DOCSLIB.ORG

Topical LOX Inhibitor  2 Compounds Phase 2 Ready in 2020

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Topical LOX Inhibitor  2 Compounds Phase 2 Ready in 2020 Investor Presentation Gary Phillips CEO 26 July 2019 For personal use only 1 Forward looking statement This document contains forward-looking statements, including statements concerning Pharmaxis’ future financial position, plans, and the potential of its products and product candidates, which are based on information and assumptions available to Pharmaxis as of the date of this document. Actual results, performance or achievements could be significantly different from those expressed in, or implied by, these forward-looking statements. All statements, other than statements of historical facts, are forward-looking statements. These forward-looking statements are not guarantees or predictions of future results, levels of performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this document. For example, despite our efforts there is no certainty that we will be successful in partnering our LOXL2 program or any of the other products in our pipeline on commercially acceptable terms, in a timely fashion or at all. Except as required by law we undertake no obligation to update these forward-looking statements as a result of new information, future events or otherwise. For personal use only 2 A business model generating a valuable pipeline in fibrotic and inflammatory diseases • Anti fibrosis / oncology drug successfully cleared initial Clinical phase 1 study trials in high • Proof of concept trials in myelofibrosis and / or profile pancreatic cancer expected in diseases 2020 Highly productive drug • Leverage small molecule expertise discovery engine and amine oxidase chemistry Significant future platform • 4 in house compounds through to cash flows from phase 1 trials in 5 years partnering deals • Topical scar revision drug in final • IPF / NASH anti fibrotic drug in pre-clinical GLP tox studies before commercial partnering process patient proof of concept study • Partnered drug with potential for 2020 $600m+ development milestones For personal use only nears end of phase 2a in NASH and diabetic retinopathy 3 Experienced senior management team Significant experience in drug development, commercialisation and partnering Gary Phillips – CEO Wolfgang Jarolimek – Drug Discovery . more than 30 years of operational management . more than 20 years’ experience in pharmaceutical drug experience in the pharmaceutical and healthcare industry discovery and published more than 30 peer reviewed in Europe, Asia and Australia articles . joined Pharmaxis in 2003 and was appointed Chief . previously Director of Assay Development and Compound Executive Officer in March 2013 at which time he was Profiling at the GlaxoSmithKline Centre of Excellence in Chief Operating Officer Drug Discovery in Verona, Italy . previously held country and regional management roles . spent 8 years as post-doc at the Max-Plank Institute in at Novartis – Hungary, Asia Pacific and Australia Munich, Germany; Baylor College of Medicine, Houston, Texas; Rammelkamp Centre, Cleveland Ohio; and University of Heidelberg, Germany David McGarvey – CFO Kristen Morgan – Alliance . more than 30 years’ experience building Australian based Management companies from inception to globally successful . more than 20 years’ experience in the pharmaceutical enterprises industry having previously held a senior role in medical . joined Pharmaxis as Chief Financial Officer and Company affairs at Sanofi-Aventis, and a commercial sales role at Secretary in December 2002 GlaxoSmithKline . previously Chief Financial Officer of the Filtration and . responsibility for alliance management and medical and Separations Division of US Filter (1998-2002), and Memtec regulatory affairs Limited (1985-1998) . commenced career at PricewaterhouseCoopers Non Executive Directors Brett Charlton - Medical . Malcolm McComas – Chair . Will Delaat . more than 25 years experience in clinical trial design and – former investment banker – former CEO of Merck Australia management – former MD Citi Group – former chair of Medicines Australia . author of more than 80 scientific papers . Kathleen Metters . Edward Rayner . founding Medical Director of the National Health Sciences – former head of worldwide basic – over 20 years’ experience in global Centre research at Merck capital markets For personal use only . previously held various positions with the Australian National University, Stanford University, the Baxter – former CEO of biopharmaceutical Centre for Medical Research, Royal Melbourne Hospital, company Lycera Corp and the Walter and Eliza Hall Institute 4 Read more on the Pharmaxis website A broad pipeline with multiple opportunities Lead Pre Indication Discovery Phase I Phase II Phase III Marketed Optimisation Clinical Commercial FDA expected to complete review of NDA in Q1 2020. Subject to FDA approval, US partner Chiesi will launch Bronchitol® US Cystic fibrosis commercially in the US in 2020. Bronchitol is currently sold in the UK, Germany, Italy, Greece & Nordic by Chiesi; in certain other European Direct & Bronchitol RoW Cystic fibrosis countries and Russia by specialist distributors; and by PXS in Australia and smaller countries. Dist Asthma Aridol is approved and sold in US, Australia, South Korea and a number of European countries. Canadian Direct & Aridol® diagnosis approval received June 2019. Dist Clinical Sold to Boehringer Ingelheim in May 2015. Phase 2a trial completed June 2019 – to AOC3 NASH report Q4 CY 2019. PXS has received payments of A$68m to date. Diabetic Boehringer commenced dosing a Phase 2a trial in January 2018. PXS received A$15m AOC3 retinopathy to date. NASH, fibrosis - LOXL-2 liver, lung, Phase 1 trials in 2 compounds complete. Commercial partnering process kidney, heart commenced. Anti-fibrotic: Completed phase 1a SAD. To complete phase 1b MAD H2 CY 2019 Progress in last 12 months Systemic LOX cancer Preclinical For personal use only Anti-fibrotic: Effective in scarring models. Commence phase 1 H1 CY 2020 Topical LOX scarring AOC3: amine oxidase copper containing type 3 inhibitor; LOXL-2 (lysyl oxidase like 2) inhibitor (also inhibits LOX-3); 5 LOX: pan (all) lysyl oxidase inhibitor; Systemic: oral drug; Topical: drug to be applied directly to the skin. AOC3: Boehringer Ingelheim deal Deal structure illustrates value generating potential of Pharmaxis business model PLUS earn-out payments First indication (NASH) on annual net sales • Tiered percentages Commencement of Commencement of Filing, regulatory & increasing from high phase 2 phase 3 pricing approvals single digits • Plus sales milestones €18m €37m €140m Upfront Total Potential Milestones (2015) €419 €29m Second indication (diabetic retinopathy) (~A$625m) Commencement of Commencement of Filing, regulatory & phase 2 phase 3 pricing approvals €10m €25m €160m For personal use only • €57m (A$83m) already received • No further investment required from Pharmaxis • Commercial go/no go for phase 2b in NASH expected Q4 2019 6 LOXL2 inhibition program in partnering process for NASH, IPF & other high value fibrotic diseases . LOXL2 and fibrosis: Excessive production and linking of LOX family of enzymes catalyse the final step in the collagen fibres results in fibrosis fibrotic disease process Clear association of increased levels of serum LOXL2 with disease progression in IPF, NASH and cardiac fibrosis Fibroblast cells in Fibroblast cells in . Competitive profile: humanhuman tissue tissue Novel target and mechanism of action LOXL2 (from fibroblasts) Once daily oral drug Best in class drug with high level inhibition of LOXL2 enzyme for 24 hours from one dose in phase 1 studies 13 week tox studies (2 species) for both compounds Collagen fibres Excessive ‘cross-linking’ of collagen fibres, stiffens tissue, Place of LOXL2 at the end of the fibrotic cascade causing fibrosis provides opportunity to treat various fibrotic diseases Potential indications / market size: and use in combination with other Pharma pipeline NASH / Liver Fibrosis; $35b1 Significant drugs Pulmonary fibrosis (IPF); $3.5b2 For personal use only . Commercial partnering process underway Kidney fibrosis market Cardiac fibrosis opportunity Data room available (under CDA) Process expected to be concluded by end 2019 1. 7 Deutsche Bank market forecast for 2025 2. iHealthcareanalyst. Inc market forecast for 2021 Global leaders in amine oxidase enzyme inhibition Two new drugs expected to start proof of efficacy studies in 2020 Targeting multiple different pathways Systemic LOX Inhibitor Chronic Inflammation . Completed phase 1a – excellent PK/PD profile . Predicted 24 hour inhibition of LOX with single daily dose . Two indications with strong academic and clinical advocacy; Myelofibrosis and Pancreatic Cancer . Phase 1b to complete by Q4 2019 . Proof of efficacy studies to commence in H1 2020 1 2 0 1 0 0 y 8 0 P la c e b o t i v i t 3 0 0 m g 6 0 c a MPO 2 0 0 m g AOC3 % 4 0 1 0 0 m g 2 0 5 0 m g LOXL2 LOX 0 0 4 8 1 2 1 6 2 0 2 4 t i m e [ h r s ] . Highly productive; Dose dependent reduction in LOX activity in plasma 1 compound partnered (AOC3) 2 compounds partner ready (LOXL2) Topical LOX Inhibitor 2 compounds phase 2 ready in 2020 . Compelling pre clinical efficacy in skin fibrosis / scarring (Systemic and topical LOX) models For personal use only . R&D tax credit funds a significant share of . Limited competition and strong clinical advocacy expenditure (43.5% of eligible expenditure .
Load more

Recommended publications
  • Zinc-Α2-Glycoprotein Is an Inhibitor of Amine Oxidase
    1 Supplemental Fig. 1 and 2 of “ZINC-α2-GLYCOPROTEIN IS AN INHIBITOR OF AMINE 2 OXIDASE COPPER-CONTAINING 3”, Matthias Romauch 3 Plasma enhances AOC3 activity 4 Endogenous plasma amine oxidase activity has previously been described in both human and 5 mouse plasma [1–3]. This activity derives from membrane-bound AOC3 which has been 6 released by metalloprotease activity [4]. A pronounced increase in levels of cleaved AOC3 is 7 observed during diabetes, congestive heart failure and liver cirrhosis [5–7]. Incubating 8 recombinant AOC3 with IEX fractions lacking ZAG (Fig. 4, B) increased amine oxidase 9 activity, which might be due to plasma-derived AOC3 activity or other plasma components. 10 To test this hypothesis, the amine oxidase activity in plasma of wt, AOC3 k.o. and ZAG k.o. 11 mice was measured directly using radioactive benzylamine as substrate. The activity linearly 12 increased with measured plasma volume of wt and ZAG k.o. mice, and the activity could be 13 blocked by the highly selective AOC3 inhibitor LJP1586 (Supplemental Fig. 1, A and B). 14 However, AOC3 activity in AOC3 k.o. plasma does not increase with increasing plasma 15 volume and residual activity cannot be further significantly reduced by adding LJP1586 16 (Supplemental Fig. 1, C). This suggests that AOC3 is the main plasma enzyme responsible for 17 benzylamine deamination, but it does not exclude other amine oxidases that are not sensitive 18 to LJP1586 or that have a higher affinity for other substrates. One such category of enzymes 19 could be the lysyl oxidases, which are also members of the copper amine oxidase family.
    [Show full text]
  • Increased Vascular Adhesion Protein 1 (VAP-1) Levels Are Associated with Alternative M2 Macrophage Activation and Poor Prognosis for Human Gliomas
    diagnostics Article Increased Vascular Adhesion Protein 1 (VAP-1) Levels Are Associated with Alternative M2 Macrophage Activation and Poor Prognosis for Human Gliomas Shu-Jyuan Chang 1 , Hung-Pin Tu 2, Yen-Chang Clark Lai 3, Chi-Wen Luo 4,5, Takahide Nejo 6, 6 3,7,8, , 9,10, , Shota Tanaka , Chee-Yin Chai * y and Aij-Lie Kwan * y 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; [email protected] 2 Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; [email protected] 3 Department of Pathology, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan; [email protected] 4 Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan; [email protected] 5 Department of Surgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan 6 Department of Neurosurgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; [email protected] (T.N.); [email protected] (S.T.) 7 Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 8 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan 9 Department of Neurosurgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan 10 Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan * Correspondence: [email protected] (C.-Y.C.); [email protected] (A.-L.K.); Tel.: +88-6-7312-1101 (ext.
    [Show full text]
  • The Role of Protein Crystallography in Defining the Mechanisms of Biogenesis and Catalysis in Copper Amine Oxidase
    Int. J. Mol. Sci. 2012, 13, 5375-5405; doi:10.3390/ijms13055375 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review The Role of Protein Crystallography in Defining the Mechanisms of Biogenesis and Catalysis in Copper Amine Oxidase Valerie J. Klema and Carrie M. Wilmot * Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church St. SE, Minneapolis, MN 55455, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-612-624-2406; Fax: +1-612-624-5121. Received: 6 April 2012; in revised form: 22 April 2012 / Accepted: 26 April 2012 / Published: 3 May 2012 Abstract: Copper amine oxidases (CAOs) are a ubiquitous group of enzymes that catalyze the conversion of primary amines to aldehydes coupled to the reduction of O2 to H2O2. These enzymes utilize a wide range of substrates from methylamine to polypeptides. Changes in CAO activity are correlated with a variety of human diseases, including diabetes mellitus, Alzheimer’s disease, and inflammatory disorders. CAOs contain a cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ), that is required for catalytic activity and synthesized through the post-translational modification of a tyrosine residue within the CAO polypeptide. TPQ generation is a self-processing event only requiring the addition of oxygen and Cu(II) to the apoCAO. Thus, the CAO active site supports two very different reactions: TPQ synthesis, and the two electron oxidation of primary amines. Crystal structures are available from bacterial through to human sources, and have given insight into substrate preference, stereospecificity, and structural changes during biogenesis and catalysis.
    [Show full text]
  • Effects of an Anti-Inflammatory VAP-1/SSAO Inhibitor, PXS-4728A
    Schilter et al. Respiratory Research (2015) 16:42 DOI 10.1186/s12931-015-0200-z RESEARCH Open Access Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration Heidi C Schilter1*†, Adam Collison2†, Remo C Russo3,4†, Jonathan S Foot1, Tin T Yow1, Angelica T Vieira4, Livia D Tavares4, Joerg Mattes2, Mauro M Teixeira4 and Wolfgang Jarolimek1,5 Abstract Background and purpose: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Methods: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Results: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity.
    [Show full text]
  • Human AOC3 ELISA Kit (ARG81991)
    Product datasheet [email protected] ARG81991 Package: 96 wells Human AOC3 ELISA Kit Store at: 4°C Component Cat. No. Component Name Package Temp ARG81991-001 Antibody-coated 8 X 12 strips 4°C. Unused strips microplate should be sealed tightly in the air-tight pouch. ARG81991-002 Standard 2 X 50 ng/vial 4°C ARG81991-003 Standard/Sample 30 ml (Ready to use) 4°C diluent ARG81991-004 Antibody conjugate 1 vial (100 µl) 4°C concentrate (100X) ARG81991-005 Antibody diluent 12 ml (Ready to use) 4°C buffer ARG81991-006 HRP-Streptavidin 1 vial (100 µl) 4°C concentrate (100X) ARG81991-007 HRP-Streptavidin 12 ml (Ready to use) 4°C diluent buffer ARG81991-008 25X Wash buffer 20 ml 4°C ARG81991-009 TMB substrate 10 ml (Ready to use) 4°C (Protect from light) ARG81991-010 STOP solution 10 ml (Ready to use) 4°C ARG81991-011 Plate sealer 4 strips Room temperature Summary Product Description ARG81991 Human AOC3 ELISA Kit is an Enzyme Immunoassay kit for the quantification of Human AOC3 in serum, plasma (heparin, EDTA) and cell culture supernatants. Tested Reactivity Hu Tested Application ELISA Specificity There is no detectable cross-reactivity with other relevant proteins. Target Name AOC3 Conjugation HRP Conjugation Note Substrate: TMB and read at 450 nm. Sensitivity 0.39 ng/ml Sample Type Serum, plasma (heparin, EDTA) and cell culture supernatants. Standard Range 0.78 - 50 ng/ml Sample Volume 100 µl www.arigobio.com 1/3 Precision Intra-Assay CV: 5.8%; Inter-Assay CV: 6.6% Alternate Names HPAO; Semicarbazide-sensitive amine oxidase; VAP-1; Vascular adhesion protein 1; Copper amine oxidase; SSAO; Membrane primary amine oxidase; EC 1.4.3.21; VAP1 Application Instructions Assay Time ~ 5 hours Properties Form 96 well Storage instruction Store the kit at 2-8°C.
    [Show full text]
  • Mechanism–Based Inhibitors for Copper Amine Oxidases
    MECHANISM–BASED INHIBITORS FOR COPPER AMINE OXIDASES: SYNTHESIS, MECHANISM, AND ENZYMOLOGY By BO ZHONG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Adviser: Dr. Lawrence M. Sayre, Dr Irene Lee Department of Chemistry CASE WESTERN RESERVE UNIVERSITY January, 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ______________________________________________________ candidate for the ________________________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Table of Contents ............................................................................................................... I List of Tables .................................................................................................................... V List of Figures .................................................................................................................. VI List of Schemes ................................................................................................................ XI Acknowledgements
    [Show full text]
  • Semicarbazide-Sensitive Amine Oxidase and Vascular Complications in Diabetes Mellitus
    ! " # $% &'((% ()*+,- .-. (,/'*,-.-, 0.1,'(, 00.1. 2332 Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Medical Pharmacology presented at Uppsala University in 2002 ABSTRACT Nordquist, J. 2002. Semicarbazide-sensitive amine oxidase and vascular complications in diabetes mellitus. Biochemical and molecular aspects. Acta Universitatis Upsaliensis. Comprehensive summaries of Uppsala Dissertations from the Faculty of Medicine 1174. 51 pp. Uppsala ISBN 91-554-5375-9. Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde- products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs). This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes.
    [Show full text]
  • ELISA Kit for Amine Oxidase, Copper Containing 3 (AOC3)
    SEC298Ra 96 Tests Enzyme-linked Immunosorbent Assay Kit For Amine Oxidase, Copper Containing 3 (AOC3) Organism Species: Rattus norvegicus (Rat) Instruction manual FOR RESEARCH USE ONLY NOT FOR USE IN CLINICAL DIAGNOSTIC PROCEDURES 12th Edition [ INTENDED USE ] The kit is a sandwich enzyme immunoassay for in vitro quantitative measurement of AOC3 in rat serum, plasma, tissue homogenates, cell lysates and other biological fluids. [ REAGENTS AND MATERIALS PROVIDED ] Reagents Quantity Reagents Quantity Pre-coated, ready to use 96-well strip plate 1 Plate sealer for 96 wells 4 Standard 2 Standard Diluent 1×20mL Detection Reagent A 1×120μL Assay Diluent A 1×12mL Detection Reagent B 1×120μL Assay Diluent B 1×12mL TMB Substrate 1×9mL Stop Solution 1×6mL Wash Buffer (30 × concentrate) 1×20mL Instruction manual 1 [ MATERIALS REQUIRED BUT NOT SUPPLIED ] 1. Microplate reader with 450 ± 10nm filter. 2. Single or multi-channel pipettes with high precision and disposable tips. 3. Microcentrifuge Tubes. 4. Deionized or distilled water. 5. Absorbent paper for blotting the microplate. 6. Container for Wash Solution. 7. 0.01mol/L (or 1×) Phosphate Buffered Saline(PBS), pH7.0-7.2. [ STORAGE OF THE KITS ] 1. For unused kit: All the reagents should be kept according to the labels on vials. The Standard, Detection Reagent A, Detection Reagent B and the 96-well strip plate should be stored at -20oC upon receipt while the others should be at 4oC. 2. For used kit: When the kit is used, the remaining reagents need to be stored according to the above storage condition. Besides, please return the unused wells to the foil pouch containing the desiccant pack, and zip-seal the foil pouch.
    [Show full text]
  • Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis
    Article Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis Raine Toivonen 1, Sanja Vanhatalo 1, Maija Hollmén 1,2, Eveliina Munukka 1,3, Anniina Keskitalo 1,3 , Sami Pietilä 4, Laura Elo 4, Pentti Huovinen 1, Sirpa Jalkanen 1,2,† and Satu Pekkala 3,5,*,† 1 Institute of Biomedicine, Faculty of Medicine, University of Turku, 20014 Turku, Finland; [email protected] (R.T.); sahevan@utu.fi (S.V.); maijal@utu.fi (M.H.); laevmu@utu.fi (E.M.); anniina.keskitalo@utu.fi (A.K.); penhuo@utu.fi (P.H.); sirjal@utu.fi (S.J.) 2 Medicity Research Laboratory, University of Turku, 20014 Turku, Finland 3 Department of Clinical Microbiology and Immunology, Turku University Hospital, 20521 Turku, Finland 4 Turku Centre for Biotechnology, 20014 Turku, Finland; sami.pietila@utu.fi (S.P.); laura.elo@utu.fi (L.E.) 5 Faculty of Sport and Health Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland * Correspondence: satu.p.pekkala@jyu.fi; Tel.: +358-45-358-28-98 † These authors contributed equally to this work. Abstract: Toll-like receptor 5 ligand, flagellin, and vascular adhesion protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. This study aimed to determine whether VAP-1 mediates flagellin- induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 weeks for 10 weeks.
    [Show full text]
  • Amine Oxidase Copper-Containing 3 (AOC3) Inhibition: a Potential Novel
    Boyer et al. Int J Retin Vitr (2021) 7:30 https://doi.org/10.1186/s40942-021-00288-7 International Journal of Retina and Vitreous REVIEW Open Access Amine oxidase copper-containing 3 (AOC3) inhibition: a potential novel target for the management of diabetic retinopathy David S. Boyer1, Joerg F. Rippmann2, Michael S. Ehrlich3, Remko A. Bakker2, Victor Chong4 and Quan Dong Nguyen5* Abstract Background: Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of visual impairment in people aged 20–65 years and can go undetected until vision is irreversibly lost. There is a need for treatments for non-proliferative diabetic retinopathy (NPDR) which, in comparison with current intravitreal (IVT) injec- tions, ofer an improved risk–beneft ratio and are suitable for the treatment of early stages of disease, during which there is no major visual impairment. Efcacious systemic therapy for NPDR, including oral treatment, would be an important and convenient therapeutic approach for patients and physicians and would reduce treatment burden. In this article, we review the rationale for the investigation of amine oxidase copper-containing 3 (AOC3), also known as semicarbazide-sensitive amine oxidase and vascular adhesion protein 1 (VAP1), as a novel target for the early treat- ment of moderate to severe NPDR. AOC3 is a membrane-bound adhesion protein that facilitates the binding of leuko- cytes to the retinal endothelium. Adherent leukocytes reduce blood fow and in turn rupture blood vessels, leading to ischemia and edema. AOC3 inhibition reduces leukocyte recruitment and is predicted to decrease the production of reactive oxygen species, thereby correcting the underlying hypoxia, ischemia, and edema seen in DR, as well as improving vascular function.
    [Show full text]
  • Absence of the Endothelial Oxidase AOC3 Leads to Abnormal Leukocyte Traffic in Vivo
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity, Vol. 22, 105–115, January, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.immuni.2004.12.006 Absence of the Endothelial Oxidase AOC3 Leads to Abnormal Leukocyte Traffic In Vivo Craig M. Stolen,1,3 Fumiko Marttila-Ichihara,1,3 2000). Selectins and their sialomucin ligands contribute Kaisa Koskinen,1 Gennady G. Yegutkin,1 Raisa Turja,1 to the initial shear-dependent interactions between the Petri Bono,1,4 Mikael Skurnik,2 Arno Ha¨ nninen,1 vascular endothelium and blood-borne leukocytes (Ley Sirpa Jalkanen,1 and Marko Salmi1,* and Kansas, 2004; Rosen, 2004). If rolling cells receive 1Department of Medical Microbiology appropriate activating signals from chemokines, they MediCity Research Laboratory can firmly bind to the endothelial cells (Kunkel and National Public Health Institute Butcher, 2002; Miyasaka and Tanaka, 2004). The firm Turku University adhesion and the subsequent transmigration step are 20520 Turku mediated by leukocyte integrins and adhesion mole- Finland cules belonging to the immunoglobulin superfamily (De- 2 Department of Bacteriology and Immunology jana, 2004; Muller, 2003; Pribila et al., 2004). However, Helsinki University the tissue selectivity and kinetics of leukocyte extrava- University of Helsinki sation in such a complex process can only be partly 00290 Helsinki explained by the function of these well-established mol- Finland ecules. We have previously provided in vitro evidence that antibodies against AOC3 (also known as EC1.4.3.6, pla- Summary cental amine oxidase, or VAP-1) partially block leuko- cyte-endothelial interactions (Koskinen et al., 2004; La- Leukocyte migration from the blood to tissues is a lor et al., 2002; Salmi and Jalkanen, 1992; Salmi et al., prerequisite for normal immune responses.
    [Show full text]
  • 19 December 2019
    – 18 December 2019 ISSN 1443P-a8g5e0 X1 Bioshares Number 824 Page 1 Bioshares Holiday Period Editions Tuesday 24 December Thurusday 2 January Tuesday 28 January 18 December 2019 Edition 824 Bioshares is publised 48 times a year Delivering independent investment research to investors on Australian biotech, pharma and healthcare companies Companies covered: ANP, PXS – This Special Edition of Bioshares provides Extract from Bioshares analysis of Antisense Therapuetics, which – Boehringer Ingelheim Discontinues has released the final results of its Phase Pharmaxis ’s Mus- IIa study of ATL1102 in Duchenne NASH Program; cular Dystrophy, and Pharmaxis, which Continues in Diabetic Retinopathy announced that Boehringer Ingelheim will discontinue the development of BI 1467335 Pharmaxis (PXS: $0.155) announced today that Boehringer Ingelheim will discontinue the (formerly PXS 4728A) in the indication of development of BI 1467335 in the indication of NASH (non-alcoholic steatohepatitis) or NASH, but is continuing with its develop- fatty liver disease. ment in diabetic retinopathy. The reason cited for the discontinuation was because of potentially drug interaction effects which were observed in a small Phase I study only recently completed by Boehringer Ingelheim. The 10 patient study evaluated the effect of BI 1467335 on monoamine oxidase B (MOA- B) levels, an enzyme involved in dopamine metabolism. Two MOA-B inhibitors, selegiline and rasagiline, are used to treat Parkinson's disease, and the hydrazine class of MOA-B drugs are used as anti-depressants. Boehringer has decided to discontinue development of BI 1467335 in NASH because of the possibility of side effects occurring in some of the patients taking those drugs, where the numbers of those patients would be significant.
    [Show full text]