Mark Yen

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimers disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.

Cerebrospinal fluid β-amyloid and dynabridging in Alzheimer’s disease drug development

Cerebrospinal fluid (CSF) has become a matrix for biomarker discovery and development in recent years. A number of biomarkers for pathogenic processes in Alzheimers disease have been identified. Studies have revealed the diagnostic potential of CSF amyloid-beta, tau and phosphorylated tau levels. California Clinical Trials has conducted a number of studies in collaboration with drug developers that demonstrate the importance of CSF amyloid-beta peptides as biomarkers for drug development. These studies also establish the utility of CSF sampling via continuous indwelling lumbar catheterization (dynabridging) for assessing pharmacokinetic and pharmacodynamic parameters in conjunction with biomarker analysis. Corroborative approaches using multiple biomarker methods including neuroimaging and CSF biomarkers will provide a complete picture of the Alzheimers disease brain.

The role for CSF dynabridging studies in developing new therapies for Alzheimer's disease

Background: b-amyloid (Ab), a main content of amyloid plaque, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Ab induces neurotoxicity and cell death mainly through the production of reactive oxygen species (ROS). Garcinia mangostana L. (mangosteen, MS) has been recognized as a major source of natural antioxidant, xanthone, that could decrease ROS. However, its role in protection of Ab-induced apoptosis in neural cells remains unclear. Objective: To investigate the protective effect of MS extract on Ab-induced apoptosis in SK-N-SH cells. Methods: MS pericarp was extracted and standardized to contain certain amount of xanthone. Apoptosis in SK-N-SH cells were induced by 5-20 mM of Ab1-42. In parallel, MS extract (200-800 mg/ml) was preincubated (30 min) in cell culture before the induction by Ab1-42. The potential protective effects of MS extract were determined by evaluating cell morphology, cell viability using MTT test, ROS levels, caspase activity, apoptotic cell count, and cellular proteome. Results: The SK-N-SH cells showed cytotoxic changes after treatment with Ab1-42 in a dose-dependent manner. ROS levels were also significantly increased (approximately 5-10 folds), which corresponded with a decrease in cell viability (to w55-70% of the control), and an increase in caspase-3 activity (w2.5-fold of the control). All these Ab1-42-induced toxic effects were significantly reduced (almost completely) by the pretreatment with 400 mg/ml of MS extract. Interestingly, proteomic analysis using 2-D PAGE (n 1⁄4 5 gels/group) revealed 63 proteins spots whose levels were significantly altered by Ab1-42 induction. Among these, changes in 10 spots could be successfully prevented or recovered by the pretreatment with MS extract. All these altered proteins are subjected to identification by mass spectrometry (on-going). Conclusions: We have demonstrated significant protective effects of MS extract against Ab-induced ROS toxicity, increased caspase activity and apoptosis in SK-N-SH cells. Moreover, proteomic analysis revealed some proteins that might be responsible for these protective effects by MS extract. Characterizations of these proteins may lead to identification of novel therapeutic targets for successful prevention and/or decreasing the severity of AD.

Su2082 Pharmacokinetics (PK), Pharmacodynamics (PD), and Safety of Amg 181, a Fully Human Anti-α4β7 Antibody for Treating Inflammatory Bowel Diseases (IBD)

Pharmacokinetics (PK), Pharmacodynamics (PD), and Safety of Amg 181, a Fully Human Anti-α4β7 Antibody for Treating Inflammatory Bowel Diseases (IBD) Wei-Jian Pan, Barbara A. Sullivan, Christine M. Evangelista, David R. Doherty, Chi-Yan J. Tam, Sonal K. Patel, Peter J. Prince, Kai O. Reynhardt, William A. Rees, Hailing Hsu, Kefei Zhou, Wen Gu, Mark Yen, Christine A. Haller, Susanna Dodson, Zhigang Yu, Larry C. Wienkers, Dominique C. Borie

Mo1069 Effect of Oral Administration of a New Proton Pump Inhibitor E3710 on 24-h Intra-Gastric pH in Japanese Subjects

Background and Aims: Due to recurring nature of GERD, Most patients require long term maintenance therapy and continuous medication of proton pump inhibitor (PPI) is an adequate option for patients with erosive esophagitis. The aim of this study was to evaluate the efficacy and cost minimization analysis of omeprazole 10 mg once daily and rabeprazole 10 mg once daily for 24 weeks in the maintenance of remission Methods:This is randomized, open-label study enrolled 279 patients with erosive esophagitis A or B (LA classification) and typical GERD symptoms. Patients who showed complete endoscopic and symptomatic healing after 8 weeks PPI treatment were randomly allocated to maintenance treatment with omeprazole 10mg once daily or rabeprazole 10mg once daily for 42 weeks. The primary efficacy endpoint was the proportion of patients with symptomatic remission at 42 weeks. Secondary assessments included healing of reflux esophagitis, severity and frequency of reflux symptoms and cost-minimization analysis in the maintenance phase Results:At the end of 42 weeks of maintenance therapy, 96.4% of omeprazole treated and 95.1% of rabeprazole treated patients remained symptom free (P>0.05). Omeprazole and rabeprazole were also similarly efficacious in terms of endoscopic non-relapse rate for RE with 93.3% of patients on omeprazole and 97.5% of patients of rabeprazle. (P>0.05) Two drugs were also comparable with regard to severity and frequency of reflux symptoms duringmaintenance phase. (P>0.05) In the cost-minimization analysis, The mean total costs per patient for remaining symptom free within 6 months was 241,775 won in omeprazole and 287,115 won in rabeprazole, respectively.(as if 24 November 2011, 1 USD= 1,176.33 won) Conclusions:Omeprazole 10mg appeared to have a similar efficacy in maintaining symptomatic remission as rabeprazole 10 mg, but had a lower total cost per patient than rabeprazole 10mg.