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First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing
P96 O1-06-04
Oral Sessions: O1-06: Therapeutics/Therapeutic Strategies: Beta-Secretase Inhibition THERAPEUTIC POTENTIAL OF BACE1/BETASECRETASE: PROTEOME-WIDE IDENTIFICATION OF PHYSIOLOGICAL BACE1 SUBSTRATES IN PRIMARY NEURONS AND MOUSE BRAIN
Stefan Lichtenthaler1, Bastian Dislich1, Sebastian Hogl1, Alessio Colombo1, Ulrike Zeitschel2, Michael Willem1, Christian Haass1, Christiane Volbracht3, Steffen Roßner2, Peer-Hendrik Kuhn1, 1 DZNE-University of Munich, Munich, Germany; 2University Leipzig, Leipzig, Germany; 3Lundbeck, Copenhagen, Denmark. Background: Beta-secretase (BACE1) is a major drug target in Alzheimer’s disease. Possible side-effects of chronic BACE1 inhibition in patients are largely unknown, but may stem from the poorly understood physiological function of BACE1. In fact, several new phenotypes in brain and pancreas of BACE1-deficient mice were reported recently, but the substrates responsible for the phenotypes are largely unknown. Methods: We developed a novel proteomic workflow based on quantitative mass spectrometry and determined BACE1 substrates in neurons and mouse brain on a proteomewide scale. Results: We identified the secretome of primary murine neurons, which may be used for biomarker studies. Additionally, we identified - besides APP and its homologs - over 20, mostly novel, physiological substrates of BACE1 and validated several of them in BACE1-deficient neurons and mice. Conclusions: The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. The identification of novel BACE1 substrates is not only the basis for a better understanding of BACE1 function and of the phenotypes in BACE1 knock-out mice, but will also allow to better evaluate the therapeutic potential of BACE1 and to develop biomarkers for monitoring potential side-effects of BACE1 inhibition in clinical trials of Alzheimer’s disease.
O1-06-05
FIRST-IN-HUMAN STUDY OF E2609, A NOVEL BACE1 INHIBITOR, DEMONSTRATES PROLONGED REDUCTIONS IN PLASMA BETAAMYLOID LEVELS AFTER SINGLE DOSING
Robert Lai1, Bruce Albala2, June M. Kaplow2, Jagadeesh Aluri2, Mark Yen3, Andrew Satlin2, 1Eisai Ltd., Hatfield, United Kingdom; 2Eisai Inc., Woodcliff Lake, New Jersey, United States; 3Parexel, Glendale, California, United States. Background: Amyloid beta (Ab) plaques are deposited in the brain in Alzheimer’s disease (AD). Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a key enzyme responsible for the production of Ab peptides. E2609 is a novel, small molecule, BACE1 inhibitor that has been shown in nonclinical studies to inhibit the production of Ab40 and Ab42 in brain, reducing Ab in cerebrospinal fluid and plasma after oral dosing. We present results on the safety, tolerability, pharmacokinetics
Figure 2. Mean % change from Baseline in plasma Ab(1-x) following single oral doses of E2609. (PK) and pharmacodynamic (PD) effects of E2609 in a first-in-human study. Methods: This was a single-center, randomized, double-blind, placebocontrolled study in 8 cohorts of healthy adult subjects aged 30 to 55 and 1 cohort of healthy elderly subjects aged 65 to 85. Each cohort comprised 8 subjects, with 6 randomized to a single dose of E2609 and 2 to placebo. Healthy young subjects received single doses of 5, 10, 25, 50, 100, 200, 400 or 800 mg. Healthy elderly subjects received a single dose of 50 mg. Subjects were dosed after fasting overnight. Blood samples were collected predose and at multiple time points up to 144 h postdose to measure plasma concentrations of E2609 and Ab peptides. Safety and tolerability were assessed by adverse events (AE), vital signs, electrocardiograms, and clinical laboratory blood tests. Results: E2609 was well-tolerated across all doses. Twelve (21.8%) subjects treated with E2609 reported at least 1 AE, compared with 3 (16.7%) on placebo. E2609 exposure was approximately dose proportional, with a terminal elimination half-life of w15.9 h at 800 mg. E2609 showed prolonged inhibition of plasma Ab1-x€ıV at all doses from 5-800 mg (Figure 1). The maximum PD inhibition relative to baseline was 56.3% (at 5 mg) and 91.0% (at 800 mg) occurring approximately 6 to 24 hours postdose (Figure 2). At 72-144 h postdose (only sampled at 200-800 mg), plasmaAb1-xlevels were still w25-45% below baseline, when E2609 was mostly eliminated. Conclusions: E2609 is a potent BACE1 inhibitor that causes prolonged reductions of plasma Ab1-x after a single dose. There were no safety concerns with single doses up to 800 mg. O1-06-06
REGULATION OF BACE1 EXPRESSION BY GSK3-BETA AND ITS THERAPEUTIC EFFECT ON ALZHEIMER’S DISEASE
Philip T. T. Ly, Yili Wu, Weihong Song, University of British Columbia, Vancouver, British Columbia, Canada.
Figure 1. Mean plasma concentrations of E2609 following single oral doses of E2609.
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia. Deposition of amyloid b protein (Ab) to form neuritic plaques in the brains is the pathological hallmark of Alzheimer’s disease (AD). Ab is generated from sequential cleavages of the b-amyloid precursor protein (APP) by the b- and g-secretases. Therefore, inhibition of the pathways that lead to Ab generation will have therapeutic implications for the treatment of AD. Beta-site APP cleaving enzyme 1 (BACE1) is the b-secretase essential for Ab generation. Increased Ab levels could facilitate AD pathogenesis and inhibition of Ab generation may have therapeutic implications for AD treatment. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating g-secretase activity, thereby facilitating Ab production. Methods: To study the role of GSK3 signaling in AD pathogenesis and its pharmaceutical potential, we treated cells and AD transgenic mice with GSK3-specific inhibitor. APP processing, Ab production, and BACE1 expression were examined by Western blot and promoter assays. Furthermore, neurotic plaque formation and memory deficits were analyzed by immunohistochemical staining and
Oral Sessions: O1-06: Therapeutics/Therapeutic Strategies: Beta-Secretase Inhibition THERAPEUTIC POTENTIAL OF BACE1/BETASECRETASE: PROTEOME-WIDE IDENTIFICATION OF PHYSIOLOGICAL BACE1 SUBSTRATES IN PRIMARY NEURONS AND MOUSE BRAIN
Stefan Lichtenthaler1, Bastian Dislich1, Sebastian Hogl1, Alessio Colombo1, Ulrike Zeitschel2, Michael Willem1, Christian Haass1, Christiane Volbracht3, Steffen Roßner2, Peer-Hendrik Kuhn1, 1 DZNE-University of Munich, Munich, Germany; 2University Leipzig, Leipzig, Germany; 3Lundbeck, Copenhagen, Denmark. Background: Beta-secretase (BACE1) is a major drug target in Alzheimer’s disease. Possible side-effects of chronic BACE1 inhibition in patients are largely unknown, but may stem from the poorly understood physiological function of BACE1. In fact, several new phenotypes in brain and pancreas of BACE1-deficient mice were reported recently, but the substrates responsible for the phenotypes are largely unknown. Methods: We developed a novel proteomic workflow based on quantitative mass spectrometry and determined BACE1 substrates in neurons and mouse brain on a proteomewide scale. Results: We identified the secretome of primary murine neurons, which may be used for biomarker studies. Additionally, we identified - besides APP and its homologs - over 20, mostly novel, physiological substrates of BACE1 and validated several of them in BACE1-deficient neurons and mice. Conclusions: The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. The identification of novel BACE1 substrates is not only the basis for a better understanding of BACE1 function and of the phenotypes in BACE1 knock-out mice, but will also allow to better evaluate the therapeutic potential of BACE1 and to develop biomarkers for monitoring potential side-effects of BACE1 inhibition in clinical trials of Alzheimer’s disease.
O1-06-05
FIRST-IN-HUMAN STUDY OF E2609, A NOVEL BACE1 INHIBITOR, DEMONSTRATES PROLONGED REDUCTIONS IN PLASMA BETAAMYLOID LEVELS AFTER SINGLE DOSING
Robert Lai1, Bruce Albala2, June M. Kaplow2, Jagadeesh Aluri2, Mark Yen3, Andrew Satlin2, 1Eisai Ltd., Hatfield, United Kingdom; 2Eisai Inc., Woodcliff Lake, New Jersey, United States; 3Parexel, Glendale, California, United States. Background: Amyloid beta (Ab) plaques are deposited in the brain in Alzheimer’s disease (AD). Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a key enzyme responsible for the production of Ab peptides. E2609 is a novel, small molecule, BACE1 inhibitor that has been shown in nonclinical studies to inhibit the production of Ab40 and Ab42 in brain, reducing Ab in cerebrospinal fluid and plasma after oral dosing. We present results on the safety, tolerability, pharmacokinetics
Figure 2. Mean % change from Baseline in plasma Ab(1-x) following single oral doses of E2609. (PK) and pharmacodynamic (PD) effects of E2609 in a first-in-human study. Methods: This was a single-center, randomized, double-blind, placebocontrolled study in 8 cohorts of healthy adult subjects aged 30 to 55 and 1 cohort of healthy elderly subjects aged 65 to 85. Each cohort comprised 8 subjects, with 6 randomized to a single dose of E2609 and 2 to placebo. Healthy young subjects received single doses of 5, 10, 25, 50, 100, 200, 400 or 800 mg. Healthy elderly subjects received a single dose of 50 mg. Subjects were dosed after fasting overnight. Blood samples were collected predose and at multiple time points up to 144 h postdose to measure plasma concentrations of E2609 and Ab peptides. Safety and tolerability were assessed by adverse events (AE), vital signs, electrocardiograms, and clinical laboratory blood tests. Results: E2609 was well-tolerated across all doses. Twelve (21.8%) subjects treated with E2609 reported at least 1 AE, compared with 3 (16.7%) on placebo. E2609 exposure was approximately dose proportional, with a terminal elimination half-life of w15.9 h at 800 mg. E2609 showed prolonged inhibition of plasma Ab1-x€ıV at all doses from 5-800 mg (Figure 1). The maximum PD inhibition relative to baseline was 56.3% (at 5 mg) and 91.0% (at 800 mg) occurring approximately 6 to 24 hours postdose (Figure 2). At 72-144 h postdose (only sampled at 200-800 mg), plasmaAb1-xlevels were still w25-45% below baseline, when E2609 was mostly eliminated. Conclusions: E2609 is a potent BACE1 inhibitor that causes prolonged reductions of plasma Ab1-x after a single dose. There were no safety concerns with single doses up to 800 mg. O1-06-06
REGULATION OF BACE1 EXPRESSION BY GSK3-BETA AND ITS THERAPEUTIC EFFECT ON ALZHEIMER’S DISEASE
Philip T. T. Ly, Yili Wu, Weihong Song, University of British Columbia, Vancouver, British Columbia, Canada.
Figure 1. Mean plasma concentrations of E2609 following single oral doses of E2609.
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia. Deposition of amyloid b protein (Ab) to form neuritic plaques in the brains is the pathological hallmark of Alzheimer’s disease (AD). Ab is generated from sequential cleavages of the b-amyloid precursor protein (APP) by the b- and g-secretases. Therefore, inhibition of the pathways that lead to Ab generation will have therapeutic implications for the treatment of AD. Beta-site APP cleaving enzyme 1 (BACE1) is the b-secretase essential for Ab generation. Increased Ab levels could facilitate AD pathogenesis and inhibition of Ab generation may have therapeutic implications for AD treatment. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating g-secretase activity, thereby facilitating Ab production. Methods: To study the role of GSK3 signaling in AD pathogenesis and its pharmaceutical potential, we treated cells and AD transgenic mice with GSK3-specific inhibitor. APP processing, Ab production, and BACE1 expression were examined by Western blot and promoter assays. Furthermore, neurotic plaque formation and memory deficits were analyzed by immunohistochemical staining and