Fabian Model

IDENTIFICATION OF PREDICTORS OF DISEASE PROGRESSION IN AN AMYLOID-BETA 42 (Aβ42)-POSITIVE, PRODROMAL ALZHEIMER’S DISEASE COHORT: ANALYSIS OF THE SCARLET ROAD STUDY

Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; 2 University of Leicester, Leicester, United Kingdom; 3 Global Innovative Pharma Business – Clinical Sciences Pfizer, Paris, France; Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; 5 VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: l.vermunt@vumc.nl

ESTIMAND IN EARLY ALZHEIMER’S DISEASE: PROGRESS UPDATE FROM THE INTERNATIONAL ALZHEIMER’S DISEASE SCIENTIFIC WORKING GROUP (AD SWG) SUBSTREAM

(CSF) and brain of rodents and primates, as well as in the CSF of patients with AD. In a previous Phase-3 trial (EPOCH) verubecestat was not effective for slowing clinical progression in participants with mild-to-moderate AD despite near maximal reduction of CSF Ab. Since Ab deposition takes place many years before clinical symptoms become apparent, implementing treatments targeting Ab earlier in the disease process may be effective. Here we report on the design of the APECS trial in prodromal AD.Methods: APECS (clinicaltrials.gov NCT01953601) is an ongoing Phase-3 randomized, double-blind, 24-month, placebo-controlled trial of verubecestat (12mg and 40mg) in participants with prodromal AD/amnestic mild cognitive impairment due to AD. Key entry criteria included: subjective memory decline with gradual onset and slow progression for at least 1 year, corroborated by an informant; objective impairment in episodic memory 1 SD below the appropriate population mean on the delayed memory index score of the Repeatable Battery for the Assessment of Neuropsychological Status; positive Ab imaging PET scan; Mini Mental State Examination score 24. Key exclusion criteria included diagnosis of dementia or other relevant neurological or psychiatric disorder. The primary efficacy endpoint is change-from-baseline in the Clinical Dementia Rating – Sum of Boxes score at Month 24. Secondary endpoints include changes in cognitive test scores, changes in biomarkers, and time to progression to AD. Results: 4483 people were screened and 1454 were randomized between 2013 and 2017 (screening failure rate of 68%). Preliminary baseline data showed a trial population with the following demographic characteristics: 53%male, mean (SD) age of 71.4 (7.2) years, 81%white (17%Asian, 1%other), 51%with an undergraduate degree or higher, 46%usingAD treatment, 69%APOE4 carriers, andmean (SD)Mini Mental State Examination score of 26.3 (1.8). The trial is expected to complete in 2019. Conclusions: Results from the APECS trial will help inform whether blocking Ab production is effective in slowing clinical progression in participants with prodromal AD.

Preliminary results of the opera i and opera ii open-label extension study

Objectives To preliminarily assess annualised relapse rate (ARR) at 144 weeks among patients with relapsing multiple sclerosis (RMS) who received ocrelizumab or interferon beta-1a (IFNβ−1a) in the Phase III 96 week OPERA I and II trials, followed by ocrelizumab in an open-label extension (OLE). The efficacy and safety of ocrelizumab in RMS have been demonstrated in the OPERA trials. Oon completion of the controlled treatment period, all patients were eligible to enter an ocrelizumab OLE phase. Methods During the controlled treatment period, patients received intravenous ocrelizumab 600 mg every 24 weeks or subcutaneous IFNβ−1a 44 mg three times weekly for 96 weeks. During the OLE, patients from the IFNβ−1a group were switched to ocrelizumab. Results Patients from OPERA I (ocrelizumab, 352/410; IFNβ−1a, 326/411) and OPERA II (ocrelizumab, 350/417; IFNβ−1a, 297/418) enrolled in the OLE. At the time of analysis, 317 (90.1%) and 322 (92.0%) continuous ocrelizumab patients and 307 (94.2%) and 268 (90.2%) patients switching from IFNβ−1a in OPERA I and II, respectively, had ≥48 weeks of follow-up in the OLE (144 weeks total). Across groups, patients received a median of two doses of ocrelizumab in the OLE. Among patients switching from IFNβ−1a to ocrelizumab, the unadjusted ARR improved from 0.245 and 0.254 over 96 weeks in OPERA I and II, respectively, to 0.092 and 0.115 in the OLE. Among continuous ocrelizumab patients, the unadjusted ARR was 0.136 and 0.138 in OPERA I and II, respectively; during the OLE, the ARR in this group was 0.118 and 0.100, respectively. Imaging metrics will be presented. Conclusions Patients who originally received ocrelizumab in the OPERA studies continued to have favourable ARR outcomes in the OLE. Patients who switched from IFNβ−1a to ocrelizumab in the OLE rapidly experienced ARR outcomes consistent with those of patients who received continuous ocrelizumab.

FREE AND CUED SELECTIVE REMINDING TEST AS AN INCLUSION CRITERION FOR EARLY ALZHEIMER'S DISEASE CLINICAL TRIAL POPULATIONS

ter the intervention with dual tracer F-FDG and C-acetoacetate PET. Cerebrospinal fluid (CSF) was collected at baseline and after each intervention and assayed for AD biomarkers (Ab42 and total tau) with INNO-BIA-Alzbio3. Results: Global C-acetoacetate uptake decreased after the lowfat diet intervention (Fig 1 A Baseline and Fig 1 B Post-Lowfat Diet) and increased after the ketogenic diet intervention (Fig 1C Baseline and Fig 1D Post-Ketogenic Diet), whereas no changes were observed for F-FDG after either diet. Interestingly, CSF total tau increased with the ketogenic diet (p<0.05), with a similar trend noted for Ab42 (p1⁄40.08). Furthermore, the increase in Ab42and tau biomarkers was correlated (r1⁄4, p1⁄40.002). No biomarker changes were observed after low fat diet intervention. Conclusions: Ketogenic diet intervention enhanced brain ketone utilization in MCI and prediabetes, and produced correlated increases in CSF total tau and Ab42. Future investigation is needed to examine the relationship of these effects to changes in cognition.