Persistence of BAN2401-Mediated Amyloid Reductions Post-Treatment: - - PowerPoint PPT Presentation

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

1

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

Declaration of Interests / Disclosures

Presenter: Chad J. Swanson, PhD

• Dr. Swanson is an employee of Eisai Inc.

2

BAN2401-G000-201: Global* Phase 2b

3 *NA, EU, Asia Pacific regions

Endpoints

Primary Endpoint (12 months Using Bayesian Statistics) (as well as IAs)

• ADCOMS as clinical outcome assessment

Secondary Endpoints (18-month Final Analysis Using Conventional Statistics [MMRM])

• Change from baseline in PET SUVr (amyloid

load)

• Conversion from amyloid positive to negative

(visual read)

• Change from baseline in ADCOMS
• Change from baseline in ADAS-Cog
• Change from baseline in CDR-SB
• Change from baseline in CSF measures

Design

• Duration and Size: 18 months and approximately

800 subjects

• Treatment: 6 arms

(1 Pbo, 5 dose arms, 2 regimens) – All subjects received biweekly infusions to maintain the blind – All subjects remained on the same randomized dose throughout dosing – Active dose arms/regimen: 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly

• Periodic blinded, automated Interim Analyses (IA)

for efficacy/futility – Computer generated algorithm allocates more subjects to the best dose(s) at each IA based on ADCOMS 12 month data

Population

Early AD: MCI due to AD (MCI) or Mild Alzheimer’s dementia (mAD) (NIA-AA Criteria)

• Amyloid pathology confirmed by amyloid PET
• r CSF
• MMSE range: 22-30
• CDR global range:

0.5 (MCI); 0.5-1.0 (mAD)

Overall Summary of Study 201 Core Data

4

• At 12 months, BAN2401 (10 mg/kg biweekly dose) showed a 64% probability

to be better than placebo by 25% on ADCOMS

• Missed the 80% pre-specified threshold for the primary endpoint
• At 18 months, BAN2401 (10 mg/kg biweekly dose) showed a 76% probability

to be better than placebo by 25% on ADCOMS

• At 18-months, BAN2401 (10 mg/kg biweekly dose) reduced brain

amyloid and slowed decline in cognition and function according to MMRM analyses:

• Brain Amyloid: 0.3 SUVr reduction (Mean Baseline 1.37; below threshold on average)
• ADCOMS: 30%-less decline
• ADAS-cog: 47%-less decline
• CDR-SB: 26%-less decline
• 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)

IMPROVEMENT

0.05 0.00 –0.05 –0.10 –0.15 –0.20 –0.25 –0.30 –0.35

Adjusted mean change from baseline (±SE)

Placebo 10 mg/kg monthly 10 mg/kg bi-weekly

PET SUVr Global Cortical Average Vs. WC Reference

–0.40 12 18

30% less decline WORSENING

Adjusted mean change from baseline (± SE) Analysis visit (months)

0.30 reduction in PET SUVr

Similar results for CDR-SB and ADAS-cog

Clinical separation observed as early as 6 months ADCOMS

Presented at the Clinical Trials on Alzheimer’s Disease Conference 2018; Barcelona, Spain. October 25, 2018

• Population:
• Subjects from 57 sites in

the 201 trial

• Treatment:
• All subjects receive

10mg/kg biweekly Key assessments/comparisons:

• Amyloid PET at baseline OLE

compared with last PET at 18 months in core study subset

• Clinical assessments (ADCOMS*1,

ADAS-cog*2, CDR-SB*3) at baseline OLE compared with last assessment at 18 months in core study

• Plasma biomarkers such as Aβ1-

42, NfL, t-tau, and p181-tau, and p217-tau

• Longitudinal amyloid PET (3, 6, 12,

18, and 24 months

• Clinical assessments collected at

6,12,18, and 24 months treatment

Population and Group Endpoints

*1: ADCOMS: Alzheimer’s Disease Composite Score *2: CDR-SB: Clinical Dementia Rating, sum of boxes *3: ADAS-cog: Alzheimer’s Disease Assessment Scale–cognitive subscale; Gap Period: time off drug between end of Core and OLE Baseline 5

Study 201 Open Label Extension (OLE)

• Not random sampling – some

subjects may have been more likely to return than others

• Time off drug between end of Core

and OLE Baseline (Gap Period) not uniform across returning subjects (and no limit)

• Distribution of Core treatment

assignments across returning subjects However Note:

• The blind has NOT been broken at

site and subject levels

Potential OLE Limitations Objectives

• Primary:
• Long-term safety and

tolerability

• Secondary/Exploratory:
• Assess whether treatment

effect of BAN2401 in Core is maintained at OLE Baseline

6

Study 201 OLE Objectives

• To assess changes in brain amyloid levels, as measured by amyloid PET, during Gap Period
• To assess changes in cognition during Gap Period
• 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

Objectives for this Presentation: Analytical Methods:

Study 201 OLE Enrollment and Demographics

7

• 856 Subjects Randomized/Dosed in Core
• LPO Core: August 2018
• Subjects were rescreened
• First OLE subject screened: December, 2018

Baseline Characteristics For Subjects Dosed in OLE

8

Core Baseline OLE Baseline 18-month Core

10 mg/kg biweekly (n) 10 mg/kg monthly (n) Placebo (n) ADCOMS 0.408±0.240 (31) 0.452±0.242 (49) 0.506±0.256 (35) ADAS-cog 21.6±9.7 (32) 23.8±11.7 (49) 25.6±10.9 (36) CDR-SB 3.26±2.04 (33) 3.56±2.08 (50) 3.83±1.95 (35) MMSE 24.2±4.6 (34) 24.4±4.2 (50) 24.3±4.5 (36) PET SUVR* 1.05±0.12 (11) 1.13±0.13 (19) 1.31±0.21 (9) 10 mg/kg biweekly (n) 10 mg/kg monthly (n) Placebo (n) ADCOMS 0.616±0.394 (33) 0.659±0.386 (49) 0.643±0.345 (35) ADAS-cog 28.8±14.0 (31) 31.2±15.8 (48) 32.8±15.8 (35) CDR-SB 5.19±4.02 (35) 5.36±3.37 (52) 4.96±3.23 (36) MMSE 20.7±6.5 (35) 21.0±7.1 (52) 20.8±6.6 (36) PET SUVR* 1.08±0.11 (12) 1.17±0.15 (19) 1.31±0.17 (10) 10 mg/kg biweekly (n) 10 mg/kg monthly (n) Placebo (n) ADCOMS 0.351±0.155 (35) 0.387±0.135 (52) 0.334±0.129 (37) ADAS-cog 20.6±8.3 (35) 21.5±7.0 (52) 20.9±6.4 (37) CDR-SB 2.84±1.33 (35) 3.16±1.28 (52) 2.55±1.14 (37) MMSE 25.5±2.5 (35) 25.8±2.5 (52) 26.0±2.5 (37) PET SUVR* 1.37±0.10 (12) 1.37±0.18 (19) 1.28±0.19 (10)

Gap Period (Time off treatment between Core and OLE Baseline)

*n is the number of subjects who were enrolled in Core PET substudy and now enrolled in OLE

Cor Core e Tx

10 mg/kg biweekly (n) 10 mg/kg monthly (n) Placebo (n) 10 mg/kg biweekly (n) 10 mg/kg monthly (n) Placebo (n) 10 mg/kg biweekly (n) 10 mg/kg monthly (n) Placebo (n)

Changes in Amyloid PET SUVr Across All Doses:

Study 201 Core Versus 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

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

9

Longitudinal amyloid PET was a sub study in the Core Longitudinal amyloid PET was a sub study in the Core

IMPROVEMENT

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 – two regressions lines were fitted , one for core period, one for

Changes in ADCOMS Across All Doses:

Study 201 Core Versus 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 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

WORSENING

11

Change in ADCOMS in Both 10 mg/kg Groups:

Study 201 Core Versus OLE Baseline

WORSENING

12

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;

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

Cor Core Tx

Change in CDR-SB & ADAS-cog in Both 10 mg/kg Groups:

Study 201 Core Versus OLE Baseline

13

Cor Core Tx Cor Core Tx

ADAS-cog CDR-SB

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 OLE Baseline was modeled to 24 mo (average time off drug for BAN-treated subjects); 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

Gap Period (Time off treatment between Core and OLE Baseline) Gap Period (Time off treatment between Core and OLE Baseline)

WORSENING WORSENING

Summary & Interpretation of BAN2401 Study 201 OLE Results

• Brain amyloid reduction persists after BAN2401 discontinuation for both amyloid PET SUVr and visual read
• Mean SUVr: 1.05 at 18 months and 1.08 at OLE Baseline for 10 mg/kg biweekly
• Negative visual read: 81% at 18 months and 84% at OLE Baseline for 10 mg/kg biweekly
• Treatment difference for clinical outcomes at the end of Core appears to be maintained following BAN2401 discontinuation
• Clinical progression appears to proceed at as similar rate as placebo after BAN2401 discontinuation

14

Interpretation

• Similar clinical progression rate of change during Gap Period

suggests potential disease modifying effects

• Continued clinical progression with persistent amyloid

reduction during Gap Period suggests:

• A potential role for soluble amyloid aggregate species

(e.g. protofibrils) in clinical decline

• Continued treatment may be necessary even after

amyloid is removed

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; OLE Baseline at 24 mo for illustrative purposes (average time off drug for BAN-treated subjects); Gap Period: time off drug between end of Core Phase and Baseline OLE

IMPROVEMENT WORSENING

We thank all the participating patients and their family members as well as the investigators and their staff conducting the BAN2401-201 study BAN2401-201 STUDY SITES

Abington Neurological Associates CHU Strasbourg - Hôpital Hautepierre Hospital de Cruces Medical College of Wisconsin, Inc. Praxis Dr. med. Volker Schumann The National Hospital for Neurology & Neurosurgery Advanced Memory Research Institute of NJ, PC CHU Toulouse - Hôpital Casselardit Hospital General de Catalunya Memory Enhancement Center of America, Inc. Praxis Dres. Bittkau The Neurology Group, LLP Akademiska Sjukhuset Clinical Trial Network Hospital San Vicente Miami Jewish Health Systems Psychiatry and Alzheimer's Care of Rochester. PLLC The Regents Of The University Of California Alexian Brothers Medical Center - Neuroscience Research Institute Clinical Trials of Texas, Inc. Hospital Universitario Clinico San Carlos Michigan State University Quantum Laboratories Inc. The University of Texas Health Science Center at San Antonio Alzheimer's Research and Treatment Center Collaborative Neuroscience Network, LLC Hospital Universitario Virgen Macarena Misael Gonzalez, MD Quest Research Institute Tokyo Medical University Hospital American Neuropsychiatric Research Institute Inc Columbus Regional Medical Center Hotel Dieu Hospital National Clinical Research Inc.-Richmond Renstar Medical Research Tokyo Metropolitan Geriatric Hospital ANI Neurology, PLLC d/b/a Alzheimer's Memory Center Cutting Edge Research Group, Inc. Hyogo Brain and Heart Center Neuro Rive Sud Clinic/Center for Diagnosis & Research on Alzheimer's Disease Rhode Island Mood & Memory Research Institute Toronto Memory Program (Neurology Research Inc.) Asan Medical Center Dent Neurologic Institute Hyogo College of Medicine Hospital Neurocare, Inc., dba Neurocare Center for Research Sahlgrenska Universitetssjukhuset, Mölndal Sjukhus Torrance Clinical Research Institute, Inc. ASCLEPES Research Centers, P.C. Diakoniekrankenhaus Henriettenstiftung gGmbH INACTIVE Margolin Brain Institute Neuropsychiatric Research Center of Southwest Florida Saneikai Tsukazaki Hospital Umberto I Pol. di Roma-Università di Roma La Sapienza Atlanta Center for Medical Research Dong-A University Hospital Indiana University School of Medicine NeuroStudies.net, LLC Senior Adult Specialty Research University of Alabama at Birmingham Axiom Clinical Research of Florida Elkhart Clinic Infinity Clinical Research, LLC New Orleans Center for Clinical Research / Volunteer Research Group, an AMR company Seoul National University Bundang Hospital University of Arizona Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia Emory University Cognitive Neurology Clinic & ADRC Innovative Clinical Trials New York University Medical Center Seoul National University Hospital University of Kansas Medical Center Research Institute, Inc. - Master Azienda Ospedaliero Universitaria di Parma Empire Neurology, PC Institute for Neurodegenerative Disorders NHO Hiroshima-Nishi Medical Center Severence Hospital, Yonsei University University of Kentucky Medical Center Azienda Ospedaliero Universitaria Pisana Florida Atlantic University IRCCS Centro San Giovanni di Dio Fatebenefratelli Oregon Health & Science University Sharp Mesa Vista Hospital University of Michigan Azienda Ospedaliero Universitaria San Martino Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico Ishikawa Clinic Osaka Saiseikai Nakatsu Hospital Shinjuku Research Park Clinic University of Rochester Berma Research Group Fondazione Santa Lucia IRCCS JEM Research Institute Osaka University Hospital Skånes Universitetssjukhus USF Suncoast Gerontology Center Bezirkskrankenhaus Guenzburg Fukuoka University Hospital Katayama Medical Clinic Pacific Institute of Medical Research

• St. Joseph's HC- Parkwood Institute

Valley Medical Primary Care Bioclinica Orlando Fundacio ACE Kawartha Centre - Redefining Healthy Aging Pacific Neuroscience Medical Group Stedman Clinical Trials, LLC Weill Cornell Medical College New York Presbyterian Hospital Bioclinica The Villages FutureSearch Trials of Dallas, LP Klinikum rechts der Isar der TU Muenchen Palm Beach Neurological Center Summit Research Network (Oregon) Inc. West London Cognitive Disorders Treatment and Research Unit Boston University School of Medicine Galiz Research, LLC Kobe University Hospital Parkinson's and Neurodegenerative Disorders Clinic Suncoast Neuroscience and Associates, Inc. Xenoscience Inc. Bradenton Research Center, Inc. Gesundheitszentrum Hoppegarten Konkuk University Medical Center Parkinson's Disease and Movement Disorders Center Synapse Saitama Neuropsychiatry Center Yale University School Of Medicine Brain Matters Research Glasgow Memory Clinic Ltd Kotobukikai Tominaga Hopital Pharmacology Research Institute Synexus Clinical Research US, Inc. Brain Research Center Great Lakes Clinical Trials Lahey Clinic Inc. Pharmakologisches Studienzentrum Chemnitz GmbH Texas Neurology, PA Brigham and Women's Hospital Groupe hospitalier Broca - La Rochefoucauld - La Collégiale Lynn Health Science Institute Policlinica Guipuzcoa The Clinical Trial Center, LLC CCM Clinical Research Group, Inc. Henry Ford Hospital MD Clinical Praxis Dr. med. Peter Franz The Memory Clinic

Acknowledgements

15