DOCSLIB.ORG

Inclisiran Lowers LDL-C and PCSK9 Irrespective Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inclisiran Lowers LDL-C and PCSK9 Irrespective Of Diabetes Care Volume 42, January 2019 173 Inclisiran Lowers LDL-C and Lawrence A. Leiter,1 Hwee Teoh,1,2 David Kallend,3 R. Scott Wright,4 PCSK9 Irrespective of Diabetes Ulf Landmesser,5 Peter L.J. Wijngaard,3 John J.P. Kastelein,6 and Kausik K. Ray7 Status: The ORION-1 Randomized Clinical Trial Diabetes Care 2019;42:173–176 | https://doi.org/10.2337/dc18-1491 OBJECTIVE To evaluate the efficacy and safety of inclisiran by diabetes status. RESEARCH DESIGN AND METHODS ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with athero- sclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C–lowering therapies, to one 1 or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael’s Hos- subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared. pital, University of Toronto, Toronto, Ontario, Canada RESULTS 2Division of Cardiac Surgery, Keenan Research Inclisiran was associated with marked declines in LDL-C (median 228% to 252%, P < Centre for Biomedical Science and Li Ka Shing 0.0001 and 228% to 255%, P < 0.005 for all doses in the without- and with-diabetes Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada groups, respectively) and PCSK9. The inclisiran-treated groups also had lower 3The Medicines Company, Parsippany, NJ apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL choles- 4Department of Cardiology, Mayo Clinic, Roches- terol. Inclisiran had an adverse profile similar to that of placebo, and adverse events ter, MN NOVEL COMMUNICATIONS IN DIABETES 5 were proportionally balanced in the baseline with- and without-diabetes groups. Departmentof Cardiology,Charite-Universit´ ats-¨ medizin Berlin, Berlin Institute of Health and CONCLUSIONS German Center for Cardiovascular Research, Partner Site Berlin, Berlin, Germany PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option 6Department of Vascular Medicine, Academic for managing dyslipidemia in the presence and absence of diabetes. Medical Center, University of Amsterdam, Am- sterdam, the Netherlands 7Department of Primary Care and Public Health, Imperial Centre for Cardiovascular Disease Pre- Many individuals at high cardiovascular risk have LDL cholesterol (LDL-C) levels vention, Imperial College London, London, U.K. exceeding recommended targets (1,2). Diabetes is a risk factor for atherosclerotic Correspondingauthor:LawrenceA.Leiter,leiterl@ cardiovascular disease (ASCVD), and guidelines underscore timely initiation of smh.ca – appropriately aggressive LDL-C lowering pharmacotherapy in individuals who co- Received 12 July 2018 and accepted 21 October present with diabetes and dyslipidemia (3–5). 2018 Although statins remain the cornerstone of LDL-C–lowering strategies, maximally Clinical trial reg. no. NCT02597127, clinicaltrials tolerated doses of statins are not always sufficiently efficacious even when used with .gov nonstatin lipid-lowering agents. The discovery that proprotein convertase subtilisin/ This article contains Supplementary Data online kexin type 9 (PCSK9) modulates the degradation of LDL receptors (LDLRs) (6), and at http://care.diabetesjournals.org/lookup/suppl/ the linking of PCSK9 polymorphisms with serum LDL-C levels and cardiovascular out- doi:10.2337/dc18-1491/-/DC1. comes (7) signaled a new era of lipid-lowering options. Novel approaches involving © 2018 by the American Diabetes Association. monoclonal antibodies that interfere with PCSK9-LDLR interaction or RNA interfer- Readers may use this article as long as the work is properly cited, the use is educational and not ence preventing PCSK9 synthesis are associated with substantial LDL-C declines for profit, and the work is not altered. More infor- among individuals with suboptimal LDL-C levels despite being on optimal background mation is available at http://www.diabetesjournals statin therapy with or without other lipid-lowering agents (8–13). Furthermore, .org/content/license. 174 Inclisiran Lowers LDL-C in Diabetes Diabetes Care Volume 42, January 2019 interventions targeting PCSK9 have dem- RESULTS Inclisiran therapy was also associated onstrated cardiovascular benefit in in- Of the 501 subjects randomized, 497 re- with decreases in total cholesterol, dividuals with stable cardiovascular ceived their assigned study agent. A total atherogenic apolipoprotein B, non-HDL disease (9,10) and recent acute coro- of 67 had diabetes at baseline (n = 25 and cholesterol, and lipoprotein(a), as well as nary syndromes (12,13) regardless of 42 for the one-dose and two-dose sub- a trend toward increases in HDL choles- whether they have diabetes (10,12). studies, respectively) and 415 did not terol, regardless of baseline diabetes Inclisiran is a synthetic siRNA that (n = 218 and 197 for the one-dose and status or whether they were assigned drives PCSK9-specific mRNA degradation two-dose substudies). The baseline clin- to the one-dose or two-dose regimen in the liver. The ORION-1 trial (Clinical- ical characteristics were generally similar (Supplementary Table 1). Trials.gov, NCT02597127) reported that between the placebo- and inclisiran- There were no clinically meaningful people with ASCVD or ASCVD risk equiv- treated groups, with minor exceptions. changes in HbA1c 180 days after treat- alents along with high LDL-C, despite The placebo group tended to have higher ment initiation, and this persisted over management with maximally tolerated BMI, and the inclisiran group with di- the course of the study. The overall LDL-C–lowering therapies, had signifi- occurrences of adverse events were abetes tended to be older. Median HbA1c cantly lower LDL-C following inclisiran values in the groups without diabetes similar in subjects with and subjects therapy (8,11). This post hoc analysis were ;5.6% (36 mmol/mol), while those without diabetes. There were no cases evaluated whether ORION-1 subjects in the groups with diabetes ranged be- of myopathyand nopersistent elevations with and without diabetes at baseline tween 7.6% (60 mmol/mol) and 8.5% of liver function tests considered to be responded differently to inclisiran with (69 mmol/mol). related to inclisiran in subjects with or fi respect to changes in lipid pro les, safety, Inclisiran treatment was associated without diabetes. and glycemic control. with robust reductions in mean LDL-C levels from day 14 until day 210 regard- CONCLUSIONS RESEARCH DESIGN AND METHODS less of baseline diabetes status (Table 1). We report that, regardless of diabetes Details for the ORION-1 trial have pre- The LDL-C nadirs with the one-dose in- status, silencing of the PCSK9 pathway via viously been published (8). Subjects were clisiran regimens normally occurred at siRNA technology on a maximally toler- randomized to either one dose of pla- day 30; LDL-C remained significantly be- ated statin background 1) yields rapid, cebo or inclisiran (200, 300, or 500 mg) low baseline levels at day 180. The significant, and extended lowering of on day 1 or two doses of placebo or groups assigned to the two-dose incli- LDL-C levels with one to two injections; inclisiran (100, 200, or 300 mg inclisiran siran regimens demonstrated further 2) improves atherogenic lipid and lipo- on days 1 and 90). For this analysis, the LDL-C lowering after the second dose protein profiles; and 3) is safe and well subjects were divided into those with or of inclisiran. The maximal changes in tolerated, including neutral effects on without diabetes at baseline. The primary LDL-C between the baseline visits and glycemia and inflammatory markers. efficacy end point was the percent change those after the second inclisiran doses The novel approach of using PCSK9- from baseline LDL-C at day 180. Second- were greater than those noted for the directed monoclonal antibodies pro- ary efficacy end points included the per- one-dose regimens and displayed a vides an option for people who are at cent change in lipid measures. Adverse slower return to baseline values for up very high risk and who have been unable events were documented up to day 210. to 210 days. to achieve their LDL-C goals. Importantly, Table 1—Similar lowering of LDL-C levels between the baseline and day 180 visits for the group without and group with diabetes Without diabetes (N = 415 [86% of cohort]) With diabetes (N = 67 [14% of cohort]) Baseline % LDL-C change, Baseline % LDL-C change, LDL-C, mmol/L, LS mean LDL-C,(mmol/L), LS mean n (%) median (IQR) (95% CI) P (vs. placebo) n (%) Median, (IQR) (95% CI) P (vs. placebo) One dose Placebo 57 (26) 3.1 (2.5, 3.8) 2.8 (22.5, 8.2) NA 6 (24) 2.3 (2.1, 2.9) 24.3 (220.9, 12.2) NA Inclisiran 200 mg 53 (24) 3.1 (2.6, 3.5) 228.0(233.6, 222.4) ,0.0001 7 (28) 2.9 (2.7, 3.0) 227.6(242.9, 212.3) 0.0670 300 mg 54 (25) 2.8 (2.2, 3.8) 236.9(242.4, 231.4) ,0.0001 6 (24) 2.7 (2.2, 3.4) 252.0(268.5, 235.5) 0.0009 500 mg 54 (25) 3.5 (2.7, 4.4) 241.4(247.0, 235.9) ,0.0001 6 (24) 3.6 (2.3, 4.3) 245.8(262.3, 229.3) 0.0031 Two dose Placebo 52 (26) 2.8 (2.3, 3.8) 2.3 (22.4, 7.1) NA 9 (21) 3.3 (3.0, 3.6) 21.2 (212.7, 10.3) NA Inclisiran 100 mg 49 (25) 3.1 (2.3, 3.8) 235.1(240.0, 230.2) ,0.0001 10 (24) 3.3 (3.0, 3.6) 237.2(248.1, 226.3) 0.0001 200 mg 44 (22) 3.1 (2.3, 4.4) 243.6(248.8, 238.4) ,0.0001 16 (38) 3.0 (2.8, 3.8) 248.3(257.0, 239.7) ,0.0001 300 mg 52 (26) 3.1 (2.5, 4.1) 252.3(257.1, 247.5) ,0.0001 7 (17) 2.9 (2.5, 4.7) 255.0(268.0, 242.0) ,0.0001 Data are presented for the modified intention-to-treat population.
Load more

Recommended publications
  • Download This PDF File
    Journal of Cardiology and Therapy Online Submissions: http: //www.ghrnet.org/index./jct/ Journal of Cardiol Ther 2021 January; 8(1): 967-970 DOI: 10.17554/j.issn.2309-6861.2021.08.183 ISSN 2309-6861(print), ISSN 2312-122X(online) REVIEW The Role of Non-statin Therapy to Improve Cardiovascular Outcomes Abdulhalim Jamal Kinsara1, FRCP, FACC,FESC; Domenico Galzerano2, FESC; Olga Vriz2, MD 1 Ministry of National Guard-Health Affairs, King Saud Bin Ab- disease risk, while other therapy are showing less evidence. The dulaziz University for Health Sciences, COM-WR, King Abdullah current review highlights the evidence related to non-statins in the International Medical Research Center, Jeddah, Saudi Arabia; reduction of CV outcomes. 2 King Faisal Specialist Hospital and Research Centre and Alfaisal University. Key words: Ezetimibe; Proprotein convertase subtilisin kexin type 9 Inhibitor; Lomitapide; Mipomersen; Inclisiran; Bempedoic acid; Conflict-of-interest statement: The author(s) declare(s) that there Nexletol & Nexlizet; Bile acid sequestrants; Fibrates; Nicotinic acid; is no conflict of interest regarding the publication of this paper. Plasmapheresis Open-Access: This article is an open-access article which was © 2021 The Author(s). Published by ACT Publishing Group Ltd. All selected by an in-house editor and fully peer-reviewed by external rights reserved. reviewers. It is distributed in accordance with the Creative Com- mons Attribution Non Commercial (CC BY-NC 4.0) license, which Kinsara AJ, Galzerano D, Vriz O. The Role of Non-statin Therapy permits others to distribute, remix, adapt, build upon this work non- to Improve Cardiovascular Outcomes. Journal of Cardiology and commercially, and license their derivative works on different terms, Therapy 2021; 8(1): 967-970 Available from: URL: http://www.
    [Show full text]
  • Intervention to Improve LDL Receptor Function Emerging Therapies
    Intervention to improve LDL receptor function Emerging Therapies Marina Cuchel, MD, PhD Perelman School of Medicine University of Pennsylvania Most Lipid Lowering Drugs Affect LDL-C Levels By Up-Regulating the LDLR B100 apoB MTP VLDL TG TG statins ezetimibe bile acid sequestrants IDL PCSK9 -inhibitors LDL TG Cuchel NLA 2017 Do we really need more LDL-C lowering drugs? • LDL-C still not a goal with existing LLTs in a significant portion of subjects • Drug intolerance (statins) • Cost of new treatments • Other reasons Cuchel NLA 2017 Outline • PCSK9 – beyond monoclonal antibodies • ETC-1002 – inhibiting upstream HMGCoAR • Replacing LDLR - Gene therapy • ANGPTL3 inhibitors and other drug affecting LDL production Cuchel NLA 2017 PCSK9 enhances LDLR degradation Cuchel NLA 2017 Use of PCSK9i is complementary to that of statins PCSK9i evolucumab alirocumab [other monoclonal ABs] statins HMG-CoA ↑LDLR ↑PCSK9 ↓LDL-C ↓Cholesterol Cuchel NLA 2017 PCSK9 inhibition is very effective in lowering LDL-C Sabatine MS et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1615664 Cuchel NLA 2017 PCSK9 – beyond monoclonal Antibodies • Monoclonal PCSK9i are expensive • Require high doses • Are injectable • ?May lose responsiveness over time? Cuchel NLA 2017 Targeting PCSK9 with novel strategies • Vaccines • siRNA • Small molecules Cuchel NLA 2017 Targeting PCSK9 with novel strategies Vaccines antibodies response SREBP-2 pathway ↑ HMGCoA Red ↑ LDL-R Target protein ↑Epitope PCSK9 identification Conjugation with Administration Antibodies foreign peptide production Clinicaltrials.gov NCT02508896 Cuchel NLA 2017 Vaccine against PCSK9 lowers LDL-C in primates Crossey E. Vaccine, 2015 , 33, 5747–5755 Cuchel NLA 2017 Targeting PCSK9 with novel strategies siRNA SREBP-2 pathway ↑ HMGCoA Red ↑ LDL-R ↓PCSK9 Gene silencing Clinicaltrials.gov NCT02597127, NCT02314442 Cuchel NLA 2017 The RNAi inhibitor of PCSK9 - inclisiran - lowers PCSK9 and LDL-C levels in humans Ray KK et al.
    [Show full text]
  • Bempedoic Acid and Inclisiran for Patients with Heterozygous Familial Hypercholesterolemia and for Secondary Prevention of ASCVD: Effectiveness and Value
    Bempedoic Acid and Inclisiran for Patients with Heterozygous Familial Hypercholesterolemia and for Secondary Prevention of ASCVD: Effectiveness and Value Draft Evidence Report November 12, 2020 Prepared for ©Institute for Clinical and Economic Review, 2020 ICER Staff and Consultants Modeling Team Grace A. Lin, MD, MAS Dhruv S. Kazi, MD, MSc, MS Associate Professor of Medicine and Health Policy Associate Director, Smith Center for Outcomes University of California, San Francisco Research in Cardiology Director, Cardiac Critical Care Unit Jane Jih, MD, MPH Beth Israel Deaconess Medical Center Assistant Professor, Division of General Internal Associate Professor, Harvard Medical School Medicine University of California, San Francisco Foluso Agboola, MBBS, MPH Director, Evidence Synthesis Dr. Kazi was responsible for the development of the ICER cost-effectiveness model, interpretation of results, and drafting of the economic sections of this report; the Rick Chapman, PhD, MS resulting ICER reports do not necessarily represent the Director of Health Economics views of Beth Israel Deaconess Medical Center or ICER Harvard Medical School. Steven D. Pearson, MD, MSc President ICER DATE OF PUBLICATION: November 12, 2020 How to cite this document: Lin GA, Kazi DS, Jih J, Agboola F, Chapman R, Pearson SD. Inclisiran and Bempedoic Acid for Patients with Heterozygous Familial Hypercholesterolemia and for Secondary Prevention of ASCVD: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, November 12, 2020. https://icer-review.org/material/high-cholesterol-update- draft-evidence-report/ Grace Lin served as the lead author for the report and wrote the background, other benefits, and contextual considerations sections of the report, with Jane Jih serving as a co-author.
    [Show full text]
  • Assessment Report
    15 October 2020 EMA/696912/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Leqvio International non-proprietary name: inclisiran Procedure No. EMEA/H/C/005333/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Leqvio applicant: Novartis Europharm Limited Vista Building Elm Park Merrion Road Dublin 4 IRELAND Active substance: INCLISIRAN International Non-proprietary Name/Common inclisiran Name: Pharmaco-therapeutic group lipid modifying agents, plain, other lipid (ATC Code): modifying agents (C10AX) treatment for primary hypercholesterolaemia Therapeutic indication(s): or mixed dyslipidaemia Pharmaceutical form(s): Solution for injection Strength(s): 284 mg Route(s) of administration: Subcutaneous use Packaging: pre-filled syringe (glass) Package size(s): 1 pre-filled syringe Assessment report EMA/696912/2020 Page 2/143 Table of contents 1. Background information on the procedure ............................................ 12 1.1. Submission of the dossier ...................................................................................
    [Show full text]
  • The Effectiveness and Value of Bempedoic Acid and Inclisiran for Heterozygous Familial Hypercholesterolemia and Secondary Prevention of ASCVD
    PERSPECTIVES ON VALUE 961 The effectiveness and value of bempedoic acid and inclisiran for heterozygous familial hypercholesterolemia and secondary prevention of ASCVD A summary from the Institute for Clinical and Economic Review’s Midwest Comparative Effectiveness Public Advisory Council Foluso Agboola, MBBS, MPH; Grace A Lin, MD, MAS; Dhruv S Kazi, MD, MSc, MS; Avery McKenna; and Steven D Pearson, MD, MSc Atherosclerotic cardiovascular dis- necessary, a proprotein convertase ease (ASCVD) encompasses a set of subtilisin/kexin type 9 (PCSK9) inhib- Author affiliations 9 chronic conditions that includes coro- itor is recommended. Foluso Agboola, MBBS, MPH; Avery nary artery disease, peripheral artery A new option for lowering choles- McKenna; and Steven D Pearson, MD, disease, cerebrovascular disease, and terol is bempedoic acid (combined MSc, Institute for Clinical and Economic aortic atherosclerotic disease. In the with ezetimibe [Nexlizet] or with- Review, Boston, MA. Grace A Lin, MD, United States, ASCVD affects approxi- out ezetimibe [Nexletol], Esperion MAS, Division of General Internal mately 1 in 10 people; represents a high Therapeutics, Inc.), which was Medicine and Philip R. Lee Institute risk for future major adverse cardio- approved by the US Food and Drug for Health Policy Studies, University of California, San Francisco. Dhruv S Kazi, vascular events (MACE), such as heart Administration (FDA) in February MD, MSc, MS, Smith Center for Outcomes attacks and strokes; and is the leading 2020. Bempedoic acid is an inhibitor of Research in Cardiology, Beth Israel 1,2 cause of death. adenosine triphosphate (ATP) citrate Deaconess Medical Center and Harvard Heterozygous familial hypercholes- lyase that lowers LDL-C by reduc- Medical School, Boston, MA.
    [Show full text]
  • Inclisiran 284Mg Solution for Injection in Pre-Filled Syringe (Leqvio®)
    1 www.scottishmedicines.org.uk SMC2358 inclisiran 284mg solution for injection in pre-filled syringe (Leqvio®) Novartis Pharmaceuticals UK Limited 09 July 2021 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHSScotland. The advice is summarised as follows ADVICE: following a full submission inclisiran (Leqvio®) is accepted for use restricted use within NHSScotland. Indication under review: for adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet: • in combination with a statin or statin with other lipid lowering therapies in patients who are unable to reach LDL-C goals with the maximum tolerated dose of a statin, or • alone or in combination with other lipid lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated. SMC restriction: for specialist use only in patients at high cardiovascular risk as follows: • patients with heterozygous familial hypercholesterolaemia (HeFH) and LDL-C ≥5.0mmol/L, for primary prevention of cardiovascular events or, • patients with HeFH and LDL-C≥3.5mmol/L, for secondary prevention of cardiovascular events or, • patients with high risk due to previous cardiovascular events and LDL-C≥4.0mmol/L or, • patients with recurrent/polyvascular disease and LDL-C≥3.5mmol/L. In three phase III studies, both the percentage reduction in LDL-C to day 510 and the time- adjusted percentage in LDL-C from day 90 to day 540 were significantly larger with inclisiran compared with placebo.
    [Show full text]
  • December 11, 2020 Maggie O'grady Program Manager Institute For
    December 11, 2020 Maggie O’Grady Program Manager Institute for Clinical and Economic Review 2 Liberty Square, 9th Floor Boston, MA 02109 Submitted Electronically: [email protected]; [email protected] Dear Ms. O’Grady, Thank you for the opportunity to provide feedback to ICER on its draft evidence report for assessing the comparative clinical effectiveness and value of inclisiran (Novartis) and bempedoic acid (Nexletol™, Esperion Therapeutics, Inc.) for treatment of high cholesterol in the setting of heterozygous familial hypercholesterolemia (HeFH) and for secondary prevention of atherosclerotic cardiovascular disease (ASCVD). We appreciate your willingness to review comments and recommendations from the National Forum’s Value & Access Steering Committee and partners working on these issues. The Value & Access (V&A) Steering Committee and partners operate under the consensus goal to enhance health and well-being by supporting people’s access to evidence-based care that is appropriate for them by: • Identifying evidence-based strategies for determining appropriateness of care • Supporting the implementation of evidence-based care that aligns incentives for patients, providers, payers, other stakeholders The (V&A) Steering Committee and partners jointly offer the following feedback for ICER’s consideration in the development of the draft evidence report. Positives The Steering Committee and partners appreciate ICER’s inclusion in the draft evidence report of our recommendations on the draft scoping document : • That ICER’s value framework includes both quantitative and qualitative comparisons across treatments to ensure that the full range of benefits and harms (e.g., health disparities and access to care issues) are evaluated. We encourage ICER to continue increasing patient advocacy groups’ involvement in the process through direct outreach to groups with expertise in areas of focus, opportunities for meetings with ICER and its experts, and enhanced explanation of ICER’s processes.
    [Show full text]
  • The Current Landscape of Nucleic Acid Therapeutics
    REVIEW ARTICLE https://doi.org/10.1038/s41565-021-00898-0 The current landscape of nucleic acid therapeutics Jayesh A. Kulkarni 1,2,3,7, Dominik Witzigmann 2,3,4,7, Sarah B. Thomson 1, Sam Chen5, Blair R. Leavitt 1, Pieter R. Cullis 2,4 and Roy van der Meel 6 ✉ The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical trans- lation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics. early half a century ago, Friedmann and Roblin concep- include Strimvelis—patient-derived CD34+ cells transduced with a tualized that inherited genetic disorders resulting in dys- γ-retroviral vector to express DNA encoding the human adenosine functional gene products could be treated by introducing deaminase (ADA) enzyme, treating severe combined immunode- N 1 5 a functional gene copy .
    [Show full text]
  • Inclisiran: a New Promising Agent in the Management of Hypercholesterolemia
    diseases Review Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia Constantine E. Kosmas 1,*, Alba Muñoz Estrella 2, Andreas Sourlas 3, Delia Silverio 4, Elizabeth Hilario 4, Peter D. Montan 4 and Eliscer Guzman 5 1 Department of Medicine, Division of Cardiology, Mount Sinai Hospital, New York, NY 11357, USA 2 Department of Medicine, Mount Sinai St. Luke’s-West Hospital, New York, NY 10025, USA; [email protected] 3 School of Medicine, University of Crete, 71003 Heraklion, Greece; [email protected] 4 Cardiology Clinic, Cardiology Unlimited, PC, New York, NY 10033, USA; [email protected] (D.S.); [email protected] (E.H.); [email protected] (P.D.M.) 5 Department of Medicine, Division of Cardiology, Montefiore Medical Center, Bronx, NY 10467, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-646-734-7969 Academic Editor: Ahmed Bakillah Received: 29 June 2018; Accepted: 11 July 2018; Published: 13 July 2018 Abstract: The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9.
    [Show full text]
  • Riktige Legemidler Til Rett Pris Områdegjennomgang Av Legemidler Under Folketrygden
    Rapport 2021/01 | For Helse- og omsorgsdepartementet og Finansdepartementet Riktige legemidler til rett pris Områdegjennomgang av legemidler under folketrygden Dag Morten Dalen, Mari Brekke Holden, Øyvind Lian, Ingeborg Rasmussen og Andreas Skulstad Riktige legemidler til rett pris. Dokumentdetaljer Tittel Riktige legemidler til rett pris. Områdegjennomgang av legemidler under folketrygden Rapportnummer 2021/01 ISBN 978-82-8126-504-2 Forfattere Dag Morten Dalen, Mari Brekke Holden, Øyvind Lian, Ingeborg Rasmussen og Andreas Skulstad Prosjektleder Ingeborg Rasmussen Kvalitetssikrer Steinar Strøm og Finn Holm Oppdragsgiver Finansdepartementet og Helse og omsorgsdepartementet Dato for overlevering 7. januar 2021 Tilgjengelighet Offentlig. Oppdragsgiver fastsetter dato for offentliggjøring Nøkkelord Legemiddeløkonomi, samfunnsøkonomi, regulering og konkurranseøko- nomi Om Vista Analyse Vista Analyse AS er et samfunnsfaglig analyseselskap med hovedvekt på økonomisk utredning, evaluering, rådgivning og forskning. Vi utfører oppdrag med høy faglig kvalitet, uavhengighet og integritet. Våre sentrale temaområder er klima, energi, samferdsel, næringsutvikling, byutvikling og velferd. Vista Analyse er vinner av Evalueringsprisen 2018. Våre medarbeidere har meget høy akademisk kompetanse og bred erfaring innenfor konsulentvirksomhet. Ved be- hov benytter vi et velutviklet nettverk med selskaper og ressurspersoner nasjonalt og internasjonalt. Selskapet er i sin helhet eiet av medarbeiderne. Om EY EY er en ledende global aktør innen revisjon, skatt og avgift, transaksjoner og rådgivning. Gjennom kontinuerlig fokus på kvalitet bygger vi tillit i kapitalmarkedene og i økonomier over hele verden. Gjennom å utvikle gode ledere som forplikter seg til å levere det vi lover bidrar vi til å bygge et bedre arbeidsliv for våre ansatte, kunder og lokalsamfunn. Vårt nettverk omfatter mer enn 280 000 ansatte i 150 land.
    [Show full text]
  • Download Info Sheet
    Why may I need to take medications that lower my blood lipids? The short answer is that even after changing your diet and sticking to an exercise program, you may still have cholesterol or triglyceride (kinds of ® lipids or “fats” in your blood) levels that are too high for your health. This can put you at risk for having heart problems in the future. Taking certain medication(s) in addition to leading a healthy lifestyle can decrease your low-density lipoprotein (LDL) cholesterol level, your triglyceride level, or both. High levels of cholesterol, especially LDL-cholesterol, can cause health problems such as heart attack and stroke. Medicines that lower LDL-cholesterol The most common medications that are used to lower LDL-cholesterol levels are medicines from the STATIN family. These are the medications ending in “statin” such as atorvastatin or rosuvastatin. Statins work by blocking cholesterol from being made in the liver. Statins are very effective but sometimes people don’t tolerate them or need additional medications to get to the ideal LDL-cholesterol level recommended by their doctor. If you are on a statin and or are unable to take a statin, there are other ways to lower your LDL-cholesterol. Drugs often work in different ways to lower cholesterol and triglycerides. However, You can learn more about statins generally, they either reduce absorption, decrease production, or increase disposal of at – just cholesterol and triglycerides to help you achieve healthy levels of both. That, in part, LearnYourLipids.com is why your doctor may recommend combinations of drugs to help you stay healthy.
    [Show full text]
  • Lipidology Trials - What’S New and What’S in the Pipeline?
    Lipidology Trials - What’s New and What’s in the Pipeline? Professor Basil S. Lewis, MD, FRCP, FACC, FESC Past Chairman, WG on Cardiovascular Pharmacotherapy European Society of Cardiology SUPPORTED BY AN EDUCATIONAL GRANT FROM AMGEN and NOVARTIS Declaration of Conflict Of Interest I have the following potential conflict(s) of interest to report Type of affiliation / financial interest Name of commercial company Receipt of grants/research support: AstraZeneca, Bayer Healthcare, MSD, Resverlogix, KOWA, Pfizer Receipt of honoraria or consultation fees: Bayer Healthcare, MSD, Pfizer, Novo Nordisk Participation in a company sponsored Pfizer, Novo Nordisk speaker’s bureau: Challenges in Lipidology Trials • What is the pathophysiology? • What are the targets? • LDL? HDL? TG? LP(a)? • Relation between lipidology, atherosclerosis and CV events? • Time discrepancies? • What are the end-points? • Surrogate endpoints? Plasma lipids? Plaque volume? Extent of disease? • Can these guide in early/late phases of drug development? • Outcome events – This is what matters! • What is the comparator? • Keeping pace with a rapidly evolving field Targets • Targeting LDL • PCSK9 Inhibitors (FOURIER, SPIRE, ODYSSEY) • RNA interference (RNAi) to reduce PCSK9 (ORION) • Decreasing LDL synthesis - Bempedoic acid • Targeting HDL • CETP inhibitors • Epigenetics - BET on MACE program • Apo-A1 infusion – AEGIS program • Targeting triglycerides • REDUCE-IT • PROMINENT • New - Targeting ANGPTL3 (inh of lipoprotein lipase) IMPROVE-IT - Proves again the LDL Hypothesis IMPROVE-IT
    [Show full text]