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BAFF-Neutralizing Interaction of Belimumab Related to Its Therapeutic Efficacy for Treating Systemic Lupus Erythematosus
ARTICLE DOI: 10.1038/s41467-018-03620-2 OPEN BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus Woori Shin1, Hyun Tae Lee1, Heejin Lim1, Sang Hyung Lee1, Ji Young Son1, Jee Un Lee1, Ki-Young Yoo1, Seong Eon Ryu2, Jaejun Rhie1, Ju Yeon Lee1 & Yong-Seok Heo1 1234567890():,; BAFF, a member of the TNF superfamily, has been recognized as a good target for auto- immune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the for- mation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases. 1 Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. 2 Department of Bio Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea. These authors contributed equally: Woori Shin, Hyun Tae Lee, Heejin Lim, Sang Hyung Lee. -
125559Orig1s000
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 125559Orig1s000 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology/Toxicology Review Date: July 14, 2015 From: Timothy J. McGovern, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO BLA: 125559 Agency receipt date: November 24, 2014 Drug: PRALUENT (alirocumab) Sponsor: Sanofi-Aventis U.S. LLC Indication: Adult patients with primary hypercholesterolemia (non-familial and heterozygous familial) or mixed dyslipidemia Reviewing Division: Division of Metabolism and Endocrinology Products Introductory Comments: The pharmacology/toxicology reviewer and supervisor concluded that the nonclinical data support approval of PRALUENT (alirocumab) for the indication listed above. Alirocumab is a human IgG1 monoclonal antibody that binds to human PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9). The recommended Established Pharmacologic Class for alirocumab is PCSK9 inhibitor antibody. There are no approved products in this class currently. An appropriate nonclinical program was conducted by the sponsor to support approval of alirocumab. Alirocumab elicited expected pharmacological responses in rats, hamsters, and monkeys; alirocumab lowered total cholesterol and LDL-cholesterol in the species tested and decreased HDL-cholesterol in rats and hamsters. The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing. No significant adverse findings were observed at the doses tested which achieved exposure multiples up to 11-fold in rats and 103-fold in monkeys compared to the maximum recommended human dose of 150 mg alirocumab administered subcutaneously once every two weeks. Findings in the liver and adrenal glands of rats were associated with exaggerated pharmacologic effects. -
(AAV1-LPLS447X) Gene Therapy for Lipoprotein Lipase Deficiency
Gene Therapy (2013) 20, 361–369 & 2013 Macmillan Publishers Limited All rights reserved 0969-7128/13 www.nature.com/gt ORIGINAL ARTICLE Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial D Gaudet1,2,JMe´ thot1,2,SDe´ry1, D Brisson1,2, C Essiembre1, G Tremblay1, K Tremblay1,2, J de Wal3, J Twisk3, N van den Bulk3, V Sier-Ferreira3 and S van Deventer3 We describe the 2-year follow-up of an open-label trial (CT-AMT-011–01) of AAV1-LPLS447X gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPLS447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a X40% reduction in fasting median plasma triglyceride (TG) at 3–12 weeks compared with baseline. Cohorts 1 (n ¼ 2) and 2 (n ¼ 4) received 3 Â 1011 gc kg À 1, and cohort 3 (n ¼ 8) received 1 Â 1012 gc kg À 1. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a X40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPLS447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG. -
WO 2017/048702 Al
(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 W O 2017/048702 A l 2 3 March 2017 (23.03.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 487/04 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/519 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 16/05 1490 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 13 September 2016 (13.09.201 6) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/218,493 14 September 2015 (14.09.2015) US (84) Designated States (unless otherwise indicated, for every 62/218,486 14 September 2015 (14.09.2015) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: INFINITY PHARMACEUTICALS, INC. -
Project Protocol
CADTH Health Technology Assessment June 2016 (Update Drugs for the management of rheumatoid May 2017) arthritis: clinical evaluation – project protocol PROSPERO Registration Number: CRD42016041498 1 Cite as: Drugs for the management of rheumatoid arthritis: clinical evaluation – project protocol. Ottawa: CADTH; 2016 Jun; updated 2017 April. This report is prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH) in collaboration with the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (DSEN). This report contains a comprehensive review of existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) available to CADTH at the time it was prepared, and its creation was guided by expert input and advice throughout its preparation. The information in this report is intended to help health care decision-makers, patients, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. The information in this report should not be used as a substitute for the application of clinical judgment in respect to the care of a particular patient or other professional judgment in any decision-making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this report to ensure that its contents are accurate, complete, and up-to-date, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or as a result of the use (or misuse) of any information contained in or implied by the information in this report. -
Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients
antibodies Review Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients Andrew T. Lucas 1,2,3,*, Ryan Robinson 3, Allison N. Schorzman 2, Joseph A. Piscitelli 1, Juan F. Razo 1 and William C. Zamboni 1,2,3 1 University of North Carolina (UNC), Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; [email protected] (J.A.P.); [email protected] (J.F.R.); [email protected] (W.C.Z.) 2 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-966-5242; Fax: +1-919-966-5863 Received: 30 November 2018; Accepted: 22 December 2018; Published: 1 January 2019 Abstract: The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. -
2017 ANNUAL REPORT | Translating SCIENCE • Transforming LIVES OUR COMMITMENT Make Every Day Count at PTC, Patients Are at the Center of Everything We Do
20 YEARS OF COMMITMENT 2017 ANNUAL REPORT | Translating SCIENCE • Transforming LIVES OUR COMMITMENT Make every day count At PTC, patients are at the center of everything we do. We have the opportunity to support patients and families living with rare disorders through their journey. We know that every day matters and we are committed to making a difference. OUR SCIENCE Our scientists are finding new ways to regulate biology to control disease We have several scientific research platforms focused on modulating protein expression within the cell that we believe have the potential to address many rare genetic disorders. OUR PEOPLE Care for each other, our community, and for the needs of our patients At PTC, we are looking at drug discovery and development in a whole new light, bringing new technologies and approaches to developing medicines for patients living with rare disorders and cancer. We strive every day to be better than we were the day before. At PTC Therapeutics, it is our mission to provide access to best-in-class treatments for patients who have an unmet need. We are a science-led, global biopharmaceutical company focused on the discovery, development and commercialization of clinically-differentiated medicines that provide benefits to patients with rare disorders. Founded 20 years ago, PTC Therapeutics has successfully launched two rare disorder products and has a global commercial footprint. This success is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. As we celebrate our 20th year of bringing innovative therapies to patients affected by rare disorders, we reflect on our unwavering commitment to our patients, our science and our employees. -
Lipid-Lowering Therapy and Low-Density Lipoprotein Cholesterol
Kristensen et al. BMC Cardiovascular Disorders (2020) 20:336 https://doi.org/10.1186/s12872-020-01616-9 RESEARCH ARTICLE Open Access Lipid-lowering therapy and low-density lipoprotein cholesterol goal attainment after acute coronary syndrome: a Danish population-based cohort study Marie Skov Kristensen1, Anders Green2,3, Mads Nybo4, Simone Møller Hede2, Kristian Handberg Mikkelsen5, Gunnar Gislason1,6,7,8, Mogens Lytken Larsen9 and Annette Kjær Ersbøll1* Abstract Background: Patients with acute coronary syndrome (ACS) are at high risk of recurrent cardiovascular (CV) event. The European guidelines recommend low-density lipoprotein cholesterol (LDL-C) levels < 1.8 mmol/L and early initiation of intensive lipid-lowering therapy (LLT) to reduce CV risk. In order to reduce the risk of further cardiac events, the study aimed to evaluate LDL-C goal attainment and LLT intensity in an incident ACS population. Methods: A cohort study of patients with residency at Funen in Denmark at a first-ever ACS event registered within the period 2010–2015. Information on LLT use and LDL-C levels was extracted from national population registers and a Laboratory database at Odense University Hospital. Treatments and lipid patterns were evaluated during index hospitalization, at 6-month and 12-month follow-up. Results: Among 3040 patients with an LDL-C measurement during index hospitalization, 40.7 and 39.0% attained the recommended LDL-C target value (< 1.8 mmol/L) within 6- and 12-month follow-up, respectively. During 6- and 12-month follow-up, a total of 89.2% (20.2%) and 88.4% (29.7%) used LLT (intensive LLT). -
Revised 6/29/2020 GEORGIA MEDICAID FEE-FOR-SERVICE
GEORGIA MEDICAID FEE-FOR-SERVICE BIOLOGIC IMMUNOMODULATORS PA SUMMARY Preferred Non-Preferred Arcalyst (rilonacept) Actemra subcutaneous (tocilizumab) Benlysta subcutaneous (belimumab) Cimzia (certolizumab) Enbrel (etanercept) Cosentyx (secukinumab) Humira (adalimumab) Dupixent (dupilumab) Ilaris (canakinumab) Fasenra Pen (benralizumab autoinjector)Kevzara Xeljanz (tofacitinib) (sarilumab) Xeljanz XR (tofacitinib extended-release) Kineret (anakinra) Nucala Pen (mepolizumab autoinjector) Olumiant (baricitinib) Orencia subcutaneous (abatacept) Otezla (apremilast) Rinvoq (upadacitinib) Siliq (brodalumab) Simponi (golimumab) Stelara (ustekinumab) Skyrizi (risankizumab) Taltz (ixekizumab) Tremfya (guselkumab) The drug names above include all available oral or subcutaneous formulations under the same primary name. LENGTH OF AUTHORIZATION: Varies NOTES: ▪ All preferred and non-preferred products require prior authorization. Intravenous (IV) formulations of the biologic immunomodulators are not covered under Pharmacy Services. ▪ The criteria details below are for the outpatient pharmacy program. If a medication is being administered in a physician’s office or clinic, then the medication must be billed through the DCH physician services program and not the outpatient pharmacy program. Information regarding the physician services program is located at www.mmis.georgia.gov. PA CRITERIA: Actemra Subcutaneous ❖ Approvable for members 2 years of age or older with a diagnosis of moderately to severely active polyarticular juvenile idiopathic arthritis -
AHFS Pharmacologic-Therapeutic Classification System
AHFS Pharmacologic-Therapeutic Classification System Abacavir 48:24 - Mucolytic Agents - 382638 8:18.08.20 - HIV Nucleoside and Nucleotide Reverse Acitretin 84:92 - Skin and Mucous Membrane Agents, Abaloparatide 68:24.08 - Parathyroid Agents - 317036 Aclidinium Abatacept 12:08.08 - Antimuscarinics/Antispasmodics - 313022 92:36 - Disease-modifying Antirheumatic Drugs - Acrivastine 92:20 - Immunomodulatory Agents - 306003 4:08 - Second Generation Antihistamines - 394040 Abciximab 48:04.08 - Second Generation Antihistamines - 394040 20:12.18 - Platelet-aggregation Inhibitors - 395014 Acyclovir Abemaciclib 8:18.32 - Nucleosides and Nucleotides - 381045 10:00 - Antineoplastic Agents - 317058 84:04.06 - Antivirals - 381036 Abiraterone Adalimumab; -adaz 10:00 - Antineoplastic Agents - 311027 92:36 - Disease-modifying Antirheumatic Drugs - AbobotulinumtoxinA 56:92 - GI Drugs, Miscellaneous - 302046 92:20 - Immunomodulatory Agents - 302046 92:92 - Other Miscellaneous Therapeutic Agents - 12:20.92 - Skeletal Muscle Relaxants, Miscellaneous - Adapalene 84:92 - Skin and Mucous Membrane Agents, Acalabrutinib 10:00 - Antineoplastic Agents - 317059 Adefovir Acamprosate 8:18.32 - Nucleosides and Nucleotides - 302036 28:92 - Central Nervous System Agents, Adenosine 24:04.04.24 - Class IV Antiarrhythmics - 304010 Acarbose Adenovirus Vaccine Live Oral 68:20.02 - alpha-Glucosidase Inhibitors - 396015 80:12 - Vaccines - 315016 Acebutolol Ado-Trastuzumab 24:24 - beta-Adrenergic Blocking Agents - 387003 10:00 - Antineoplastic Agents - 313041 12:16.08.08 - Selective -
Scientific Program Saturday, 17. July 2021 Factor VIII, Factor IX and Rare
Scientific programThe XXIX Congress of the International Society on Thrombosis and Haemostasis July 17-21, 2021 Philadelphia, U.S. Saturday, 17. July 2021 SSC Session 08:00 - 10:00 R1 Factor VIII, Factor IX and Rare Coagulation Disorders Introduction 08:00 - 08:02 Speaker: Johnny Mahlangu, ZA Non-Factor Replacement Therapies 08:02 - 08:02 Moderators: Johnny Mahlangu, South Africa, Tarek Owaidah, Saudi Arabia In Patients on Non-Factor Therapies, Exposure to Clotting 08:02 - 08:14 Factor Replacement Should Be Early (Debate) Speaker: Manuel Carcao, CA In Patients on Non-Factor Therapies, Exposure to Clotting 08:14 - 08:26 Factor Replacement Should Be Early (Debate) Speaker: Jayanthi Alamelu, GB Non-Factor Replacement Therapy Versus Factor Replacement 08:26 - 08:38 Therapy Risks -There Is No Free Lunch (Debate) Speaker: Bhavya Doshi, US Non-Factor Replacement Therapy Versus Factor Replacement 08:38 - 08:50 Therapy Risks -There Is No Free Lunch (Debate) Speaker: Gili Kenet, IL Beyond Annualized Bleed Rates What Should Be the Alternative 08:50 - 09:02 Endpoints for Non-Replacement Therapies Speaker: Alok Srivastava, IN Q&A Session 09:02 - 09:06 Gene Therapy 09:06 - 09:06 Moderators: Valder Arruda, United States, Savita Rangarajan, United Kingdom Anti Adeno-Associated Virus Antibodies Antibodies: What Are 09:06 - 09:18 the Standardization Issues? Speaker: David Lillicrap, CA Rationale for Adeno-associated Virus (AAV) Mediated Gene 09:24 - 09:30 Therapy in Patients With Anti Adeno-associated Virus Antibodies Speaker: David Cooper, NL What Should We Be Following-up Post Gene Therapy? 09:30 - 09:42 Speaker: Barbara A. -
Classification of Medicinal Drugs and Driving: Co-Ordination and Synthesis Report
Project No. TREN-05-FP6TR-S07.61320-518404-DRUID DRUID Driving under the Influence of Drugs, Alcohol and Medicines Integrated Project 1.6. Sustainable Development, Global Change and Ecosystem 1.6.2: Sustainable Surface Transport 6th Framework Programme Deliverable 4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Due date of deliverable: 21.07.2011 Actual submission date: 21.07.2011 Revision date: 21.07.2011 Start date of project: 15.10.2006 Duration: 48 months Organisation name of lead contractor for this deliverable: UVA Revision 0.0 Project co-funded by the European Commission within the Sixth Framework Programme (2002-2006) Dissemination Level PU Public PP Restricted to other programme participants (including the Commission x Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services) DRUID 6th Framework Programme Deliverable D.4.4.1 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Page 1 of 243 Classification of medicinal drugs and driving: Co-ordination and synthesis report. Authors Trinidad Gómez-Talegón, Inmaculada Fierro, M. Carmen Del Río, F. Javier Álvarez (UVa, University of Valladolid, Spain) Partners - Silvia Ravera, Susana Monteiro, Han de Gier (RUGPha, University of Groningen, the Netherlands) - Gertrude Van der Linden, Sara-Ann Legrand, Kristof Pil, Alain Verstraete (UGent, Ghent University, Belgium) - Michel Mallaret, Charles Mercier-Guyon, Isabelle Mercier-Guyon (UGren, University of Grenoble, Centre Regional de Pharmacovigilance, France) - Katerina Touliou (CERT-HIT, Centre for Research and Technology Hellas, Greece) - Michael Hei βing (BASt, Bundesanstalt für Straßenwesen, Germany).