June Kaplow

Reference measurement procedures for Alzheimer’s disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid β42

Cerebrospinal fluid (CSF) biomarkers for Alzheimers disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a candidate reference method for quantification of CSF amyloid β42.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ‐secretase modulator, E2212, in healthy human subjects

E2212, a novel γ‐secretase modulator, is under development for the treatment of Alzheimers disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10–250 mg, double‐blind, placebo‐controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C‐SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5–19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aβ(x–42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0–24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212.

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team

Abstract Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

Soluble BACE-1 Activity and sAβPPβ Concentrations in Alzheimer’s Disease and Age-Matched Healthy Control Cerebrospinal Fluid from the Alzheimer’s Disease Neuroimaging Initiative-1 Baseline Cohort

β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays an important role in the development of Alzheimers disease (AD), freeing the amyloid-β (Aβ) N-terminus from the amyloid-β protein precursor (AβPP), the first step in Aβ formation. Increased BACE1 activity in AD brain or cerebrospinal fluid (CSF) has been reported. Other studies, however, found either no change or a decrease with AD diagnosis in either BACE1 activity or sAβPPβ, the N-terminal secreted product of BACE1 (sBACE1) activity on AβPP. Here, sBACE1 enzymatic activity and secreted AβPPβ (sAβPPβ) were measured in Alzheimers Disease Neuroimaging Initiative-1 (ADNI-1) baseline CSF samples and no statistically significant changes were found in either measure comparing healthy control, mild cognitively impaired, or AD individual samples. While CSF sBACE1 activity and sAβPPβ demonstrated a moderate yet significant degree of correlation with each other, there was no correlation of either analyte to CSF Aβ peptide ending at residue 42. Surprisingly, a stronger correlation was demonstrated between CSF sBACE1 activity and tau, which was comparable to that between CSF Aβ₄₂ and tau. Unlike for these latter two analytes, receiver-operator characteristic curves demonstrate that neither CSF sBACE1 activity nor sAβPPβ concentrations can be used to differentiate between healthy elderly and AD individuals.

A single dose of the beta-secretase inhibitor, e2609, decreases CSF bace1 enzymatic activity in cynomolgus monkeys

Figure 2. Correlation Between CSF BACE1 Activity Levels and CSF Ab 1-x levels in All Monkey Samples Mark Matijevic, Hideki Watanabe, Yoshiaki Sato, Francois Bernier, Shannon McGrath, Lynne Burns, Noboru Yamamoto, Makoto Ogo, Zoltan Dezso, Jesse Chow, Yoshiya Oda, June Kaplow, Bruce Albala, Eisai, Andover, MA, USA; Eisai, Tsukuba, Japan; Formerly Eisai (when work was completed), Worcester, MA, USA; Eisai, Woodcliff Lake, NJ, USA; Eisai,Woodcliffe Lake, NJ, USA. Contact e-mail: mark_matijevic@eisai.com

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

Soluble BACE activity and sAPPβ levels do not differentiate Alzheimer's disease and age-matched control cerebrospinal fluid in the ADNI-1 cohort

P1-140 SOLUBLE BACE ACTIVITYAND SAPPb LEVELS DO NOT DIFFERENTIATE ALZHEIMER’S DISEASE AND AGE-MATCHED CONTROL CEREBROSPINAL FLUID IN THEADNI-1 COHORT Mary Savage, Dan Holder, Guoxin Wu, June M. Kaplow, Judith Siuciak, William Potter, ADNI 6,7 The Foundation for NIH Biomarkers Consortium CSF Proteomics Project Team, Merck and Company, West Point, Pennsylvania, United States; Merck & Co., West Point, Pennsylvania, United States; Merck Research Laboratories, West Point, Pennsylvania, United States; Eisai Inc., Woodcliff Lake, New Jersey, United States; Foundation for the NIH, Bethesda, Maryland, United States; Foundation for the National Institutes of Health, Bethesda, Maryland, United States; ADNI, ANBDI, District of Columbia, United States; FNIH, Bethesda, Maryland, United States. Contact e-mail: mary_savage@merck. com

ELENBECESTAT, A NOVEL BACE INHIBITOR, DEMONSTRATES SIMILAR PHARMACOKINETICS AND TOLERABILITY IN JAPANESE SUBJECTS WITH MULTIPLE DOSINGS

in the clinical outcomes. The decline in cognition and other clinical endpoints over 18 months in participants receiving verubecestat was similar across all exposure quartiles. The estimated slope of AUC effect on ADAS-cog disease progression was small (-4.4e-5) and the 90% CI contained zero. Conclusions:Overall, these results indicate that EPOCH tested drug exposures and target engagement consistent with 72% and 90% inhibition of Ab production at the 12 and 40 mg doses, respectively. Together with the lack of exposure-dependency in the cognition data, these results suggest that insufficient dose or target engagement was not the driver for the failure to meet the clinical endpoints as expected exposures were achieved. Ref 1. Clin Pharmacol Ther. 2015 Mar;97(3):210-4.

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.