DOCSLIB.ORG

Type 1 Interferons in SLE Rontalizumab [Anti-Interferon-Α] the Interferon Signature Metric (ISM) Baseline ISM Status Defines 2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Type 1 Interferons in SLE Rontalizumab [Anti-Interferon-Α] the Interferon Signature Metric (ISM) Baseline ISM Status Defines 2 Disclosures 1 EFFICACY AND SAFETY OF RONTALIZUMAB (ANTI-INTERFERON- • Contracts and Grants ALPHA) IN SLE PATIENTS WITH RESTRICTED – LCTC IMMUNOSUPPRESSANT USE: – NIH/NIAID/ITN – Kirin RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO- – Medimmune CONTROLLED PHASE 2 TRIAL – UCB – Biogen Idec – GSK – Genentech • Consultant/Medical Advisory Board K. Kalunian1, JT. Merrill2, R. Maciuca3, W. Ouyang3, JM. McBride3, M. Townsend3, E. Park3, – Anthera X. Wei3, A. Morimoto3, R. Boismenu3, J. Davis, Jr3. and WP. Kennedy3 – Questcor – Merck Serono 1UCSD, Dept. Medicine, La Jolla, CA; 2Oklahoma Medical Research Foundation, Oklahoma – Eli Lilly City, OK; 3Genentech Inc., South San Francisco, CA CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD Type 1 Interferons in SLE 2 Rontalizumab [anti-interferon-α] 3 IgG1 Humanized, monoclonal Molecule Rontalizumab •Increased IFN signals play a central role antibody to interferon-alpha in the complex pathogenesis of SLE Neutralizes all 12 known human IFN-a subtypes •Type I IFNs, especially IFNα, have been shown MOA and to associate with lupus disease activity and Biological Evidence Murine analog decreased flares proteinuria in animal model of lupus nephritis Formulation IV and SC Phase I single/multiple dose study1 2 Clinical Phase II study in lupus Studies 1. McBride JM, et al Arthritis Rheum. 2012 2. ACR, 2012 Aghemo, A. Nat Rev Gastro Hep 7(9): 495 [2010] Adapted from Banchereau and Pascual in Immunity 35(3) [2006] CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 4 5 The Interferon Signature Metric (ISM) Baseline ISM status defines 4 5 2 sub-populations of SLE patients Many SLE patients have an (1) elevated ISM score compared to (1) Many SLE patients have elevated healthy controls with a distinct expression of ~100 interferon-regulated bimodal distribution genes, the interferon signature ISM-Hi and ISM-Lo (2) Average gene expression from 3 interferon-regulated genes were chosen SLE patients with mild disease to represent the interferon signature (2) activity patients (Phase I) ~ 1:1 ISM-Hi / ISM-Lo (3) (3) The 3 gene signature correlates well with the entire interferon signature SLE patients with moderate-to- severe disease (Phase II) A calculated score for the mean expression ~ 3:1 ISM-Hi / ISM-Lo level for the 3 genes is a novel biomarker for lupus, called the ISM CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 1 Rontalizumab Phase 2 Trial (ROSE) Rontalizumab Phase 2 Trial (ROSE) 6 7 Objectives Key Inclusion / Exclusion Criteria • Randomized, placebo-controlled study of the safety and efficacy of • Inclusion criteria: rontalizumab in SLE patients without background immunosuppressants – SLE patients by ACR classification with positive ANA • Objective – Moderate to severe disease with 1 BILAG A or 2 BILAG B domains – Evaluate rontalizumab’s efficacy and safety without background immunosuppressants (e.g. azathioprine, mycophenylate) – Subjects were allowed steroids at screening but underwent taper by 6 weeks post randomization to ≤ 10mg/day, if tolerated • Key Exclusion: – Immunosuppressants were discontinued at randomization – Unstable anti-phospholipid syndrome – Rescue medication, including immunosuppressants, available to all – Unstable neuropsychiatric lupus patients • Endpoints – Active lupus nephritis – Primary Endpoint: BILAG Responder Index at 24 weeks – Key Secondary Endpoint: SLE Responder Index (SRI) at 24 weeks – Safety – Exploratory measures : steroid reduction and flare rates over time, efficacy correlated to ISM status CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD ROSE Trial Design 8 Patient Demographics in ROSE Studies 9 Sequential, global studies in SLE patients ROSE IV : IV dosing q4wk Countries Race Gender Patients (%) Patients (%) 6% Male Rontalizumab 750mg IV (N= 81) Steroid taper / Rescue Therapy 94% Female Placebo Mean age : 39yrs IV (N= 41) -4 0 4 8 12 16 20 24 Week Safety follow-up Baseline ISM Status Primary Endpoint (48 wks) (Week 24) 24% Ethnicity lo Open-label ISM ROSE SC : SC dosing q2wk extension 76% . 238 patients total (159 active + 79 placebo) hi . 95-100% completed study through wk 24 ISM . 85-93% completed treatment period Rontalizumab 300mg SC (N= 78) . Demographics, baseline characteristics generally balanced within each Steroid taper / Rescue Therapy cohort, reflecting moderate to severe disease activity (mean SELENA SLEDAI of ~ 10, mean disease duration ~6.5 yrs). Placebo SC (N= 38) -4 0 4 8 12 16 20 24 Week Safety follow-up . More Hispanics were enrolled in Part 2 (SC) compared to Part 1 (IV), 60% Primary Endpoint (48 wks) vs. 40%, respectively due to added sites (Week 24) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD Patient Baseline Characteristics 10 Patient Baseline Characteristics 11 ROSE IV ROSE SC Pooled (IV+SC) ROSE IV ROSE SC Pooled (IV+SC) Placebo 750mg Placebo 300mg Placebo Rontalizumab Placebo 750 mg Placebo 300mg Placebo Rontalizumab Subject Number, N 41 81 38 78 79 159 Subject Number, N 41 81 38 78 79 159 Age (yrs), mean (SD) 38.4 37.3 43.7 38.2 40.9 37.8 (11.6) (11.4) (9.0) (11.5) (10.7) (11.4) ISM status, n (%) High 30 (73) 63 (78) 25 (66) 62 (79) 55 (70) 125 (79) SLE duration (yrs), mean (SD) 6.2 (6.2) 6.3 (6.4) 6.9 (6.0) 6.6 (6.5) 6.6 (6.1) 6.4 (6.4) Low 11 (27) 18 (22) 13 (34) 16 (21) 24 (30) 34 (21) BILAG index at screening, % ANA positive (>=1:80), % 90 96 90 89 90 93 >= 2 A 5 10 11 14 8 12 >= 1 A 68 67 79 77 73 72 C3 complement (mg/dL), mean (SD) 101.7 (33.3) 108.5 (33.5) 100.3(34.6) 96.5 (34.2) 101 (33.7) 102.6 (34.3) BILAG index global score, 11.0 Low (<90),% 37 28 34 45 35 37 mean (SD) (3.7) 11.0 (4.3) 12.1 (6.3) 11.1 (4.7) 11.5 (5.1) 11.1 (4.4) SELENA SLEDAI score, mean C4 complement (mg/dL), (SD) 9.7 (2.4) 10.1 (3.1) 9.3 (4.5) 9.8 (3.1) 9.5 (3.6) 10.0 (3.1) mean (SD) 17.5 (9.4) 16.5 (8.7) 17.0 (8.6) 15.0 (12.1) 17.3 (9.0) 15.7 (10.5) Low (<10), % 32 21 29 44 30 32 59.6 51.9 53.0 56.4 PGA score (mm), mean (SD) 59.2 55.7 (15.1) (14.6) (17.3) (17.5) (16.5) (16.4) Anti-dsDNA (IU/mL) On any immunosuppressant at 29 25 37 24 33 25 median, 68.5 38.8 27.1 85.3 40.1 65.8 screening, % % Positive (>=30) 66 61 42 71 54 66 % on steroids, mean 82, Anti-ENA positive prednisone dose 88, 87, 89, 84, 88, 44 68 63 59 53 64 (9.0) (10.1) (aRo/aLa/aRNP/aSm), % (mg/day) (10.8) (11.3) (12.7) (11.7) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 2 Rontalizumab shows treatment effect in Baseline characteristics of ISM-Hi and ISM- 12 13 Lo subgroups ISM-Lo population using the SRI endpoint Baseline characteristics ISM-Hi ISM-Lo Primary endpoint: BILAG Responder Index Secondary endpoint: SLE Responder Index Active BILAG Index Active % Response Placebo % Response Placebo ≥ 2 A 9% 16% All Patients 46 All Patients 51 ≥ 1 A 70% 79% 41 46 ≥ 1 A or 2 B 100% 100% BILAG global score (mean/median) 11.0/11.0 11.9/12.0 ISM-Hi 45 SELENA-SLEDAI score ISM-Hi 43 (mean/median) 10.0/10.0 9.2 /10.0 38 47 PGA score (mean/median) 57/59 52/57 ISM-Lo 73 Swollen Joints Count 4.6/4 5.1/5 ISM-Lo 55 42 (mean/median) 50 dsDNA+ (≥30 IU/mL) 71% 35% ENA+ (Ro/La/Sm/RNP) 74% 19% C3, C4 (mean) 95, 14 122, 22 . High SRI response rate in ISM-Lo patients given rontalizumab Low C3, Low C4 43%, 39% 16%, 11% (for both IV and SC); treatment difference = 31% (p=0.029) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD Exploratory: Rontalizumab Treatment Effect in 14 SELENA SLEDAI over time – all subjects 15 ISM-Lo population with higher SRI thresholds (Mean Change from Baseline) Exploratory: Improvement Threshold by SRI All efficacy-evaluable patients (N=235) % Response in ISM-Lo p<0.05 p<0.01 p<0.05 p>0.15 p>0.15 Active Placebo (n = 33) (n=24) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD SELENA SLEDAI over time – IV, SC, pooled SELENA SLEDAI over time – ISM-Lo Group 16 17 (Mean Change from Baseline) (Mean Change from Baseline) All efficacy-evaluable patients (N=235) ISM-Lo patients (N=57) CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD 3 Reduction in Steroid Use by Week 24 in ISM-Lo Reduction in Flare Frequency 18 19 (exploratory endpoint; pooled IV & SC studies) over time and by Week 24 Frequency of all flares (by SFI) Decrease in prednisone use by week 24 (≤10mg/day) All efficacy-evaluable patients Active % Flares Active Patients (%) (N=235) Placebo Placebo All Patients 65 All Patients 76 76 63 ISM-Hi 68 ISM-Hi 72 76 62 Hazard Ratio ISM-Lo 55 ISM-Lo 91 Ronta vs. 0.61 (0.46-0.81) 75 67 Pbo p=0.0040 750mg IV 0.64 (0.43-0.94) vs. Pbo IV p=0.0553 300mg SC 0.58 (0.39-0.88) vs.
Load more

Recommended publications
  • Review Article Biological Therapy in Systemic Lupus Erythematosus
    Hindawi Publishing Corporation International Journal of Rheumatology Volume 2012, Article ID 578641, 9 pages doi:10.1155/2012/578641 Review Article Biological Therapy in Systemic Lupus Erythematosus Mariana Postal, Lilian TL Costallat, and Simone Appenzeller Rheumatology Unit, Department of Medicine, Faculty of Medical Science, State University of Campinas, 13083-887 Campinas, SP, Brazil Correspondence should be addressed to Simone Appenzeller, [email protected] Received 25 August 2011; Accepted 8 October 2011 Academic Editor: Jozelio´ Freire de Carvalho Copyright © 2012 Mariana Postal et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Systemic lupus erythematosus (SLE) is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end- organ manifestations. Despite new and improved therapy having positively impacted the prognosis of SLE, a subgroup of patients do not respond to conventional therapy. Moreover, the risk of fatal outcomes and the damaging side effects of immunosuppressive therapies in SLE call for an improvement in the current therapeutic management. New therapeutic approaches are focused on B- cell targets, T-cell downregulation and costimulatory blockade, cytokine inhibition, and the modulation of complement. Several biological agents have been developed, but this encouraging news is associated with several disappointments in trials and provide a timely moment to reflect on biologic therapy in SLE. 1. Introduction molecules [4]. Beside autoantibody production, B-cells are the key for the activation of the immune system, particularly Systemic lupus erythematosus (SLE) is an autoimmune, through cytokines and as antigen-presenting cells.
    [Show full text]
  • 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]
  • New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production Laura M
    C al & ellu ic la n r li Im C m Journal of Clinical & Cellular f u o Davison and Jorgensen et al., J Clin Cell Immunol n l o a l n o 2017, 8:6 r g u y o J Immunology DOI: 10.4172/2155-9899.1000534 ISSN: 2155-9899 Commentary Open Access New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production Laura M. Davison and Trine N. Jorgensen* Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA *Corresponding author: Dr. Trine N. Jorgensen, Department of Immunology, NE40, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA, Phone: +1 216-444-7454; Fax: +1 216-444-9329; E-mail: [email protected] Received date: December 4, 2017; Accepted date: December 13, 2017; Published date: December 20, 2017 Copyright: © 2017 Davison LM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFNα), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFNα supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell- targeting antibody-mediated depletion strategies, which do not eliminate autoantibody-secreting plasma cells.
    [Show full text]
  • WO 2018/027204 Al 08 February 2018 (08.02.2018) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/027204 Al 08 February 2018 (08.02.2018) W !P O PCT (51) International Patent Classification: only): F. HOFFMANN-LA ROCHE AG [CH/CH]; Gren- C07K 16/28 (2006.01) A61K 39/00 (2006.01) zacherstrasse 124, 4070 Basel (CH). (21) International Application Number: (72) Inventor; and PCT/US20 17/045642 (71) Applicant: HARRIS, Seth [US/US]; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). (22) International Filing Date: 04 August 2017 (04.08.2017) (72) Inventors: LAZAR, Greg; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). YANG, (25) Filing Language: English Yanli; c/o Genentech, Inc., 1 DNA Way, South San Fran (26) Publication Language: English cisco, California 94080 (US). CHRISTENSEN, Erin H.; c/ o Genentech, Inc., 1 DNA Way, South San Francisco, Cali (30) Priority Data: fornia 94080 (US). HANG, Julie; 6606 Wisteria Way, San 62/371,671 05 August 2016 (05.08.2016) US Jose, California 95 129 (US). KIM, Jeong; c/o Genentech, (71) Applicant (for all designated States except AL, AT, BA, BE, Inc., 1 DNA Way, South San Francisco, California 94080 BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, (US). HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, (74) Agent: JONES, Kevin et al; Morrison & Foerster LLP, NO, PL, PT RO, RS, SE, SI, SK, SM, TR): GENENTECH, 425 Market Street, San Francisco, California 94105-2482 INC.
    [Show full text]
  • WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A01N 43/00 (2006.01) A61K 31/33 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2016/028383 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 20 April 2016 (20.04.2016) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/154,426 29 April 2015 (29.04.2015) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: KARDIATONOS, INC. [US/US]; 4909 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Lapeer Road, Metamora, Michigan 48455 (US).
    [Show full text]
  • (INN) for Biological and Biotechnological Substances
    INN Working Document 05.179 Update 2013 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 2013 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) © World Health Organization 2013 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int ) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected] ). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html ). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Association of Endogenous Antiinterferon Autoantibodies with Decreased Interferonpathway and Disease Activity in Patients with S
    ARTHRITIS & RHEUMATISM Vol. 63, No. 8, August 2011, pp 2407–2415 DOI 10.1002/art.30399 © 2011 American College of Rheumatology Association of Endogenous Anti–Interferon-␣ Autoantibodies With Decreased Interferon-Pathway and Disease Activity in Patients With Systemic Lupus Erythematosus Alyssa M. Morimoto,1 Donna Thibault Flesher,1 Jihong Yang,1 Kristen Wolslegel,1 Xiangdan Wang,1 Ann Brady,1 Alexander R. Abbas,1 Valerie Quarmby,1 Eric Wakshull,1 Bruce Richardson,2 Michael J. Townsend,1 and Timothy W. Behrens1 Objective. Numerous observations implicate bioactivity, IFN-regulated gene expression, BAFF, anti– interferon-␣ (IFN␣) in the pathophysiology of systemic ribosomal P, and anti-chromatin autoantibodies, and in lupus erythematosus (SLE); however, the potential im- AIAA status. The majority of AIAA-positive patients had pact of endogenous anti-IFN␣ autoantibodies (AIAAs) significantly lower levels of serum type I IFN bioactivity, on IFN-pathway and disease activity is unclear. The aim reduced downstream IFN-pathway activity, and lower of this study was to characterize IFN-pathway activity disease activity compared with the IFNhigh patients. and the serologic and clinical profiles of AIAA-positive AIAA-positive sera were able to effectively neutralize patients with SLE. type I IFN activity in vitro. Methods. Sera obtained from patients with SLE Conclusion. Patients with SLE commonly harbor ؍ ؍ (n 49), patients with rheumatoid arthritis (n 25), AIAAs. AIAA-positive patients have lower levels of se- ؍ and healthy control subjects (n 25) were examined for rum type I IFN bioactivity and evidence for reduced the presence of AIAAs, using a biosensor immunoassay. downstream IFN-pathway and disease activity.
    [Show full text]
  • Roche Group Development Pipeline
    Roche Group development pipeline Marketed products development programmes Roche Pharma global development programmes Roche Pharma research and early development Genentech research and early development Roche Group HY 2013 results Diagnostics Foreign exchange rate information 59 Changes to the development pipeline Q2 2013 update New to Phase I New to Phase II New to Phase III New to Registration 3 NMEs 3 NMEs 3 AIs 1 NME NDA submissions EU RG7410 in metabolic diseases RG7853 ALK inhibitor in NSCLC RG1273 Perjeta in HER2-positive and US RG7745 in infectious diseases RG7446 PD-L1 MAb in mNSCLC gastric cancer RG7159 obinutuzumab in CLL RG7842 in solid tumors RG7601 Bcl-2 inh in CLL RG435 Avastin in recurrent cervical 1 AI submission to FDA 3 AIs relapsed/refractory 17pdel cancer RG1273 Perjeta in neoadjuvant RG7446 PD-L1+Zelboraf in RG1569 Actemra in giant cell HER2-positive breast cancer metastatic melanoma arteritis RG7446 PD-L1 + Avastin in solid tumors RG7446 PD-L1 in solid tumors Removed from Removed from Phase I Removed from Phase II Removed from Phase III Registration 1 NME due to selection of 1 NME 2 NMEs 1 NME EU approval alternative molecule RG7160 imgatuzumab (GA201, RG1439 aleglitazar CV risk RG3616 Erivedge in advanced RG7112 MDM2 ant. in solid and EGFR MAb) in solid tumors reduction post ACS in type 2 basal cell carcinoma hematological tumors 2 AIs diabetes; complete programme 1 AI EU+US approval RG3638 onartuzumab in triple-neg terminated RG1569 RoActemra/Actemra in mBC 1st/2nd line SST arbaclofen in fragile X syndrome polyarticular
    [Show full text]
  • United States Patent (10 ) Patent No.: US 10,471,211 B2 Rusch Et Al
    US010471211B2 United States Patent (10 ) Patent No.: US 10,471,211 B2 Rusch et al. (45 ) Date of Patent: Nov. 12 , 2019 ( 54 ) MEDICAL DELIVERY DEVICE WITH A61M 2005/31506 ; A61M 2205/0216 ; LAMINATED STOPPER A61M 2205/0222 ; A61M 2205/0238 ; A61L 31/048 ( 71 ) Applicant: W.L. Gore & Associates, Inc., Newark , See application file for complete search history. DE (US ) ( 56 ) References Cited ( 72 ) Inventors : Greg Rusch , Newark , DE (US ) ; Robert C. Basham , Forest Hill , MD U.S. PATENT DOCUMENTS (US ) 5,374,473 A 12/1994 Knox et al . 5,708,044 A 1/1998 Branca ( 73 ) Assignee : W. L. Gore & Associates, Inc., 5,792,525 A 8/1998 Fuhr et al. Newark , DE (US ) ( Continued ) ( * ) Notice: Subject to any disclaimer , the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154 (b ) by 0 days . WO WO2014 / 196057 12/2014 WO WO2015 /016170 2/2015 ( 21) Appl. No .: 15 /404,892 OTHER PUBLICATIONS ( 22 ) Filed : Jan. 12 , 2017 International Search Report PCT/ US2017 /013297 dated May 16 , (65 ) Prior Publication Data 2017 . US 2017/0203043 A1 Jul. 20 , 2017 Primary Examiner Lauren P Farrar Related U.S. Application Data ( 74 ) Attorney , Agent, or Firm — Amy L. Miller (60 ) Provisional application No.62 / 279,553, filed on Jan. ( 57 ) ABSTRACT 15 , 2016 . The present disclosure relates to a medical delivery device that includes a barrel having an inner surface , a plunger rod ( 51 ) Int. Cl. having a distal end inserted within the barrel , and a stopper A61M 5/315 ( 2006.01) attached to the distal end of the plunger rod and contacting A61L 31/04 ( 2006.01) at least a portion of the inner surface of the barrel .
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • NETTER, Jr., Robert, C. Et Al.; Dann, Dorf- (21) International Application
    ll ( (51) International Patent Classification: (74) Agent: NETTER, Jr., Robert, C. et al.; Dann, Dorf- C07K 16/28 (2006.01) man, Herrell and Skillman, 1601 Market Street, Suite 2400, Philadelphia, PA 19103-2307 (US). (21) International Application Number: PCT/US2020/030354 (81) Designated States (unless otherwise indicated, for every kind of national protection av ailable) . AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 29 April 2020 (29.04.2020) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (26) Publication Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/840,465 30 April 2019 (30.04.2019) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, (71) Applicants: INSTITUTE FOR CANCER RESEARCH TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. D/B/A THE RESEARCH INSTITUTE OF FOX CHASE CANCER CENTER [US/US]; 333 Cottman Av¬ (84) Designated States (unless otherwise indicated, for every enue, Philadelphia, PA 191 11-2497 (US). UNIVERSTIY kind of regional protection available) . ARIPO (BW, GH, OF KANSAS [US/US]; 245 Strong Hall, 1450 Jayhawk GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, Boulevard, Lawrence, KS 66045 (US).
    [Show full text]