RIA TA Strategy 2013
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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. -
Kyntheum, INN-Brodalumab
ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Kyntheum 210 mg solution for injection in pre-filled syringe 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre-filled syringe contains 210 mg brodalumab in 1.5 ml solution. 1 ml solution contains 140 mg brodalumab. Brodalumab is a recombinant human monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection) The solution is clear to slightly opalescent, colourless to slightly yellow and free from particles. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Kyntheum is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy. 4.2 Posology and method of administration Kyntheum is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis. Posology The recommended dose is 210 mg administered by subcutaneous injection at weeks 0, 1, and 2 followed by 210 mg every 2 weeks. Consideration should be given to discontinuing treatment in patients who have shown no response after 12-16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special populations Elderly (aged 65 years and over) No dose adjustment is recommended in elderly patients (see section 5.2). -
Biological Therapies for Atopic Dermatitis: an Update (Review)
EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 1061-1067, 2019 Biological therapies for atopic dermatitis: An update (Review) DIANA DELEANU1-3 and IRENA NEDELEA1,2 1Allergology and Immunology Discipline, ‘Iuliu Hatieganu’ University of Medicine and Pharmacy, 400058 Cluj-Napoca; Departments of 2Allergy and 3Internal Medicine, ‘Professor Doctor Octavian Fodor’ Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania Received July 6, 2018; Accepted August 22, 2018 DOI: 10.3892/etm.2018.6989 Abstract. Severe atopic dermatitis, which affects both adults in low-income countries (3). Furthermore, the past decades and children, is a debilitating disorder with a significant decline brought a 2-3-fold increase in prevalence in industrialized of patients' quality of life. Although aetiopathogenic factors countries (3). Generally AD onset is in early childhood, as are currently a topic of study and interpretation, the main one of the first steps of the ‘atopic march’, which describes the features of atopic eczema are skin barrier disturbance and natural history of atopic manifestations, and it is character- immune dysregulation. Severe refractory disease that fails to ized by xerotic skin and acute flare-ups of intensely pruritic improve with conventional therapy may benefit from biologic eczematous lesions (4). Recent studies recognize a predilection therapy. Progress in understanding immunopathology of atopic of AD for persistence in adulthood, with a lifetime prevalence dermatitis have allowed identification of therapeutic molecular accounting for 34.1% (5). Early onset, allergic rhinitis and targets in the field of biological therapy. We reviewed the hand eczema in childhood are high-risk factors for persistent different biological treatments with a focus on novel targeted AD (5). -
Evaluation of Antibody Properties and Clinically Relevant Immunogenicity
Drug Safety https://doi.org/10.1007/s40264-018-00788-w ORIGINAL RESEARCH ARTICLE Evaluation of Antibody Properties and Clinically Relevant Immunogenicity, Anaphylaxis, and Hypersensitivity Reactions in Two Phase III Trials of Tralokinumab in Severe, Uncontrolled Asthma Mats Carlsson1 · Martin Braddock2 · Yuling Li3 · Jihong Wang3 · Weichen Xu3 · Nicholas White4 · Ayman Megally5 · Gillian Hunter6 · Gene Colice5 © The Author(s) 2019 Abstract Introduction Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma. Objective The objectives of this study were to characterize the potential immunogenic properties of tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials. Methods The oligosaccharide structure of tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699). Results No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G 4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1—every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2—Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1—Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2—Q2 W 13.2%, placebo 9.0%. -
Study Protocol
PROTOCOL SYNOPSIS A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in Adult Subjects with Active Systemic Lupus Erythematosus International Coordinating Investigator Study site(s) and number of subjects planned Approximately 450 subjects are planned at approximately 173 sites. Study period Phase of development Estimated date of first subject enrolled Q2 2015 3 Estimated date of last subject completed Q2 2018 Study design This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab (150 mg or 300 mg) versus placebo in subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age. Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to receive a fixed intravenous dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo every 4 weeks (Q4W) for a total of 13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit. Investigational product will be administered as an intravenous (IV) infusion via an infusion pump over a minimum of 30 minutes, Q4W. Subjects must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. Randomisation will be stratified using the following factors: SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening (<10 points versus ≥10 points); Week 0 (Day 1) OCS dose 2(125) Revised Clinical Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00005 Edition Number 5 Date 18 May 2016 (<10 mg/day versus ≥10 mg/day prednisone or equivalent); and results of a type 1 interferon (IFN) test (high versus low). -
Astra Makes Quiet Progress with Respiratory Pipeline
June 18, 2014 Astra makes quiet progress with respiratory pipeline Jonathan Gardner In defending AstraZeneca against acquisition by Pfizer its executives pointed to oncology candidates such as the checkpoint inhibitor Medi4736 and lung cancer project AZD9291 as assets not fully valued by the American pursuer. Less well appreciated is Astra's portfolio of clinical-stage respiratory programmes, one of which appears to be the only project of its class to be tested in the clinic. Given Astra's relative position in each therapy area, one might think that respiratory disease would draw more attention, even though oncology remains the hottest area of drug development. A focus on novel classes and severe disease – demonstrated by a licensing deal last week for an inhalable interferon for asthma – could allow Astra to expand even as growth in respiratory therapies flattens through the rest of the decade. Ordinary and unusual Astra executives themselves have made less of the respiratory disease pipeline, forecasting sales that are in line with consensus figures even as they pumped up the group’s collective R&D (Don’t blame Soriot, he’s just doing his job, May 7, 2014). In some respects, it is somewhat ordinary: the phase III pipeline features some candidates in well-established classes like long-acting beta-2 agonists (LABAs) in the form of assets brought on board with the acquisition of Pearl Therapeutics (Astra’s Soriot finds hidden value in private assets, June 10, 2013). James Ward-Lilley, the UK group’s vice-president of respiratory, inflammation and autoimmune disease, acknowledged that the respiratory group had not received the attention of the investor community in part because the potential payoff of a clinical gamble is not valued as highly. -
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. -
Safety of Specifically Targeting Interleukin 13 with Tralokinumab In
Safety of specifically targeting interleukin 13 with tralokinumab in adult patients with moderate-to-severe atopic dermatitis: pooled analysis of five randomized, double-blind, placebo-controlled Phase 3 and Phase 2 trials Eric Simpson,1 Joseph F Merola,2 Jonathan I Silverberg,3 Rebecca Zachariae,4 Christina Kurre Olsen,4 Andreas Wollenberg5 1Department of Dermatology, Oregon Health & Science University, Portland, OR, USA; 2Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 3Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA; 4LEO Pharma A/S, Ballerup, Denmark; 5Klinikum der Universität München, Klinik und Poliklinik für Dermatologie und Allergologie, Munich, Germany ● AEs are summarised by the number and proportion of patients with AEs and the number and rate of Safety: monotherapy pool events by treatment group Table 3. Overall safety summary (safety analysis set, initial treatment period) ● Medical Dictionary for Regulatory Activities (MedDRA) version 2.0 was used (initial and maintenance treatment period) Introduction ● The overall frequency of AEs during the initial treatment period was similar for tralokinumab (69.0%) ● Event rates are presented as the number of events per 100 patient-years of exposure (PYE) AD pool Monotherapy pool and placebo (71.5%) and similar to the AD pool (Table 3) ● Atopic dermatitis (AD) is a chronic, debilitating, inflammatory skin disease1,2 characterised by Statistical analysis — The majority of AEs were mild -
Advances in Interferon-Alpha Targeting-Approaches for Systemic Lupus Erythematosus Treatment
Full title: Advances in Interferon-alpha targeting-approaches for Systemic Lupus Erythematosus treatment Running title: Interferon-alpha targeting in SLE Authors: Filipa Farinha - Rheumatology Department, Centro Hospitalar do Baixo Vouga E.P.E. – Aveiro, Portugal David A Isenberg - Centre for Rheumatology, Division of Medicine, University College London – London, UK Correspondence to: Professor David Isenberg The Rayne Building Room 424, 4th Floor 5 University Street London WC1E 6JF E-mail: [email protected] Tel: 0044 203 108 2148 Fax: 0044 203 108 2152 1 Contents Summary 1. Introduction 1.1. IFN alpha 1.2. IFN alpha and SLE 2. IFN alpha targeting approaches 2.1. Anti-IFN alpha antibodies 2.2. Anti-IFN alpha receptor antibodies 2.3. IFN alpha Kinoid 3. Discussion 4. Conclusion Acknowledgements References 2 Summary Conventional therapies seem to have reached the limit of their ability to treat patients with Systemic Lupus Erythematosus (SLE). To improve the outcome for these patients, new drugs are needed. Several attempts have been made to introduce targeted therapies for this complex disease. One of these targets is Interferon (IFN) alpha, whose production is increased in SLE, contributing to its pathogenesis. In this review we consider some recent advances in IFN alpha targeting-approaches. Three monoclonal antibodies (mAbs) against several IFN alpha subtypes have been tested in phase I and II trials, showing an acceptable safety profile and promising results in terms of reducing the IFN signature and disease activity. A mAb specific for the IFN alpha receptor and active immunization against IFN alpha are also being tested. Further trials will be essential to ascertain the safety and efficacy of all these approaches. -
Summary of Late-Stage Clinical Trials
Summary of late-stage clinical trials As of Dec. 31, 2017 The document contains information available on the date indicated in its cover page. The public information of clinicaltrials.gov is continuously updated as the trials make progress. See the current information on our ongoing trials at the Website. https://clinicaltrials.gov/ The whole picture of our pipeline is available on the following website: http://www.kyowa-kirin.com/research_and_development/pipeline/index.html List of abbreviations AE Adverse Events DLT Dose Limiting Toxicity iv Intravenous MTD Maximum Tolerated Dose ORR Overall Response Rate OS Overall Survival PD Pharmacodynamics PFS Progression Free Survival PK Phamacokinetics po Peroral PPK Population Pharmacokinetics Q2W Every Two Weeks Q3W Every Three Weeks Q4W Every Four Weeks QD Once Daily QW Once Weekly sc Subcutaneous TID Three Times a Day Late-stage pipeline summary Phase II Phase III AMG531 (romiplostim) AMG531 (romiplostim) KW-0761 (mogamulizumab) Aplastic Anemia Aplastic Anemia HAM ASKP1240 (bleselumab) Recurrence of focal segmental KHK4563 (benralizumab) glomerulosclerosis in de novo kidney Asthma transplant recipients KHK2375 (entinostat) KHK4563 (benralizumab) Breast cancer COPD KHK4083 KHK4827 (brodalumab) Ulcerative colitis Psoriasis KHK4563 (benralizumab) KHK4827 (brodalumab) Eosinophilic chronic rhinosinusitis axSpA KRN23 (burosumab) KHK7580 (evocalcet) TIO/ENS Primary hyperparathyroidism KRN23 (burosumab) KRN23 (burosumab) XLH (pediatric) XLH (adult) KW-0761 (mogamulizumab) KRN23 (burosumab) ATL XLH -
Atopic Dermatitis (AD)
This activity is provided by PRIME Education. There is no fee to participate. This activity is supported by education grants from AbbVie, Inc., Sanofi Genzyme and Regeneron Pharmaceuticals. © 2019 PRIME® Education, LLC. All Rights Reserved.. Overview This downloadable fact‐sheet provides an easy‐to‐follow collection of the latest evidence shaping the treatment and management of psoriasis (PsO) and atopic dermatitis (AD). Learn about validated tools, evidence‐based strategies, and new and emerging targeted therapies that can be incorporated in daily practice to improve outcomes for patients with these conditions. © 2019 PRIME® Education, LLC. All Rights Reserved.. 2 1 Learning Objectives • Identify major barriers to evidence‐based treatment and management in federal and public sectors • Implement appropriate methods for diagnosis and assessment of disease activity • Assess current evidence on targeted biologic and small‐molecule therapies to guide treatment decisions for patients with moderate to severe disease • Monitor treatment responses according to treat‐to‐target principles and methods • Apply current evidence and guidelines to inform treatment decisions for patients with inadequate responses to initial therapies • Incorporate patient‐reported outcomes and shared decision‐making into clinical practice • Apply effective strategies for multidisciplinary care coordination and shared patient management © 2019 PRIME® Education, LLC. All Rights Reserved.. 3 Accreditation In support of improving patient care, PRIME® is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. This activity was planned by and for the healthcare team, and learners will receive 2.25 Interprofessional Continuing Education (IPCE) credits for learning and change. -
New Drug Therapies for Systemic Lupus
icine- O ed pe M n l A a c n c r e e s t s n I Beenken, Intern Med 2018, 8:1 Internal Medicine: Open Access DOI: 10.4172/2165-8048.1000268 ISSN: 2165-8048 Review Article Open Access New Drug Therapies for Systemic Lupus Erythematosus: A Systematic Review Beenken AE* Institute for Medical Immunology at the Campus Charité Mitte of the Medical Faculty of the Charité - Universitätsmedizin Berlin, Germany *Corresponding author: Beenken AE, Institute for Medical Immunology, Berlin, Germany, Tel: 4915161419493; E-mail: [email protected] Received date: January 31, 2018; Accepted date: February 20, 2018; Published date: February 25, 2018 Copyright: © 2018 Beenken AE, 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 From the literature research the belimumab studies were the only ones to meet the primary and some of the secondary endpoints. Introduction: Systemic Lupus Erythematosus (SLE) is a multiorganic autoimmune disease caused by an immune reaction against DNA. Despite continuous research progress, the mortality of SLE patients is still 2‐4 times higher than the healthy populations and the standard drugs’ adverse effects (especially corticosteroids) hamper the patients’ quality of life. That is why there is an urgent need for new therapies. This paper reviews all phase III clinical trials of new SLE medication that were published since 2011 and analyses the drugs for their respective effects. Methods: MEDLINE (PubMed), Livivo, The Cochrane Library and Embase were systematically searched for relevant publications.