DOCSLIB.ORG

New Approaches to Lipid Modification

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Approaches to Lipid Modification NEW APPROACHES TO LIPID MODIFICATION David Preiss MRC Population Health Research Unit Clinical Trial Service Unit University of Oxford Nuffield Department of Clinical Trial Service Unit & Population Health Epidemiological Studies Unit Content • Background • PCSK9 inhibition – Monoclonal antibodies – Small interfering RNA • CETP inhibition • Final word – statin therapy Lipoprotein structure The various circulating lipoproteins Lipids and their association with coronary disease 13,000 incident coronary events Non HDL- HDL- Triglycerides cholesterol cholesterol 3.5 3.0 2.5 2.0 1.5 Hazard ratio (95% CI) ratio Hazard 1.0 3.0 3.5 4.0 4.5 5.0 5.5 0.8 1.0 1.2 1.4 1.6 1.8 1.0 2.0 3.0 Mean lipid level (mmol/L) Adjusted for age and sex only Further adjusted for non-lipid and lipid factors Sarwar et al. ERFC, JAMA 2009 Evidence of causality – cardiovascular disease Observational Monogenic Randomized Polymorphisms (association) disease trials lowering PCSK9 LDL cholesterol raising CETP HDL cholesterol lowering triglyceride - (?) Expected reduction in MAJOR VASCULAR EVENT risk from lowering LDL-C with STATIN therapy Control 20 22% relative risk Statin reduction per mmol/L 15 15% relative risk More statin reduction per 0.5 mmol/L 10 Combined evidence: Or: 34% relative risk reduction ~40% relative risk reduction per 1.5 mmol/L vascular % event, vascular per 2 mmol/L (0.78 x 0.78) (since 0.78 x 0.85 = 0.66) 5 Five Five year risk ofa major 0 0 1 2 3 4 5 LDL cholesterol, mmol/L PCSK9 – an attractive CVD target • Proprotein convertase subtilisin/kexin type 9 • Circulating protein largely produced in the liver • Intimately involved in LDL receptor turnover – Higher PCSK9 = reduced LDL expression = higher LDL-c – Lower PCSK9 = increased LDL expression = lower LDL-c • Seminal genetic studies1-4: – Gain of function mutations = rare type of FH – Loss of function mutations = reduced CVD; no clinical disadvantage – PCSK9 polymorphisms 1. Abifadel M, Nat Gen 2003, 34:154–156 2. Cohen JC, NEJM 2006, 354:1264–1272 3. Benn M, JACC 2010, 55:2833–2842 4. Zhao Z, Am J Hum Gen 2006, 79:514–523 PCSK9 and the hepatic LDL receptor Approaches to reducing PCSK9 (and LDL-c) • Monoclonal antibodies – Evolocumab PCSK9 inhibitor – Alirocumab (act in circulation) – Bococizumab • Adnectins • Small interfering RNA PCSK9 synthesis inhibitor – Inclisiran (acts in liver) Monoclonal antibodies to PCSK9 Mechanism of action – within the circulation FOURIER Trial - evolocumab 27,564 high-risk, stable patients with established CVD High or moderate intensity statin therapy (± ezetimibe) LDL-C ≥1.8 mmol/L or non-HDL-C ≥2.6 mmol/L Evolocumab SC Placebo SC 140 mg Q2W or 420 mg QM Q2W or QM Median follow up 26 months An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J 2016;173:94-101 LDL Cholesterol 100 Placebo 90 80 70 59%LDL-cholesterol mean reduction reduced (95%CI by 1.4mmol/L 58-60), (~60%) P<0.00001 60 All patients on statin therapy Absolute reduction: 56 mg/dl (95%CI 55-57) 50 40 LDL CholesterolLDL (mg/dl) 30 Evolocumab 20 (median 30 mg/dl, IQR 19-46 mg/dl) 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. NEJM 2017; 376:1713-22 Primary Endpoint 16% Hazard ratio 0.85 14.6% 14% (95% CI, 0.79-0.92) P<0.0001 12.6% 12% Placebo Revasc 10% Cor 8% Evolocumab 6% CV Death, MI, Stroke, 4% Hosp for UA, for Hosp UA, or CVD death, MI, stroke, unstable angina, coronary revascularization 2% 0% 0 6 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. NEJM 2017; 376:1713-22 Key Secondary Endpoint 10% 9.9% 9% Hazard ratio 0.80 (95% CI, 0.73-0.88) 8% P<0.00001 7.9% Placebo 7% 6% 5% 4% Evolocumab 3% CV Death, MI, or Stroke 2% CVD death, MI, stroke 1% 0% 0 6 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. NEJM 2017; 376:1713-22 SPIRE trials - bococizumab SPIRE trials stopped early – bococizumab program stopped Ridker P et al. NEJM 2017; 376:1527-39 Ridker P et al. NEJM 2017; 376:1527-39 SPIRE trials - bococizumab Ridker P et al. NEJM 2017; 376:1527-39 Is there a threshold for LDL-c and CVD benefit? Giugliano R et al. Lancet 2017; 390:1962-71 Safety of very low LDL-c: extreme fifths Achieved LDL-c Achieved LDL-c P value across all <0.5mmol/L ≥2.6mmol/L groups All SAEs 23% 23% 0.13 AST or ALT >3X ULN 2% 2% 0.19 CK >5X ULN 1% 1% 0.99 New-onset diabetes 8% 8% 0.63 Neuro-cognitive 0.019 2% 1% events (adjusted 0.15) Cataract 2% 1% 0.15 Malignancy 2% 2% 0.22 Non CVD death 1% 1% 0.67 Giugliano R et al. Lancet 2017; 390:1962-71 Summary: monoclonal antibodies to PCSK9 Lessons learned Disadvantages • PCSK9 inhibition reduces • Hassle LDL-c substantially – Injection each 2-4 weeks • Effect on CVD as predicted (self administered) – Storage conditions • Very low LDL-c achieved • Cost – Regardless of statin therapy • Safe • Immune reaction – Bococizumab – Cognition – New-onset DM • Not organ specific – Cancer Nuffield Department of Clinical Trial Service Unit & Population Health Epidemiological Studies Unit Inclisiran: an inhibitor of PCSK9 synthesis • Small interfering RNA – Protein synthesis transcribed translated DNA mRNA protein – Specifically reduces hepatic PCSK9 synthesis i.e. ‘at source’ • Given by subcutaneous injection (300mg inclisiran sodium): – Baseline – 3 months – Every 6 months thereafter GalNAc-siRNA conjugates facilitate rapid hepatic uptake Background GalNAC: N-acetylgalactosamine; ASPGR: Asialoglycoprotein receptor 24 Small interfering RNA (siRNA) targeted to PCSK9 Mechanism of action RISC: RNA Induced Silencing Complex GalNAc: N-acetylgalactosamine Whitehead et al. Nat Rev Drug Discov 2009;8:129-38 mRNA: messenger RNA 25 Methods ORION-1 trial design Screened (696) Stratified by country and Rx One dose start Randomized (501) Two dose start Placebo 200 mg 300 mg 500 mg Treated (497) Placebo 100 mg 200 mg 300 mg N=65 N=60 N=61* N=65* N=62 N=61* N=62* N=61 Day 1 Study drug given Completed (483) Day 1 Study drug given Day 14 1st follow-up visit Day 14 1st follow-up visit Day 30 Monthly follow-up visits Day 30 Monthly follow-up visits Day 90 Day 90 Study drug given Day 180 Primary evaluation Day 180 Primary evaluation Day 210 End of study visit Day 210 End of study visit Day 360 Extended follow-up Day 360 Extended follow-up 26 Efficacy: One dose starting regimen—300 mg optimal Robust, sustained LDL-C reductions 300 mg 300 mg 300 mg 50.9% reduction 38.6% reduction 19.0% reduction 10 95% CI) 95% 0 ± -10 P-value for all comparisons to placebo <0.0001 -20 -30 -40 Placebo 200 mg -50 Mean percent change ( 300 mg 500 mg -60 0 30 60 90 120 150 180 210 240 270 300 330 360 Days from first injection 27 Efficacy: Two dose starting regimen—optimal Robust, sustained LDL-C reductions 300 mg x2 300 mg x2 55.5% 52.5% 31.4% 10 Placebo 100 mg 95% CI) 95% 0 ± 200 mg 300 mg -10 P-value for all comparisons to placebo <0.0001 -20 -30 -40 -50 Mean percent change ( -60 0 30 60 90 120 150 180 210 240 270 300 330 360 Days from first injection 28 Inclisiran: summary of available data Key information Advantages • 300mg • Injection timing • Baseline, 3 months, then – Injection each 6 months every 6 months is the (healthcare professional optimal regimen administered) • 50% average reduction in • Mechanism of action: organ LDL-c specific • Appears safe • 5% injection site reaction Nuffield Department of Clinical Trial Service Unit & Population Health Epidemiological Studies Unit The role of CETP CETP – cholesteryl ester transfer protein CETP inhibition CETP inhibitors WEAK POTENT Dalcetrapib Torcetrapib Evacetrapib Anacetrapib HDL cholesterol +27% +70% +132% +104% Apolipoprotein B 0% -15% -19% -18% Blood pressure ↔ ↑↑ ↔ ↔ CVD outcome trial DalOUTCOMES ILLUMINATE ACCELERATE REVEAL CVD trial size 15,871 15,067 12,092 30,000 CVD trial duration 2.6 years 1.5 years 2.3 years 4.1 years Why stopped? Futility Harm Futility As planned CVD trial HR 1.04 1.25 1.01 0.91 REVEAL trial: design REVEAL – primary outcome Benefit is related to LDL-c reduction Content • Background • PCSK9 inhibition – Monoclonal antibodies – Small interfering RNA • CETP inhibition • Final word – statin therapy Statins: benefits are substantial, risks are very small Based on treating 10,000 patients with atorvastatin 40mg daily for 5 years (approximate reduction in LDL-cholesterol 2mmol/L) Benefit or Risk Number of Patients with Benefit or Harm CVD events prevented (secondary prevention) 1000 CVD events prevented (primary prevention) 500 New onset diabetes mellitus 50-100 Muscle symptoms (uncomplicated) 100 Myopathy (including rhabdomyolysis) 5 Hemorrhagic stroke 5-10 Severe liver disease <1 From multiple landmark randomized trials with 200,000 participants.
Load more

Recommended publications
  • 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).
    [Show full text]
  • Repatha) Reference Number: PA.CP.PHAR.123 Effective Date: 01/18 Last Review Date: 01/19 Revision Log
    Clinical Policy: Evolocumab (Repatha) Reference Number: PA.CP.PHAR.123 Effective Date: 01/18 Last Review Date: 01/19 Revision Log Description Evolocumab (RepathaTM) is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor antibody. FDA Approved Indication(s) Repatha is indicated: • To reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease • As an adjunct to diet, alone, or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C) • As an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria It is the policy of health plans affiliated with Pennsylvania Health and Wellness that Repatha is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Heterozygous Familial Hypercholesterolemia and Atherosclerotic Cardiovascular Disease (must meet all): 1. Diagnosis of one of the following (a or b): a. HeFH as defined by one of the following (i or ii): i. World Health Organization (WHO)/Dutch Lipid Network familial hypercholesterolemia diagnostic criteria score of > 8 as determined by requesting provider; ii. Definite diagnosis per Simon Broome criteria); b. Atherosclerotic cardiovascular disease (ASCVD) as evidenced by a history of any one of the following conditions (i-vii): i. Acute coronary syndromes; ii.
    [Show full text]
  • Clinical Policy: Evolocumab (Repatha) Reference Number: CP.CPA.269 Effective Date: 10.15 Last Review Date: 02.19 Line of Business: Commercial Revision Log
    Clinical Policy: Evolocumab (Repatha) Reference Number: CP.CPA.269 Effective Date: 10.15 Last Review Date: 02.19 Line of Business: Commercial Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Evolocumab (Repatha®) is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor antibody. FDA Approved Indication(s) Repatha is indicated: • To reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease • As an adjunct to diet, alone, or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C) • As an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Repatha is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Heterozygous Familial Hypercholesterolemia and Atherosclerotic Cardiovascular Disease (must meet all): 1. Diagnosis of one of the following (a or b): a. HeFH as defined by one of the following (i or ii): i. World Health Organization (WHO)/Dutch Lipid Network familial hypercholesterolemia diagnostic criteria score of > 8 as determined by requesting provider (see Appendix D); ii. Definite diagnosis per Simon Broome criteria (see Appendix D); b.
    [Show full text]
  • Us 2018 / 0296525 A1
    UN US 20180296525A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0296525 A1 ROIZMAN et al. ( 43 ) Pub . Date: Oct. 18 , 2018 ( 54 ) TREATMENT OF AGE - RELATED MACULAR A61K 38 /1709 ( 2013 .01 ) ; A61K 38 / 1866 DEGENERATION AND OTHER EYE (2013 . 01 ) ; A61K 31/ 40 ( 2013 .01 ) DISEASES WITH ONE OR MORE THERAPEUTIC AGENTS (71 ) Applicant: MacRegen , Inc ., San Jose , CA (US ) (57 ) ABSTRACT ( 72 ) Inventors : Keith ROIZMAN , San Jose , CA (US ) ; The present disclosure provides therapeutic agents for the Martin RUDOLF , Luebeck (DE ) treatment of age - related macular degeneration ( AMD ) and other eye disorders. One or more therapeutic agents can be (21 ) Appl. No .: 15 /910 , 992 used to treat any stages ( including the early , intermediate ( 22 ) Filed : Mar. 2 , 2018 and advance stages ) of AMD , and any phenotypes of AMD , including geographic atrophy ( including non -central GA and Related U . S . Application Data central GA ) and neovascularization ( including types 1 , 2 and 3 NV ) . In certain embodiments , an anti - dyslipidemic agent ( 60 ) Provisional application No . 62/ 467 ,073 , filed on Mar . ( e . g . , an apolipoprotein mimetic and / or a statin ) is used 3 , 2017 . alone to treat or slow the progression of atrophic AMD Publication Classification ( including early AMD and intermediate AMD ) , and / or to (51 ) Int. CI. prevent or delay the onset of AMD , advanced AMD and /or A61K 31/ 366 ( 2006 . 01 ) neovascular AMD . In further embodiments , two or more A61P 27 /02 ( 2006 .01 ) therapeutic agents ( e . g ., any combinations of an anti - dys A61K 9 / 00 ( 2006 . 01 ) lipidemic agent, an antioxidant, an anti- inflammatory agent, A61K 31 / 40 ( 2006 .01 ) a complement inhibitor, a neuroprotector and an anti - angio A61K 45 / 06 ( 2006 .01 ) genic agent ) that target multiple underlying factors of AMD A61K 38 / 17 ( 2006 .01 ) ( e .
    [Show full text]
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]
  • PCSK9 Inhibitors – Clinical Applications
    VOLUME 39 : NUMBER 5 : OCTOBER 2016 EXPERIMENTAL AND CLINICAL PHARMACOLOGY PCSK9 inhibitors – clinical applications Robert Schmidli Consultant endocrinologist SUMMARY Department of Endocrinology The enzyme PCSK9 has an important role in regulating low-density lipoprotein (LDL) receptors Canberra Hospital and concentrations of LDL cholesterol. Inhibiting this enzyme could therefore reduce the incidence of ischaemic heart disease. Keywords The monoclonal antibodies alirocumab, evolocumab and bococizumab are directed against alirocumab, bococizumab, PCSK9 and inhibit its activity. Phase II trials have shown alirocumab and evolocumab to be evolocumab, ischaemic heart disease, LDL effective at lowering LDL cholesterol. cholesterol, proprotein Preliminary results of these phase II trials show potential benefits in ischaemic heart disease. convertase subtilisin/kexin type 9 Reports of adverse effects, including muscular symptoms and neurocognitive changes, were low. Large phase III cardiovascular outcome trials of these monoclonal antibodies will determine their Aust Prescr 2016;39:168–70 safety and efficacy. These drugs may have a role in the management of patients at very high risk http://dx.doi.org/10.18773/ of cardiovascular events such as those with familial hypercholesterolaemia. austprescr.2016.061 Introduction PCSK9 inhibitory antibodies The incidence of deaths from ischaemic heart disease Studies of uncommon mutations, such in Australia has reduced since the 1960s. While about as the LDL‑receptor mutations in familial half of this reduction is due to interventions such as hypercholesterolaemia, have led to important coronary revascularisation and secondary prevention, therapeutic advances in the study of lipids and the remainder is due to addressing risk factors such as cardiovascular disease. Proprotein convertase smoking, lipids and hypertension.
    [Show full text]
  • A61p1/16 (2006.01) A61p3/00 (2006.01) Km, Ml, Mr, Ne, Sn, Td, Tg)
    ( (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, A61P1/16 (2006.01) A61P3/00 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/192 (2006.01) C07C 321/28 (2006.01) Declarations under Rule 4.17: (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/IB2020/000808 earlier application (Rule 4.17(iii)) (22) International Filing Date: Published: 25 September 2020 (25.09.2020) — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (26) Publication Language: English amendments (Rule 48.2(h)) (30) Priority Data: 62/906,288 26 September 2019 (26.09.2019) US (71) Applicant: ABIONYX PHARMA SA [FR/FR] ; 33-43 Av¬ enue Georges Pompidou, Batiment D, 31130 Bahna (FR). (72) Inventor: DASSEUX, Jean-Louis, Henri; 7 Allees Charles Malpel, Bat. B, 31300 Toulouse (FR). (74) Agent: HOFFMANN EITLE PATENT- UND RECHTSANWALTE PARTMBB, ASSOCIATION NO. 151; Arabellastrasse 30, 81925 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 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, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
    [Show full text]
  • PCSK9 Inhibitor Non-Response in a Patient with Preserved LDL Receptor
    PCSK9 inhibitor non-response in a patient with preserved LDL receptor function: A case study Losh C, Underberg J Murray Hill Medical Group and New York University School of Medicine, New York, NY Background Results Conclusions PCSK9 inhibitors (PCSK9Is) are monoclonal LDL-C levels after three and seven weeks Absence of LDL receptor activity is not the antibodies that bind to serum PCSK9 and Response to Statin Therapy of therapy with alirocumab 75 mg were 235 only mechanism of PCSK9 inhibitor non- delay LDL receptor degradation. Two mg/dL and 239 mg/dL respectively. Three response. An alteration in the PCSK9 PCSK9Is are commercially available: and seven weeks after up-titration, LDL-C Intervention LDL-C (mg/dL) Change (%) evolocumab and alirocumab. FDA approved binding site for alirocumab and indications include LDL cholesterol (LDL-C) was 249 mg/dL and 292 mg/dL, evolocumab is proposed as a hypothetical lowering on maximally tolerated statin respectively. Total duration of alirocumab None 283 — mechanism for non-response in this therapy was 16 weeks. LDL-C was 253 therapy in patients with ASCVD and Familial patient. Other alternatives include Hypercholesterolemia (FH). Among patients mg/dL after 3 weeks of therapy with pitavastatin 2 mg 238 -15.9% immunogenicity, noncompliance, or faulty with LDL receptor mutations, those with evolocumab, at which time PCSK9 1 dose/week partial loss of function typically respond well inhibitor therapy was discontinued due to pitavastatin 2 mg injection techniqueReferences. 216 -23.7% to PCSK9 inhibition, while those with lack of clinical response. 2 doses/week Amgen Inc. (2015). Repatha: Highlights of homozygous receptor-negative mutations, pitavastatin 2 mg ie.
    [Show full text]
  • Praluent (Alirocumab) Repatha (Evolocumab) Effective 12/1/2019
    Praluent (alirocumab) Repatha (evolocumab) Effective 12/1/2019 ☒ MassHealth Plan ☒ ☒Commercial/Exchange Prior Authorization Program Type ☐ Quantity Limit ☒ Pharmacy Benefit Benefit ☐ Step Therapy ☐ Medical Benefit (NLX) Specialty N/A Limitations Specialty Medications All Plans Phone: 866-814-5506 Fax: 866-249-6155 Non-Specialty Medications Contact MassHealth Phone: 877-433-7643 Fax: 866-255-7569 Information Commercial Phone: 800-294-5979 Fax: 888-836-0730 Exchange Phone: 855-582-2022 Fax: 855-245-2134 Medical Specialty Medications (NLX) All Plans Phone: 844-345-2803 Fax: 844-851-0882 Exceptions N/A Overview Alirocumab (Praluent) and evolocumab (Repatha) are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to LDL-receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation in the liver. LDLR is the primary receptor that clears LDL; therefore, the decrease in LDLR levels by PCSK9 results in increased blood levels of LDL- C. By inhibiting PCSK9 binding to LDLR, these medications increase the number of LDLRs to lower LDL-C levels. Approvable Indications Alirocumab (Praluent) 1. Adjunct to diet and maximally tolerated statin therapy for the treatment of adults with Heterozygous Familial Hypercholesterolemia (HeFH) 2. Clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low- density lipoprotein (LDL)-cholesterol (LDL-C). 3. To reduce the risk of serious cardiovascular events (e.g., MI, stroke and unstable angina) requiring hospitalization in adults with established cardiovascular disease. 4. Secondary prevention of cardiovascular events: To reduce the risk of MI, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease Evolocumab (Repatha) 1.
    [Show full text]
  • CAR-T and Gene Therapies: Hope Is on the Horizon
    Magellan Rx Report Fall 2017 Opioid-Induced Osteoporosis in the Star Ratings and Variable Fee Schedule Constipation: Managed Care Setting: Quality Improvement: Reimbursement: Associated Costs of A Rising Challenge with Forecasted Measures Impact on Antiemetic Care and Length of Growing Treatment for 2019 and Program Utilization and Hospitalization Opportunities Successes Quality of Care Magellan Rx Report MEDICAL AND PHARMACY BENEFIT MANAGEMENT Fall 2017 CAR-T and Gene Therapies: Hope Is on the Horizon magellanrx.com See for yourself what it’s like in virtual reality Download the free app at InMyEyesApp.com. Doctor-recommended screening, diagnosis, and potential treatment are important for your members with Wet AMD, Macular Edema following RVO, DME, and DR in Patients with DME.* Otherwise, these members may be facing serious risk of vision loss, which may require ongoing resources.1-3 THERE’S EYLEA—A treatment option that can fit your plan • EYLEA has proven outcomes as demonstrated in phase 3 clinical trials in patients with Wet AMD, Macular Edema following RVO, DME, and DR in Patients with DME4 • With monthly and every-other-month dosing,† EYLEA offers exible dosing options to help meet the needs of your providers and your members4 INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS • EYLEA® (aflibercept) Injection is indicated for the treatment • There is a potential risk of arterial thromboembolic events of patients with Neovascular (Wet) Age-related Macular (ATEs) following intravitreal use of VEGF inhibitors, including Degeneration (AMD), Macular Edema following Retinal Vein EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial Occlusion (RVO), Diabetic Macular Edema (DME), and infarction, or vascular death (including deaths of unknown Diabetic Retinopathy (DR) in Patients with DME.
    [Show full text]
  • Secondary Analysis of Patients with Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial
    Research JAMA Cardiology | Brief Report Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial Robert P. Giugliano, MD, SM; Anthony Keech, MD; Sabina A. Murphy, MPH; Kurt Huber, MD; S. Lale Tokgozoglu, MD; Basil S. Lewis, MD; Jorge Ferreira, MD; Armando Lira Pineda, MD; Ransi Somaratne, MD; Peter S. Sever, PhD, FRCP; Terje R. Pedersen, PhD; Marc S. Sabatine, MD, MPH Invited Commentary IMPORTANCE Current guidelines for atherosclerotic cardiovascular disease focus on page 1392 high-intensity statins and targeting or using a threshold low-density lipoprotein cholesterol Supplemental content (LDL-C) level of less than 70 mg/dL for the highest-risk patients. Whether further reduction of LDL-C beyond these boundaries would be beneficial is unknown. OBJECTIVE To compare outcomes of evolocumab vs placebo in patients with stable atherosclerotic cardiovascular disease and a baseline LDL-C of less than 70 mg/dL and in those receiving background treatment with a maximal-potency statin. DESIGN, SETTING, AND PARTICIPANTS This secondary ad hoc analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial compared randomized treatments in 2 subgroups of patients with stable atherosclerotic cardiovascular disease currently receiving statin. Patients were classified by a baseline LDL-C of less than 70 or at least 70 mg/dL and by statin intensity (maximal: atorvastatin calcium, 80 mg/d, or rosuvastatin, 40 mg/d; submaximal: all other dosages). Patients with baseline LDL of less than 70 mg/dL either had a final screening LDL-C of at least 70 mg/dL or a final screening non–high-density lipoprotein cholesterol level of at least 100 mg/dL.
    [Show full text]
  • Evolocumab (REPATHA®) National Drug Monograph December 2015 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives
    Insert Generic Drug Name Here Monograph Evolocumab (REPATHA®) National Drug Monograph December 2015 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a focused drug review for making formulary decisions. Updates will be made when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. FDA Approval Information1 Description/Mechanism of Action Evolocumab (REPATHA®) is a humanized monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). Proprotein convertase subtilisin/ kexin type 9 binds to LDL receptors on the surface of hepatocytes and promotes degradation of the LDL receptor in the liver. Inhibition of PCSK9 by evolocumab leads to reduced degradation of the LDL receptor resulting in a greater number of LDL receptors available to clear LDL and subsequently, lower circulating LDL. Indication(s) Under Review in Evolocumab was approved by the FDA as an adjunct to diet and: this document (may include 1) Maximally tolerated statin therapy for the treatment of adults with off label) heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein cholesterol (LDL-C). 2) Other LDL lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional LDL lowering. *The effect of evolocumab on cardiovascular morbidity or mortality has not yet been determined. Dosage Form(s) Under For patients with HeFH or those with established ASCVD who require Review additional LDL lowering, the initial dose of evolocumab is 140 mg given subcutaneously (SQ) every 2 weeks OR 420 mg once a month.
    [Show full text]