statistics [MMRM]) – Active dose arms/regimen: • CDR global range: 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg • Change from baseline in PET SUVr (amyloid 0.5 (MCI); 0.5-1.0 (mAD) biweekly, 10 mg/kg monthly, 10 mg/kg biweekly load) • Periodic blinded, automated Interim Analyses (IA) • Conversion from amyloid positive to negative for efficacy/futility (visual read) – Computer generated algorithm allocates more • Change from baseline in ADCOMS subjects to the best dose(s) at each IA based on • Change from baseline in ADAS-Cog ADCOMS 12 month data • Change from baseline in CDR-SB • Change from baseline in CSF measures *NA, EU, Asia Pacific regions 3
Overall Summary of Study 201 Core Data PET SUVr • At 12 months, BAN2401 (10 mg/kg biweekly dose) showed a 64% probability Global Cortical Average Vs. WC Reference to be better than placebo by 25% on ADCOMS 0.05 Adjusted mean change from baseline (±SE) 0.00 • Missed the 80% pre-specified threshold for the primary endpoint – 0.05 IMPROVEMENT – 0.10 • At 18 months, BAN2401 (10 mg/kg biweekly dose) showed a 76% probability – 0.15 to be better than placebo by 25% on ADCOMS – 0.20 • At 18-months, BAN2401 (10 mg/kg biweekly dose) reduced brain – 0.25 amyloid and slowed decline in cognition and function according to – 0.30 Placebo MMRM analyses: 10 mg/kg monthly – 0.35 0.30 reduction in PET SUVr 10 mg/kg bi-weekly – 0.40 • Brain Amyloid: 0.3 SUVr reduction (Mean Baseline 1.37; below threshold on average) 12 18 0 ADCOMS • ADCOMS: 30%-less decline Adjusted mean change from baseline Clinical separation observed • ADAS-cog: 47%-less decline as early as 6 months • CDR-SB: 26%-less decline WORSENING 30% less decline (± SE) • BAN2401 was generally well-tolerated, with ARIA-E incidence <10% at the highest dose of 10 mg/kg biweekly • These results and others prompted the initiation of an Open Label Extension (OLE) Similar results for CDR-SB and ADAS-cog Presented at the Clinical Trials on Alzheimer’s Disease Conference 2018; Barcelona, Spain. October 25, 2018 4 Analysis visit (months)
Study 201 Open Label Extension (OLE) Population and Group Endpoints Potential OLE Limitations • Population: • Not random sampling – some Key assessments/comparisons: • Subjects from 57 sites in subjects may have been more likely • Amyloid PET at baseline OLE the 201 trial to return than others compared with last PET at 18 • Time off drug between end of Core months in core study subset • Treatment: and OLE Baseline (Gap Period) not • Clinical assessments (ADCOMS* 1 , • All subjects receive uniform across returning subjects ADAS-cog* 2 , CDR-SB* 3 ) at 10mg/kg biweekly (and no limit) baseline OLE compared with last • Distribution of Core treatment assessment at 18 months in core Objectives assignments across returning study subjects • Plasma biomarkers such as Aβ1 - • Primary: 42, NfL, t-tau, and p181-tau, and • Long-term safety and However Note: p217-tau tolerability • The blind has NOT been broken at • Longitudinal amyloid PET (3, 6, 12, site and subject levels 18, and 24 months • Secondary/Exploratory: • Clinical assessments collected at • Assess whether treatment 6,12,18, and 24 months treatment effect of BAN2401 in Core is maintained at OLE Baseline *1: ADCOMS: Alzheimer’s Disease Composite Score *2: CDR-SB: Clinical Dementia Rating, sum of boxes *3: ADAS-cog: 5 Alzheimer’s Disease Assessment Scale– cognitive subscale; Gap Period: time off drug between end of Core and OLE Baseline
Study 201 OLE Objectives Objectives for this Presentation: • To assess changes in brain amyloid levels, as measured by amyloid PET, during Gap Period • To assess changes in cognition during Gap Period Analytical Methods: • Piece-wise regression analyses for Core Phase, and during Gap Period for all subjects who participate in OLE for a given measure • Duration of the Gap Period (time off drug) and Core treatment assignment were included as factors in the model 6
Study 201 OLE Enrollment and Demographics • 856 Subjects Randomized/Dosed in Core • LPO Core: August 2018 • Subjects were rescreened • First OLE subject screened: December, 2018 7
Baseline Characteristics For Subjects Dosed in OLE Gap Period (Time off treatment between Core and OLE Baseline) Cor Core e Tx OLE Baseline 18-month Core Core Baseline 10 mg/kg 10 mg/kg Placebo 10 mg/kg 10 mg/kg Placebo 10 mg/kg 10 mg/kg Placebo 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg biweekly (n) monthly (n) (n) biweekly (n) monthly (n) (n) biweekly (n) monthly (n) (n) Placebo (n) Placebo (n) Placebo (n) biweekly (n) monthly (n) biweekly (n) monthly (n) biweekly (n) monthly (n) 0.351 ± 0.155 0.387 ± 0.135 0.334 ± 0.129 0.616 ± 0.394 0.659 ± 0.386 0.643 ± 0.345 0.408 ± 0.240 0.452 ± 0.242 0.506±0.256 ADCOMS ADCOMS ADCOMS (35) (52) (37) (33) (49) (35) (31) (49) (35) 20.6 ± 8.3 21.5 ± 7.0 20.9 ± 6.4 28.8 ± 14.0 31.2 ± 15.8 32.8 ± 15.8 21.6 ± 9.7 23.8 ± 11.7 25.6±10.9 ADAS-cog ADAS-cog ADAS-cog (35) (52) (37) (31) (48) (35) (32) (49) (36) 2.84 ± 1.33 3.16 ± 1.28 2.55 ± 1.14 5.19 ± 4.02 5.36 ± 3.37 4.96 ± 3.23 3.26 ± 2.04 3.56 ± 2.08 3.83±1.95 CDR-SB CDR-SB CDR-SB (35) (52) (37) (35) (52) (36) (33) (50) (35) 25.5 ± 2.5 25.8 ± 2.5 26.0 ± 2.5 24.2 ± 4.6 24.4 ± 4.2 20.7 ± 6.5 21.0 ± 7.1 20.8 ± 6.6 24.3±4.5 MMSE MMSE MMSE (35) (52) (37) (34) (50) (36) (35) (52) (36) 1.31 ± 0.17 1.05 ± 0.12 1.13 ± 0.13 1.08 ± 0.11 1.17 ± 0.15 1.37 ± 0.10 1.37 ± 0.18 1.28 ± 0.19 1.31±0.21 PET SUVR* PET SUVR* PET SUVR* (10) (11) (19) (9) (12) (19) (12) (19) (10) 8 *n is the number of subjects who were enrolled in Core PET substudy and now enrolled in OLE
Changes in Amyloid PET SUVr Across All Doses: Study 201 Core Versus OLE Baseline Longitudinal amyloid PET was a sub study in the Core Longitudinal amyloid PET was a sub study in the Core IMPROVEMENT Piecewise regression by treatment; Core phase model: change from Core baseline = slope*month from baseline; Gap model: change from Core 18m = slope*month from 18m 9 OLE Baseline at 24 mo off drug for illustrative purposes (average time off drug for BAN-treated subjects); Gap Period: time off drug between end of Core Phase and Baseline OLE
Change in Amyloid PET SUVr in Both 10 mg/kg Groups: Study 201 Core Versus OLE Baseline IMPROVEMENT Gap Period (Time off treatment between Core and OLE Baseline) Piecewise regression by treatment; Core phase model: change from Core baseline = slope*month from baseline; Gap model: change from Core 18m = slope*month from 18m. Thick lines are predicted change from Core baseline; Gap Period: time off drug between end of Core Phase and Baseline OLE; OLE Baseline at 24 mo off drug for illustrative purposes (average time off drug for BAN-treated subjects
Change from baseline ADCOMS: Piecewise regression analyses – Changes in ADCOMS Across All Doses: two regressions lines were fitted , one for core period, one for Study 201 Core Versus OLE Baseline WORSENING Piecewise regression by treatment; Core phase model: change from Core baseline = slope*month from baseline; Gap model: change from Core 18m = slope*month from 18m 11 OLE Baseline at 24 mo off drug for illustrative purposes (average time off drug for BAN-treated subjects); Gap Period: time off drug between end of Core Phase and Baseline OLE
Change in ADCOMS in Both 10 mg/kg Groups: Study 201 Core Versus OLE Baseline WORSENING Gap Period (Time off treatment between Core and OLE Baseline) Cor Core Tx Piecewise regression by treatment; Core phase model: change from Core baseline = slope*month from baseline; Gap model: change from Core 18m = slope*month from 18m. Thick lines are predicted change from Core baseline; 12 OLE Baseline at 24 mo off drug for illustrative purposes (average time off drug for BAN-treated subjects); Gap Period: time off drug between end of Core Phase and Baseline OLE
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