( 12 ) United States Patent

Total Page:16

File Type:pdf, Size:1020Kb

( 12 ) United States Patent US010233174B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,233 , 174 B2 Long ( 45) Date of Patent : Mar. 19 , 2019 ( 54 ) THIOCARBAMATE PRODRUGS OF FOREIGN PATENT DOCUMENTS TOFACITINIB CN 106496233 A 3 /2017 WO 93 /22334 Al 11/ 1993 (71 ) Applicant : THERAVANCE BIOPHARMA R & D wo 2011 /097987 A1 8 / 2011 IP , LLC , South San Francisco , CA WO 2011097087 AL 8 / 2011 (US ) OTHER PUBLICATIONS ( 72 ) Inventor: Daniel D . Long , San Francisco , CA Amidon et al ., " Colon - targeted oral drug delivery systems: Design (US ) trends and approaches ” , AAPS PharmSciTech , 16 ( 4 ) : 731 - 741 ( 2015 ) . (73 ) Assignee : THERAVANCE BIOPHARMA R & D Azad Khan et al. , “ Tissue and bacterial splitting of sulphasalazine ” , IP , LLC , South San Francisco , CA Clinical Science, 64 : 349 - 354 ( 1983 ) . Bouvier et al. , “ First enzymatically activated Taxotere prodrugs (US ) designed for ADEPT and PMT” , Bioorganic & Medicinal Chem istry , 12 : 969 -977 (2004 ) . ( * ) Notice: Subject to any disclaimer, the term of this Bunnelle , “ Reagents for stereoselective preparation of N - carbamyl patent is extended or adjusted under 35 beta - D - glucuronides ” , The Journal of Organic Chemistry , 76 : 5429 5432 ( 2011 ) . U . S . C . 154 ( b ) by 0 days . Burke et al. , “ Development of novel quaternary ammonium linkers for antibody -drug conjugates ” , Molecular Cancer Therapeutics, (21 ) Appl. No. : 15 / 986 ,018 15 ( 5 ) : 938 - 945 (May 2016 ) . Chourasia et al. , “ Pharmaceutical approaches to colon targeted drug delivery systems” , J Pharm Pharmaceut Sci, 6 ( 1 ) : 33 -66 (2003 ) . ( 22) Filed : May 22 , 2018 Clark et al. , “ Discovery and development of Janus Kinase (JAK ) inhibitors for inflammatory diseases ” , Journal of Medicinal Chem istry , 57 : 5023 - 5038 ( 2014 ) . Prior Publication Data Danese, " New therapies for inflammatory bowel disease: from the US 2018 /0339980 A1 Nov. 29, 2018 bench to the bedside” , Gut, 61: 918 - 932 ( 2012 ) . Friend et al . , “ A colon - specific drug -delivery system based on drug glycosides and the glycosidases of colonic bacteria ” , J Med Chem , 27 : 261 - 266 ( 1984 ) . Related U . S . Application Data (Continued ) (60 ) Provisional application No . 62 /509 , 852 , filed on May Primary Examiner — Venkataraman Balasubramanian 23 , 2017 , provisional application No . 62/ 544, 318 , ( 74 ) Attorney, Agent, or Firm — Jeffrey A . Hagenah ; filed on Aug . 11 , 2017 . Florence Jovic (51 ) Int. CI. (57 ) ABSTRACT C07D 405 / 14 ( 2006 . 01 ) The invention relates to thiocarbamate prodrug compounds C07D 487 /04 ( 2006 .01 ) of the Janus kinase ( JAK ) inhibitor tofacitinib having for CO7H 15 / 26 ( 2006 . 01 ) mula 1: C12P 17 / 16 ( 2006 . 01 ) A61P 1 /00 ( 2006 . 01 ) A61K 31 / 7028 ( 2006 . 01 ) (52 ) U .S . CI. CPC . .. .. .. C07D 405 / 14 ( 2013 .01 ) ; A61K 31 / 7028 ( 2013 .01 ) ; A61P 1 /00 (2018 .01 ) ; C07D 487/ 04 -z ( 2013 .01 ) ; C07H 15 / 26 ( 2013 .01 ) ; C12P 17 / 165 ( 2013. 01 ) ( 58 ) Field of Classification Search CH3 CPC . .. CO7D 405 / 14 ; CO7D 487 /04 ; CO7H 15 / 26 ; N CH3 C12P 17 / 165 ; A61K 31 /7028 (( R2 ) ) :n 1 USPC .. .. 544 /280 ; 514 / 265. 1 R1 See application file for complete search history. HOCO O ( 56 ) References Cited HO Y " OH NC U . S . PATENT DOCUMENTS OH 5 ,811 , 388 A 9 / 1998 Friend et al. RE41 ,783 E 9 / 2010 Blumenkopf et al. wherein R1, R², RS, R4 and n are as defined . The invention 2011 /0086810 A1 4 / 2011 Rodgers et al. also relates to pharmaceutical compositions comprising such 2011 /0152207 AL 6 / 2011 Goff et al . compounds ; methods of using such compounds to treat 2012 / 0289571 AL 11/ 2012 Zhao et al . gastrointestinal inflammatory diseases, and processes and 2014 / 0357557 Al 12/ 2014 Cole et al. 2017 /0145044 A1 * 5 / 2017 Hudson .. C07H 15 / 26 intermediates for preparing such compounds . 2018 / 0258094 AL 9 / 2018 Long et al. 27 Claims, No Drawings US 10 , 233 , 174 B2 Page 2 References Cited Heller et al. , “ Oxazolone coatis , a Th2 colitis model resembling ( 56 ) ulcerative colitis , is mediated by IL - 13 - producing NK - T cells ” , Immunity , 17 : 629 -638 (Nov . 2002 ) . OTHER PUBLICATIONS Kodela et al. , “ NOSH -aspirin : a novel nitric oxide - hydrogen sulfide Friend et al. , “ Drug glycosides: Potential prodrugs for colon releasing hybrid : a new class of anti - inflammatory pharmaceuti cals ” , ACS Med Chem Lett, 3 : 257 - 262 ( 2012 ) . specific drug delivery ” , J Med Chem , 28: 51 - 57 (1985 ) . Lonnerholm et al. , “ Amount and distribution of carbonic anhydrases Friend , “ Glycosides in colonic drug delivery ” , Oral colon -specific CAI and CA II in the gatrointestinal tract" , Gastroenterology , 88 : drug delivery , pp . 153 - 187 ( 1992 ) . 1151 - 1161 ( 1985 ) . Goff et al. , “ Targeted delivery of vitamin D to the colon using Schmidt et al. , “ Prodrug mono therapy : synthesis and biological beta - glucuronides of vitamin D : therapeutic effects in a murine evaluation of an etoposide glucuronide - prodrug” , Bioorganic & model of inflammatory bowel disease” , Am J Physiol Gastrointest Medicinal Chemistry , 11 : 2277 -2283 (2003 ) . Liver Physiol , 302 : G460 -G469 ( 2012 ) . Schmidt et al. , “ Cancer chemotherapy : a paclitaxel prodrug for Jeffrey et al. , “ Expanded utility of the beta - glucuronide linker : ADEPT ( antibody -directed enzyme prodrug therapy ) ” , Eur J Org Chem , pp . 2129 -2134 (2001 ) . ADCs that deliver phenolic cytotoxic agents ” , ACS Medicinal Steiger et al. , “ Bio - orthogonal “ click -and - release ” donation of caged Chemisty Letters , 1 : 277 - 280 ( 2010 ) . carbonyl sulfide (COS ) and hydrogen sulfide (H2S ) ” , Chem Com Kagan et al. , “ Systems for region selective drug delivery in the mun , 53 : 1378 -1380 (2017 ) . gastrointestinal tract : biopharmaceutical considerations ” , Expert Steiger et al. , “ Self - immolative thiocarbamates provide access to Opin Drug Deliv , 5 ( 6 ) : 681 -692 ( 2008 ) . triggered H2S donors and analyte replacement fluorescent probes” , Kolakowski et al . , “ The methylene alkoxy carbamate self J Am Chem Soc, 138 : 7256 -7259 (2016 ) . immolative unit : utilization for the targeted delivery of alcohol Tan et al. , “ New method for quantification of gasotransmitter containing payloads with antibody - drug conjugates” , Angew Chem hydrogen sulfide in biologicalmatrices by LC -MS / MS ” , Nature , pp . Int Ed , 55 : 1 - 5 ( 2016 ) . 1 - 12 ( 2017 ) . Kolakowski et al ., “ The methylene alkoxy carbamate self Wallace et al. , " Gastrointestinal safety and anti - inflammatory effects immolative unit : utilization for the targeted delivery of alcohol of a hydrogen sulfide - releasing diclofenac derivative in the rat ” , containing payloads with antibody - drug conjugates ” , Angew Chem Gastroenterology , 132 : 261- 271 ( 2007 ) . Int Ed , 55 : 1 - 5 Supporting Information (2016 ) . Wallace et al. , “ Hydrogen sulfide -based therapeutics : exploiting a Lam et al. , “ Vedolizumab for ulcerative colitis and Crohn ' s disease : unique but ubiquitous gasotransmitter” , Nature Reviews, 14 : 329 results and implications of GEMINI studies” , Immunotherapy , 6 ( 9 ) : 345 (May 2015 ) . 963 - 971 ( 2014 ) . Angenault et al ., " Cancer chemotherapy: A SN - 38 ( 7 -ethyl - 10 Lougerstay -Madec et al. , “ Synthesis of self- immolative glucuronide hydroxycamptothecin ) glucuronide prodrug for treatment by a based prodrugs of a phenol mustard ” , Anti - Cancer Drug Design , 13 : PMT (prodrug montherapy ) strategy ” , Bioorganic & Medicinal Chem 995 - 1007 ( 1998 ) . istry Letters, 13 : 947 - 950 (2003 ) . Mozaffari et al. , “ New biologic therapeutics for ulcerative colitis Desbene et al. , “ Application of the ADEPT strategy to the MDR and Crohn ' s disease” , Expert Opin Biol Ther, 14 ( 5 ) : 583 -600 resistance in cancer chemotherapy ” , Anti- cancer Drug Design , ( 2014 ) . 14 ( 2 ) : 93 - 106 ( 1999 ) . Panes et al. , “ Randomized trial of tofacitinib in active ulcerative Desbene et al. , “ Application of the ADEPT strategy to the MDR colitis : analysis of efficacy based on patient- reported outcomes ” , resistance in cancer chemotherapy ” , XP- 002780712 ( 1999 ). BMC Gastroenterology , 15 : 14 - 23 ( 2015 ) . Goto et al ., “ Synthesis and biological activity of the metabolites of Philip et al. , “ Colon targeted drug delivery systems: A review on diethyl 4 - [ ( 4 -bromo - 2 -cyanophenyl ) carbamoyl] benzylphosphonate primary and novel approaches ” , Oman Medical Journal, 25 ( 2 ) : (NO - 1886 ) ” , Chem Pharm Bull , 44 ( 3 ) : 547 -551 ( 1996 ) . 70 - 78 (2010 ) . Kiss et al. , “ Synthesis and O . R . D ./ C . D . spectra of the anomers of Sandborn et al. , “ Tofacitinib , an oral janus kinase inhibitor, in active 2 - amino - 5 - ethoxyphenyl d - glucopyranosiduronic acid and some ulcerative colitis ” , The New England Journal of Medicine , pp . derivatives thereof” , Carbohydrate Research , 12 : 115 - 129 ( 1970 ) . 616 -624 ( 2012 ) . Kreuzer et al. , “ Aufbau von oligosacchariden mit glycosylfluoriden Scheline, “ Drug metabolism by intestinal microorganisms” , Journal unter lewissaure -katalyse ” , Carbohydrate Research , 149 : 347 -361 of Pharmaceutical Sciences , 57 ( 12 ) : 2021- 2037 ( 1968 ) . ( 1986 ) . Schmidt et al. , " Glucuronide prodrugs of hydoxy compounds for Papot et al. , “ Design of selectively activated anticancer prodrugs : antibody directed enzyme prodrug therapy (ADEPT ) : a phenol Elimination and cyclization strategies ” , Current Medicinal Chem nitrogen mustard carbamate ” , Bioorganic & Medicinal Chemistry istry , 2 ( 2 ) : 155 -185 (2002
Recommended publications
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • Download PDF Document
    Journal for ImmunoTherapy of Cancer 2019, 7(Suppl 1):283 https://doi.org/10.1186/s40425-019-0764-0 MEETINGABSTRACTS Open Access 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 2 National Harbor, MD, USA. 10 November 2019 Published: 6 November 2019 About this supplement These abstracts have been published as part of Journal for ImmunoTherapy of Cancer Volume 7 Supplement 1, 2019. The full contents of the supplement are available online at https://jitc.biomedcentral.com/articles/supplements/volume-7-supplement-1. Please note that this is part 2 of 2. Poster Presentations median survival; 3) FTN203 did not negate the efficacy of anti- PD-1 or anti-PD-L1 immunotherapy antibody when combined; 4) Biomarkers, Immune Monitoring, and Novel FTN203 significantly improved the efficacy of anti-PD-1 by further Technologies reducing the tumor growth (by 80% on day 26, P=0.046) and in- creasing the median survival (by 5 days or 14%, Log-rank test P= P501 0.031), against the combo of COMPLETE and anti-PD-1; 5) None Dietary deprivation of non-essential amino acids improves anti-PD- of the mono or combo treatments caused body weight loss. 1 immunotherapy in murine colon cancer Conclusions Zehui Li, PhD, Grace Yang, PhD, Shuang Zhou, PhD, Xin Wang, MD, PhD, Our data supports the use of dietary NEAA deprivation to improve Xiyan Li, PhD the efficacy of anti-PD-1 or anti-PD-L1 immunotherapy for colorectal Filtricine, Inc., Santa Clara, CA, United States cancer without noticeable side effects.
    [Show full text]
  • PD-1 / PD-L1 Combination Therapies
    PD-1 / PD-L1 Combination Therapies Jacob Plieth & Edwin Elmhirst – May 2017 Foreword Sprinkling the immuno-oncology dust When in November 2015 EP Vantage published its first immuno- oncology analysis we identified 215 studies of anti-PD-1/PD-L1 projects combined with other approaches, and called this an important industry theme. It is a measure of how central combos have become that today, barely 18 months on, that total has been blown out of the water. No fewer than 765 studies involving combinations of PD-1 or PD-L1 assets are now listed on the Clinicaltrials.gov registry. This dazzling array owes much to the transformational nature of the data seen with the first wave of anti-PD-1/PD-L1 MAbs. It also indicates how central combinations will be in extending immuno-oncology beyond just a handful of cancers, and beyond certain patient subgroups. But the combo effort is as much about extending the reach of currently available drugs like Keytruda, Opdivo and Tecentriq as it is about making novel approaches viable by combining them with PD-1/PD-L1. On a standalone basis several of the industry’s novel oncology projects have underwhelmed. As data are generated it will therefore be vital for investors to tease out the effect of combinations beyond that of monotherapy, and it is doubtful whether the sprinkling of magic immuno-oncology dust will come to the rescue of substandard products. This is not stopping many companies, as the hundreds of combination studies identified here show. This report aims to quantify how many trials are ongoing with which assets and in which cancer indications, as well as suggesting reasons why some of the most popular approaches are being pursued.
    [Show full text]
  • Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis
    REVIEW published: 09 July 2021 doi: 10.3389/fimmu.2021.686155 Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis † † Jie Huang 1 , Xuekun Fu 1 , Xinxin Chen 1, Zheng Li 1, Yuhong Huang 1 and Chao Liang 1,2* 1 Department of Biology, Southern University of Science and Technology, Shenzhen, China, 2 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China Rheumatoid arthritis (RA) is a systemic poly-articular chronic autoimmune joint disease that mainly damages the hands and feet, which affects 0.5% to 1.0% of the population worldwide. With the sustained development of disease-modifying antirheumatic drugs (DMARDs), significant success has been achieved for preventing and relieving disease activity in RA patients. Unfortunately, some patients still show limited response to DMARDs, which puts forward new requirements for special targets and novel therapies. Understanding the pathogenetic roles of the various molecules in RA could facilitate discovery of potential therapeutic targets and approaches. In this review, both Edited by: existing and emerging targets, including the proteins, small molecular metabolites, and Trine N. Jorgensen, epigenetic regulators related to RA, are discussed, with a focus on the mechanisms that Case Western Reserve University, result in inflammation and the development of new drugs for blocking the various United States modulators in RA. Reviewed by: Åsa Andersson, Keywords: rheumatoid arthritis, targets, proteins, small molecular metabolites, epigenetic regulators Halmstad University, Sweden Abdurrahman Tufan, Gazi University, Turkey *Correspondence: INTRODUCTION Chao Liang [email protected] Rheumatoid arthritis (RA) is classified as a systemic poly-articular chronic autoimmune joint † disease that primarily affects hands and feet.
    [Show full text]
  • 2017 Immuno-Oncology Medicines in Development
    2017 Immuno-Oncology Medicines in Development Adoptive Cell Therapies Drug Name Organization Indication Development Phase ACTR087 + rituximab Unum Therapeutics B-cell lymphoma Phase I (antibody-coupled T-cell receptor Cambridge, MA www.unumrx.com immunotherapy + rituximab) AFP TCR Adaptimmune liver Phase I (T-cell receptor cell therapy) Philadelphia, PA www.adaptimmune.com anti-BCMA CAR-T cell therapy Juno Therapeutics multiple myeloma Phase I Seattle, WA www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 "armored" CAR-T Juno Therapeutics recurrent/relapsed chronic Phase I cell therapy Seattle, WA lymphocytic leukemia (CLL) www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 CAR-T cell therapy Intrexon B-cell malignancies Phase I Germantown, MD www.dna.com ZIOPHARM Oncology www.ziopharm.com Boston, MA anti-CD19 CAR-T cell therapy Kite Pharma hematological malignancies Phase I (second generation) Santa Monica, CA www.kitepharma.com National Cancer Institute Bethesda, MD Medicines in Development: Immuno-Oncology 1 Adoptive Cell Therapies Drug Name Organization Indication Development Phase anti-CEA CAR-T therapy Sorrento Therapeutics liver metastases Phase I San Diego, CA www.sorrentotherapeutics.com TNK Therapeutics San Diego, CA anti-PSMA CAR-T cell therapy TNK Therapeutics cancer Phase I San Diego, CA www.sorrentotherapeutics.com Sorrento Therapeutics San Diego, CA ATA520 Atara Biotherapeutics multiple myeloma, Phase I (WT1-specific T lymphocyte South San Francisco, CA plasma cell leukemia www.atarabio.com
    [Show full text]
  • Looking for Therapeutic Antibodies in Next Generation Sequencing Repositories
    bioRxiv preprint doi: https://doi.org/10.1101/572958; this version posted March 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Title: Looking for Therapeutic Antibodies in Next Generation Sequencing Repositories. Authors: Konrad Krawczyk1*, Matthew Raybould2, Aleksandr Kovaltsuk2, Charlotte M. Deane2 1 NaturalAntibody, Hamburg, Germany 2 Oxford University Department of Statistics, Oxford, UK *Correspondence to [email protected] Abstract: Recently it has become possible to query the great diversity of natural antibody repertoires using Next Generation Sequencing (NGS). These methods are capable of producing millions of sequences in a single experiment. Here we compare Clinical Stage Therapeutic antibodies to the ~1b sequences from 60 independent sequencing studies in the Observed Antibody Space Database. Of the 242 post Phase I antibodies, we find 16 with sequence identity matches of 95% or better for both heavy and light chains. There are also 54 perfect matches to therapeutic CDR-H3 regions in the NGS outputs, suggesting a nontrivial amount of convergence between naturally observed sequences and those developed artificially. This has potential implications for both the discovery of antibody therapeutics and the legal protection of commercial antibodies. Introduction Antibodies are proteins in jawed vertebrates that recognize noxious molecules (antigens) for elimination. An organism expresses millions of diverse antibodies to increase the chances that some of them will be able to bind the foreign antigen, initiating the adaptive immune response.
    [Show full text]
  • Antibodies to Watch in 2021 Hélène Kaplona and Janice M
    MABS 2021, VOL. 13, NO. 1, e1860476 (34 pages) https://doi.org/10.1080/19420862.2020.1860476 PERSPECTIVE Antibodies to watch in 2021 Hélène Kaplona and Janice M. Reichert b aInstitut De Recherches Internationales Servier, Translational Medicine Department, Suresnes, France; bThe Antibody Society, Inc., Framingham, MA, USA ABSTRACT ARTICLE HISTORY In this 12th annual installment of the Antibodies to Watch article series, we discuss key events in antibody Received 1 December 2020 therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The Accepted 1 December 2020 coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the KEYWORDS healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two Antibody therapeutics; anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were cancer; COVID-19; Food and authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed Drug Administration; antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 European Medicines Agency; in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the immune-mediated disorders; first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may Sars-CoV-2 be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency.
    [Show full text]
  • Appendix 1 – Protocol for Preventing Or Reversing Chronic Disease The
    Appendix 1 – Protocol for Preventing or Reversing Chronic Disease The first author has developed a protocol over the past decade for preventing or reversing chronic disease based on the following systemic medical principle: “at the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective”[1]. The protocol methodology refines the age-old principles of both reducing harm in addition to providing treatment, and allows better identification of factors that contribute to the disease process (so that they may be eliminated if possible). These contributing factors are expansive and may include a combination of Lifestyle choices (diet, exercise, smoking), iatrogenic and biotoxin exposures, environmental/occupational exposures, and psychosocial stressors. This strategy exploits the existing literature to identify patterns of biologic response using biomarkers from various modalities of diagnostic testing to capture a much broader list of potential contributing factors. Existing inflammatory bowel diseases (IBD) Biomarker Identification to Remove Contributing Factors and Implement Treatment The initial protocol steps are diagnostic. The main output of these diagnostics will be identification of the biomarker levels and symptoms that reflect abnormalities, and the directions of change required to eliminate these abnormalities. In the present study, hundreds of general and specific biomarkers and symptoms were identified from the core IBD literature. The highest frequency (based on numbers of record appearances) biomarkers and symptoms were extracted, and are listed in Table 1 (highest frequency items first, reading down each column before proceeding to the next column). They are not necessarily consensus biomarkers. They are biomarkers whose values were altered by a treatment or contributing factor, and reported in the core IBD literature.
    [Show full text]
  • Emtree Terms Changed in January 2017
    Emtree Terms Added and Changed (January 2017) This is an overview of new terms added and changes made in the first Emtree release in 2017. Overall, Emtree has grown by 782 preferred terms (269 drug terms and 513 non-drug terms) compared with the previous version released in September 2016. In total Emtree now counts 75,488 preferred terms. Because the terms added include replacements for existing preferred terms (which become synonyms of the new terms) as well as completely new concepts, the number of terms added exceeds the net growth in Emtree. Other changes could include the merging of two or more existing preferred terms into a single concept. The terms added and changed are summarized below and specified in detail on the following pages. Emtree Terms Added in January 2017 930 new terms (including 148 replacement terms and promoted synonyms) have been added to Emtree as preferred terms in version January 2017 (compared to September 2016): 308 drug terms (terms assigned to the Chemicals and Drugs facet). 622 non-drug terms (terms not assigned as Chemicals and Drugs). The new terms (including the replacement terms and the promoted synonyms) are listed as Terms Added on the following pages. Note that many of these terms will have been indexed prior to 2017 (typically as candidate terms), sometimes for several years, before they were added to Emtree. Emtree Terms Changed in January 2017 148 terms (39 drug terms and 109 non-drug terms) from Emtree September 2016 have been replaced by 148 different terms in January 2017 (39 drug terms and 109 non-drug terms).
    [Show full text]
  • (PDCO) Minutes of the Meeting on 20-23 March 2018
    23 March 2018 EMA/PDCO/187894/2018 Inspections, Human Medicines Pharmacovigilance and Committees Division Paediatric Committee (PDCO) Minutes of the meeting on 20-23 March 2018 Chair: Dirk Mentzer – Vice-Chair: Koenraad Norga 20 March 2018, 17:30- 19:00, room 3A 21 March 2018, 08:30- 19:00, room 3A 22 March 2018, 08:30- 19:00, room 3A 23 March 2018, 08:30- 13:00, room 3A Disclaimers Some of the information contained in this set of minutes is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the PDCO Committee meeting reports (after the PDCO Opinion is adopted), and on the Opinions and decisions on paediatric investigation plans webpage (after the EMA Decision is issued). Of note, this set of minutes is a working document primarily designed for PDCO members and the work the Committee undertakes. Further information with relevant explanatory notes can be found at the end of this document. Note on access to documents Some documents mentioned in the minutes cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on-going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006).
    [Show full text]
  • Lääkeaineiden Yleisnimet (INN-Nimet) 21.6.2021
    Lääkealan turvallisuus- ja kehittämiskeskus Säkerhets- och utvecklingscentret för läkemedelsområdet Finnish Medicines Agency Lääkeaineiden yleisnimet (INN-nimet) 21.6.
    [Show full text]
  • Challenges in the Treatment of Rheumatoid Arthritis
    Autoimmunity Reviews 18 (2019) 706–713 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Challenges in the treatment of Rheumatoid Arthritis T ⁎ Paola Conigliaro , Paola Triggianese, Erica De Martino, Giulia Lavinia Fonti, Maria Sole Chimenti, Flavia Sunzini, Alessandra Viola, Claudia Canofari, Roberto Perricone Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome Tor Vergata, Italy ARTICLE INFO ABSTRACT Keywords: Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by a heterogeneous clinical response Rheumatoid Arthritis to the different treatments. Some patients are difficult to treat and do not reach the treatment targets asclinical bDMARDs remission or low disease activity. Known negative prognostic factors, such as the presence of auto-antiantibodies HLA and joint erosion, the presence of a genetic profile, comorbidities and extra-articular manifestations, pregnancy Diet or a pregnancy wish may concur to the treatment failure. In this review we aimed at identify difficult to treat RA Pregnancy patients and define the optimal therapeutic and environmental targets. Genetic markers of severity such asHLA- Physical activity Comorbidities DRB1, TRAF1, PSORS1C1 and microRNA 146a are differently associated with joint damage; other gene poly- Extra-articular manifestations morphisms seem to be associated with response to biologic disease modifying anti-rheumatic drugs (bDMARDs). The presence of comorbidities and/or extra-articular manifestations may influence the therapeutic choice; overweight and obese patients are less responsive to TNF inhibitors. In this context the patient profiling can improve the clinical outcome. Targeting different pathways, molecules, and cells involved in the pathogenesis of RA may in part justify the lack response of some patients.
    [Show full text]