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Single oral doses of the novel bace inhibitor bi 1181181 significantly reduce concentrations of cerebrospinal fluid amyloid-beta peptides in healthy subjects
P740 P3-281
Poster Presentations: P3 ENHANCING PERSON-CENTERED CARE BY COMPARING COGNITIVE FUNCTIONING IN LONG-TERM AND SHORT-STAY NURSING HOME RESIDENTS
Ryan A. Mace1, Kristen M. Clark1, William E. Mansbach1, Isabella E. Firth2, 1Mansbach Health Tools, LLC, Simpsonville, MD, USA; 2 The Beacon Institute, Columbia, MD, USA. Contact e-mail: rmace@ thebcat.com Background: In the US, the Affordable Care Act of 2010
mandated a transition to person-centered care for long-term care facilities. Yet, it can be difficult to determine choice preferences, needs, and values for cognitively impaired individuals if they are unable to clearly communicate them to facility providers. The high base rate of dementia and Mild Cognitive Impairment (MCI) in nursing homes is well documented on a general basis; however, our understanding of the unique prevalence of cognitive levels in long-term care and short stay residents is limited. Our aims are to investigate the rates of cognitive impairment in long-term and short stay nursing home residents and determine if there are significant differences in specific cognitive levels between these two groups. Methods: Five hundred seventy-nine long-term and short stay residents were randomly selected from 18 Maryland skilled nursing facilities. Three hundred forty-five met inclusion criteria for participation (mean age 79.41 6 10.79) and completed a cognitive evaluation tool (Brief Cognitive Assessment Tool; BCAT). Results: Based on BCAT scores, 78.9% of the long-term residents had dementia compared to 61.4% for short stay residents. A Pearson’s chi-square test for independence indicated the proportions of MCI, mild, and moderate to severe dementia were significantly different between the long-term and short stay nursing home residents (p ¼ .00). The odds of being moderately to severely demented was 2.76 times greater for nursing home residents who were long-term care compared to short stay. A one-way multivariate analysis of variance indicated that BCAT Total scores and BCAT Factor scores were significantly different at the between long-term and short stay nursing home residents (p < .001 for all tests). Conclusions: We discuss implications of these empirical findings in terms of facilitating person-centered care in nursing homes.
P3-282
SINGLE ORAL DOSES OF THE NOVEL BACE INHIBITOR BI 1181181 SIGNIFICANTLY REDUCE CONCENTRATIONS OF CEREBROSPINAL FLUID AMYLOID-BETA PEPTIDES IN HEALTHY SUBJECTS
Andreas Borta1, Laurent Nicolas1, Oliver Kleiner1, Klaus-Peter Kammerer2, Jennifer Schaible1, Kerstin Pietzko1, Jana Podhorna2, Cornelia Dorner-Ciossek3, Joachim Scholpp1, 1Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 3Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. Contact e-mail: [email protected] Background: Strong evidence has accumulated in favor of amyloid-beta (Ab) as the triggering factor in the pathogenesis of Alzheimer’s disease. In the single-ascending-dose study, the novel potent inhibitor of the BACE-1 enzyme, BI 1181181, which was discovered in collaboration with Vitae Pharmaceuticals, was well tolerated and showed plasma pharmacokinetics and pharmacodynamics (via Ab1-40 reduction) compatible with
once-a-day dosing. The focus of the present study was on cerebrospinal fluid (CSF) pharmacodynamics (changes in Ab isoforms and soluble amyloid precursor protein (sAPP)) and pharmacokinetics of BI 1181181 in healthy male subjects. Methods: This study had a randomized, double-blind, placebocontrolled design and included 36 subjects (n¼ 12 on active and n¼6 on placebo in each dose group) of 22 to 45 years of age, who received a single oral dose of 50 or 100 mg BI1181181. CSF samples for pharmacokinetics and pharmacodynamics were collected over a period of 36 h using an intrathecal catheter. Results: All 36 subjects completed the study. BI 1181181 was well tolerated. No serious adverse events (AEs) were reported. Twenty-nine subjects (80.6%) experienced at least one AE. The most frequent AEs were procedural headache (44.4%). The majority of AEs were of mild and moderate intensity. Severe AEs, all procedural headaches, occurred in 6 subjects (16.7%). The frequency and the intensity of AEs did not differ significantly between treatments. There was no treatment-related effect of BI 1181181 on vital signs, ECGs, or clinical laboratory parameters. In plasma and CSF, exposure to BI1181181 increased dose-proportionally. BI 1181181 induced a dose-dependent reduction in CSF Ab1-40 concentrations. At 24 h after dosing, the mean CSF Ab1-40 placebo-corrected percent change from baseline was -63.6% (90% CI: -80.3, -47.0) in the 50 mg dose group and -82.7% (90% CI: -99.5, -66.0) in the 100 mg dose group. Substantial and sustained decreases of CSF Ab1-42 and sAPPb concentrations were also observed. Conclusions: BI 1181181 is present in the CSF following a single oral dose and induces a substantial and sustained CSF Ab reduction.
P3-283
PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF THE NOVEL BACE INHIBITOR BI1181181 AFTER ORAL ADMINISTRATION OF SINGLE ASCENDING DOSES IN HEALTHY SUBJECTS
Laurent Nicolas1, Klaus-Peter Kammerer2, Jennifer Schaible1, Jasmin Link1, Oliver Kleiner1, Andreas Borta1, Jana Podhorna2, Joachim Scholpp1, 1Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Contact e-mail: laurent.nicolas@ boehringer-ingelheim.com Background: Amyloid beta (Ab) is thought to be a triggering factor in the pathogenesis of Alzheimer’s disease. BI1181181, a novel potent inhibitor of the BACE-1 enzyme discovered in collaboration with Vitae Pharmaceuticals, inhibits the production of plasma, brain, and cerebrospinal fluid Ab in several preclinical in vitro and in vivo models. The present singleascending-dose study evaluated the safety, pharmacokinetics, and pharmacodynamics of BI 1181181 in healthy male subjects. Methods: This study, conducted in subjects of 22 to 50 years of age, included a food-effect evaluation. The single-ascending-dose part had a partially randomized, single-blind, placebo-controlled design and included 53 subjects (n¼ 5-6 on active and n¼1-2 on placebo in each dose group) who received single oral doses of 2 to 200 mg BI 1181181. The food-effect part with its randomized, open-label, cross-over design, was conducted in 12 subjects who received a dose of 50 mg BI 1181181 in the fed or fasted condition. Results: All subjects were evaluable for safety, pharmacokinetics, and pharmacodynamics. BI 1181181 was well tolerated. No serious adverse events (AEs) were reported. A total of 26 subjects (40%)
Poster Presentations: P3 ENHANCING PERSON-CENTERED CARE BY COMPARING COGNITIVE FUNCTIONING IN LONG-TERM AND SHORT-STAY NURSING HOME RESIDENTS
Ryan A. Mace1, Kristen M. Clark1, William E. Mansbach1, Isabella E. Firth2, 1Mansbach Health Tools, LLC, Simpsonville, MD, USA; 2 The Beacon Institute, Columbia, MD, USA. Contact e-mail: rmace@ thebcat.com Background: In the US, the Affordable Care Act of 2010
mandated a transition to person-centered care for long-term care facilities. Yet, it can be difficult to determine choice preferences, needs, and values for cognitively impaired individuals if they are unable to clearly communicate them to facility providers. The high base rate of dementia and Mild Cognitive Impairment (MCI) in nursing homes is well documented on a general basis; however, our understanding of the unique prevalence of cognitive levels in long-term care and short stay residents is limited. Our aims are to investigate the rates of cognitive impairment in long-term and short stay nursing home residents and determine if there are significant differences in specific cognitive levels between these two groups. Methods: Five hundred seventy-nine long-term and short stay residents were randomly selected from 18 Maryland skilled nursing facilities. Three hundred forty-five met inclusion criteria for participation (mean age 79.41 6 10.79) and completed a cognitive evaluation tool (Brief Cognitive Assessment Tool; BCAT). Results: Based on BCAT scores, 78.9% of the long-term residents had dementia compared to 61.4% for short stay residents. A Pearson’s chi-square test for independence indicated the proportions of MCI, mild, and moderate to severe dementia were significantly different between the long-term and short stay nursing home residents (p ¼ .00). The odds of being moderately to severely demented was 2.76 times greater for nursing home residents who were long-term care compared to short stay. A one-way multivariate analysis of variance indicated that BCAT Total scores and BCAT Factor scores were significantly different at the between long-term and short stay nursing home residents (p < .001 for all tests). Conclusions: We discuss implications of these empirical findings in terms of facilitating person-centered care in nursing homes.
P3-282
SINGLE ORAL DOSES OF THE NOVEL BACE INHIBITOR BI 1181181 SIGNIFICANTLY REDUCE CONCENTRATIONS OF CEREBROSPINAL FLUID AMYLOID-BETA PEPTIDES IN HEALTHY SUBJECTS
Andreas Borta1, Laurent Nicolas1, Oliver Kleiner1, Klaus-Peter Kammerer2, Jennifer Schaible1, Kerstin Pietzko1, Jana Podhorna2, Cornelia Dorner-Ciossek3, Joachim Scholpp1, 1Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 3Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. Contact e-mail: [email protected] Background: Strong evidence has accumulated in favor of amyloid-beta (Ab) as the triggering factor in the pathogenesis of Alzheimer’s disease. In the single-ascending-dose study, the novel potent inhibitor of the BACE-1 enzyme, BI 1181181, which was discovered in collaboration with Vitae Pharmaceuticals, was well tolerated and showed plasma pharmacokinetics and pharmacodynamics (via Ab1-40 reduction) compatible with
once-a-day dosing. The focus of the present study was on cerebrospinal fluid (CSF) pharmacodynamics (changes in Ab isoforms and soluble amyloid precursor protein (sAPP)) and pharmacokinetics of BI 1181181 in healthy male subjects. Methods: This study had a randomized, double-blind, placebocontrolled design and included 36 subjects (n¼ 12 on active and n¼6 on placebo in each dose group) of 22 to 45 years of age, who received a single oral dose of 50 or 100 mg BI1181181. CSF samples for pharmacokinetics and pharmacodynamics were collected over a period of 36 h using an intrathecal catheter. Results: All 36 subjects completed the study. BI 1181181 was well tolerated. No serious adverse events (AEs) were reported. Twenty-nine subjects (80.6%) experienced at least one AE. The most frequent AEs were procedural headache (44.4%). The majority of AEs were of mild and moderate intensity. Severe AEs, all procedural headaches, occurred in 6 subjects (16.7%). The frequency and the intensity of AEs did not differ significantly between treatments. There was no treatment-related effect of BI 1181181 on vital signs, ECGs, or clinical laboratory parameters. In plasma and CSF, exposure to BI1181181 increased dose-proportionally. BI 1181181 induced a dose-dependent reduction in CSF Ab1-40 concentrations. At 24 h after dosing, the mean CSF Ab1-40 placebo-corrected percent change from baseline was -63.6% (90% CI: -80.3, -47.0) in the 50 mg dose group and -82.7% (90% CI: -99.5, -66.0) in the 100 mg dose group. Substantial and sustained decreases of CSF Ab1-42 and sAPPb concentrations were also observed. Conclusions: BI 1181181 is present in the CSF following a single oral dose and induces a substantial and sustained CSF Ab reduction.
P3-283
PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF THE NOVEL BACE INHIBITOR BI1181181 AFTER ORAL ADMINISTRATION OF SINGLE ASCENDING DOSES IN HEALTHY SUBJECTS
Laurent Nicolas1, Klaus-Peter Kammerer2, Jennifer Schaible1, Jasmin Link1, Oliver Kleiner1, Andreas Borta1, Jana Podhorna2, Joachim Scholpp1, 1Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Contact e-mail: laurent.nicolas@ boehringer-ingelheim.com Background: Amyloid beta (Ab) is thought to be a triggering factor in the pathogenesis of Alzheimer’s disease. BI1181181, a novel potent inhibitor of the BACE-1 enzyme discovered in collaboration with Vitae Pharmaceuticals, inhibits the production of plasma, brain, and cerebrospinal fluid Ab in several preclinical in vitro and in vivo models. The present singleascending-dose study evaluated the safety, pharmacokinetics, and pharmacodynamics of BI 1181181 in healthy male subjects. Methods: This study, conducted in subjects of 22 to 50 years of age, included a food-effect evaluation. The single-ascending-dose part had a partially randomized, single-blind, placebo-controlled design and included 53 subjects (n¼ 5-6 on active and n¼1-2 on placebo in each dose group) who received single oral doses of 2 to 200 mg BI 1181181. The food-effect part with its randomized, open-label, cross-over design, was conducted in 12 subjects who received a dose of 50 mg BI 1181181 in the fed or fasted condition. Results: All subjects were evaluable for safety, pharmacokinetics, and pharmacodynamics. BI 1181181 was well tolerated. No serious adverse events (AEs) were reported. A total of 26 subjects (40%)