O4‐06‐08: Safety and tolerability of BMS‐708163 in a phase II study in mild‐to‐moderate Alzheimer's disease
Year: 2011
Type: article
Study design: Clinical Trial
Abstract: BMS-708163 is an oral gamma secretase inhibitor designed for selective inhibition of amyloid beta (Aß) synthesis. 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). 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 50mg doses of BMS-708163 were 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. 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 125mg were not sufficiently well-tolerated to advance. These findings provide a therapeutic window for BMS-708163 that warrants longer term efficacy studies.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1999833898