Chad Swanson

Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease

Recent failures in phase 3 clinical trials in Alzheimers disease (AD) suggest that novel approaches to drug development are urgently needed. Phase 3 risk can be mitigated by ensuring that clinical efficacy is established before initiating confirmatory trials, but traditional phase 2 trials in AD can be lengthy and costly.

A first-in-human study of BAN2401, a novel monoclonal antibody against beta-amyloid protofibrils

a similar pattern to that described in Finland[4] . Possible environmental aetiological factors include a rural-urban effect [1], proximity to mining, selenium[5], or another factor, yet to be identified. 1. Russ et al. (2012) Int J Epidemiol 41:1012-32.2. Starr et al. (1997) Pyschiat Genet 7:147-52.3. Gat z et al. (2005) Neurobiol Aging 26:439-47.4. Sulkava et al. (1988) Regional differences in the prevalence of Alzheimer’s disease. In: Proceedings of the International Symposium on Alzheimer’s Disease, University of Kuopio, Finland.5. Parkman & Hultberg (2002) Occurrence and effects of selenium in the environment a literature review.

A multimodal imaging study of mAb158, a murine monoclonal antibody with high selectivity for amyloid protofibrils, in Tg2576 mice

P4-282 A MULTIMODAL IMAGING STUDY OF MAB158, A MURINE MONOCLONAL ANTIBODY WITH HIGH SELECTIVITY FOR AMYLOID PROTOFIBRILS, IN TG2576 MICE Bradford Navia, Carlos Perdomo, Stephen Krause, June M. Kaplow, Akihiko Koyama, Tyler Teceno, Ben Gershman, Veronika Logovinsky, Chad Swanson, Robert Lai, Christer M€oller, Lars Lannfelt, Andrew Satlin, Paul McCracken, Eisai Inc., Woodcliff Lake, New Jersey, United States; Eisai Inc., Andover, Massachusetts, United States; InviCRO, LLC, Boston, Massachusetts, United States; Eisai Ltd., Hatfield, United Kingdom; BioArctic Neuroscience AB, Stockholm, Sweden; Uppsala University, Uppsala, Sweden. Contact e-mail: paul_mccracken@ eisai.com

TREATMENT OF EARLY AD SUBJECTS WITH BAN2401, AN ANTI-Aβ PROTOFIBRIL MONOCLONAL ANTIBODY, SIGNIFICANTLY CLEARS AMYLOID PLAQUE AND REDUCES CLINICAL DECLINE

estimated the effect of Ab pathology on decline over a spectrum of cognitive domains. Results:Despite considerable study differences in terms of demographics, recruitment, follow-up schedule, and neuropsychological test battery, the magnitude of the differences in decline between Ab groups was consistent for the cognitive composite (PACC, the Preclinical Alzheimer Cognitive Composite) (Figure 1). To achieve 80% power with 800 subjects per arm in a simulated 4-year treatment trial in preclinical AD, estimates of the required drug effect ranged from 34% to 50%. Ab+ groups declined significantly faster on all cognitive domains in all cohorts compared to the Abgroups (Figure 2, the only exception was Trails B in BioFINDER). Several baseline factors interacted significantly with Ab to predict cognitive decline including APOE e4-positivity, baseline cognition, and education in AIBL; age in BioFINDER; and sex in ADNI, however these interactions were cohort specific. On average, Ab+ subjects performed similarly to early MCI patients on cognitive tests 6 years after baseline. Conclusions: We provide robust estimates of expected cognitive decline in preclinical AD. Comparing cohorts side by side demonstrates that large sample sizes with sufficient follow-up times result in consistent estimates of cognitive decline in preclinical AD across measures spanning multiple cognitive domains. Despite design differences, cognitive composites can provide precise information with which to inform study design decisions. These results support the potential for internationally-conducted clinical trials in preclinical AD.

BASELINE FLORBETAPIR AMYLOID PET STANDARD UPTAKE VALUE RATIO (SUVR) CAN PREDICT CLINICAL PROGRESSION IN PRODROMAL AD

delirium also have dementia. The 4AT (4“A”s Test: Alertness, Attention (Months of the Year Backwards), Abbreviated Mental Test-4 to test orientation; Acute change)is a short (<2 min) delirium assessment tool incorporating brief cognitive testing designed for routine clinical use which does not require special training: www.the4AT.com. Primary objective:diagnostic accuracy of the 4AT for delirium detection in acute patients aged>1⁄470. Secondary objectives: comparative performance of Confusion Assessment Method (CAM); assess performance of individual 4AT test items in the 4AT in detecting dementia; to determine if 4AT scores predict outcomes.Methods:This was a STARD-compliant, prospective, randomized, double-blind diagnostic test accuracy multi-site study of 785 patients aged >1⁄470 in the Emergency Department within 12 hours, or acute wards within 96 hours of attendance. Each patient underwent (1) DSM-IV reference standard delirium assessment informed by the Delirium Rating Scale-Revised-98, and (2) assessment with either 4AT or CAM (randomized). Results: Mean age was 81.4 (SD 6.4) years, 45% male, 9% known dementia diagnosis. 96 (11.7%) had reference standard delirium. The 4AT had an area under the receiver operating characteristic curve of 0.90. The 4AT had specificity of 95%(95% CI 92-97%) and sensitivity of 76%(95% CI 61-87%).The CAM had specificity of 100%(95% CI 98-100%) and sensitivity of 40%(95% CI 26-57%). Patients with positive 4AT had longer lengths of stay (median 5 days (IQR 2.0-14.0) than negative 4AT (median 2 days (IQR1.0 -6.0) and higher mortality. Cognitive test items of the 4AT were highly specific (AMT4 score 2: 97%(94-98%); attention score of 2: 98%(96-99%); but showed lower sensitivity (AMT4 score 2: 47% (32-62%; attention score of 2: 62% (36-83%) in detecting existing dementia. Conclusions: The 4AT is a rapid delirium assessment instrument which is feasible in routine care, including with patients with dementia, which has good diagnostic accuracy for delirium for acutely unwell older patients. Funding source: National Institute of Health Research Technology Assessment Programme (NIHR DTA) grant number 11/143/01.

Composite measures in Alzheimer’s disease clinical trials: How an in-study data quality program ensures immediate and ongoing quality of the sum of their parts

Hospital, Second Military Medical University, Shanghai, China; Department of Neurology, The 10th People’s Hospital, Tongji University, Shanghai, China; Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Geriatric Neurology, Chinese PLA General Hospital, Beijing, China; Department of Neurology, The First Hospital of Jilin University, Shanghai, China; Mental Health Center of Hebei Province, Baoding, China; Department of Neurology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Beijing Hui-Long-Guan Hospital, Peking University, Beijing, China; Department of Geratology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; First Affiliated Hospital of Kunming Medicine University, Kunming, China; Guangzhou Psychiatric Hospital, Guangzhou, China; Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Affiliated Hospital of GuilinMedical School, Guilin, China; Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China; Neurological Department, The Third Xiangya Hospital of Central South University, Hunan, China; Department of Health Statistics, Second Military Medical University, Shanghai, China. Contact e-mail: wtshhwy@ 163.com

INITIAL LEARNINGS FROM SCREENING STRATEGIES IN THE BAN 2401-G000-201 TRIAL: AN EARLY ALZHEIMER'S DISEASE STUDY

University of Toronto Toronto, Ontario, Canada; Toronto Rehabilitation Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; Lawson Health Research Institute, Western University, London, Ontario, Canada; Toronto Memory Program, Toronto, Ontario, Canada; St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; Providence Care St. Mary’s of the Lake Hospital, Queen’s University, Kingston, Ontario, Canada; Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Kawartha Regional Memory Clinic, Peterborough, Ontario, Canada; Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; The Centre for Memory and Aging, Toronto, Ontario, Canada; Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Baycrest, University of Toronto, Toronto, Ontario, Canada. Contact e-mail: sandra.black@sunnybrook.ca

Pharmacology of BAN2401: A monoclonal antibody selective for beta-amyloid protofibrils

its antigen in the brain (stealth antibody). The effect of the clinical candidate, SAR228810, was evaluated in the same model after induction of immunotolerance by transient depletion of CD4+ T lymphocytes. SAR228810 at 10mg/kg/week showed the same level of efficacy as the murineSAR255952. SAR255952 (up to 50 mg/kg/week IV) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSLmice. Conversely, brain cortical microhemorrhages or degeneration/necrosis in meningeal and/or cerebral arteries was notedwith 3D6, the murine antibody of bapineuzumab.Conclusions:Based on SAR228810 improved efficay/safety profile, a phase1 single andmultiple dose administration clinical study in AD patientshas been initiated.