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O4‐07‐01: Amyloid imaging in nondemented oldest‐old
Author(s) -
Mathis Chester,
Snitz Beth,
Price Julie,
Klunk William,
Saxton Judith,
Weissfeld Lisa,
Rosario Bedda,
Kuller Lewis,
Lopez Oscar,
DeKosky Steven
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.2012
Subject(s) - pittsburgh compound b , posterior cingulate , nuclear medicine , medicine , quartile , cognitive impairment , cohort , psychology , cortex (anatomy) , neuroscience , confidence interval , disease
Background: BMS-708163 is an oral gamma secretase inhibitor designed for selective inhibition of amyloid beta (Aß) synthesis. Methods: CN156013 was a randomized, double-blind, placebo-controlled, 24 week Phase 2 study designed to assess the safety and tolerability of BMS-708163 in patients with mild-to-moderate AD. Patients were randomized to placebo or one of four treatment groups: 25mg, 50mg, 100mg, and 125mg/day of BMS-708163. Secondary analyses evaluated the pharmacodynamic effects of BMS-708163 on CSF biomarkers, volumetric MRI and clinical outcomes of cognition and function (ADAS-cog, ADCS-ADL, and CDR-SB).Results: 209 patients were randomized across treatment groups. Median age was 75 years; 96% were white; 48% female; and, 62% APOE4 carriers. Baseline measures of disease severity were similar among groups. The overall incidence of treatment-emergent SAEs was similar across placebo and treatment groups. Discontinuation rates for 25mg and 50mgdoses of BMS-708163were comparable with placebo, but higher in the 100mg and 125mg groups. The most common reason for discontinuation was AEs, predominately gastrointestinal (diarrhea, nausea, and vomiting) and dermatological (rash and pruritus). Other selected treatment-emergent AEs and laboratory abnormalities occurring more frequently on treatment, compared with placebo, included: reversible glycosuria, non-melanoma skin cancer and asymptomatic MRI findings. No serum glucose changes were noted. No deaths occurred during treatment. Evidence for pharmacodynamic effects on CSF biomarkers were observed across the dose range. Conclusions: In this dose finding and safety study, the 25mg and 50mg arms of BMS-708163 were relatively well-tolerated with low discontinuation rates and demonstrated PD biomarker effects. Fixed doses of 100mg and 125mgwere not sufficiently well-tolerated to advance. These findings provide a therapeutic window for BMS-708163 that warrants longer term efficacy studies.