1971 Akira Endo discovered Mevastatin from the fungus Penicillinum citrinum Merck isolated Lovastatin from Aspergillus terreus
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1 ΠΑΝΕΛΛΗΝΙΑ ΣΕΜΙΝΑΡΙΑ ΟΜΑ ΩΝ ΕΡΓΑΣΙΑΣ ΘΕΣΣΑΛΟΝΙΚΗ ΦΕΒΡΟΥΑΡΙΟΣ 2014 «Τι νεότερο για τη φαρµακευτική αντιµετώπιση της δυσλιπιδαιµίας;» Βασιλική Ν. Γιαννακοπούλου MD, Phds, FESC, FEAS ιευθ. ΕΣΥ Θριάσιο Νοσοκοµείο Συνεργάτης Λιπιδαιµικού Ιατρείου ΩΚΚ
2 Short history 1971 Akira Endo discovered Mevastatin from the fungus Penicillinum citrinum 1978 Merck isolated Lovastatin from Aspergillus terreus 1987 marketed as Mevacor and FDA approved it 1988 discovery of Simvastatin in Sweden 1991 discovery of Pravastatin 1994 discovery of Fluvastatin 1997 discovery of Atorvastatin 2003 discovery of Rosuvastatin
3 Pitavastatin (Livalo) Available in Japan since 2003, In the US, it received FDA approval in 2009 Pitavastatin appears to be a substrate of CYP2C9, and not CYP3A4 resulting less interaction to other drugs that are metabolized via CYP3A4, which might be important for elderly patients who need to take multiple medicines
4 LIVES Study pts Japaneses treated for 104 weeks LDL 29,1% (from the first 4 weeks) TGs 22,7% HDL 19,9% (24,6% in pts with HDL< 40mg/dl) 10,4% experienced adverse events (84% mild & 1,8% severe) Only 7,4% discontinued the treatment Subanalysis shows an improvement, after long term treatment, of HbA1C & of egrf in pts with CKD Atheroscler Suppl Nov
5 LIVES Trial 1mg 2mg 4mg
6 LIVES Trial
7 The PATROL Trial Circulation 2011
8 Conclusion:The safety & efficacy of these 3 strong statins are equal Circulation 2011
9 CIRCLE study (secondary prevention) 743 pts underwent PCI ( ) 2008) Atorvastatin/Pitavastatin compared with Pravastatin or no statin Only Pitavastatin vs no statin HDL 22,9% LDL 34,2% vs 32,8% in Atorva vs 23,7% in Prava Circ J 2011
10 Novel Targets for Lipid Management 1. Lowering Levels of Atherogenic Lipoproteins A. Blocking Lipoprotein Output - MTP Inhibition (Lomitapide) - ApoB Blockade (Mipomersen) B. Increasing Lipoprotein Clearance (PCSK9 Inhibitors) 2. Raising Levels of Anti-Atherogenic Lipoproteins A. Increasing HDL Levels, Maturation, Function - Increasing apoai Synthesis (RVX-208 Lyon 2013-ASSURE study) - Improving LCAT Activity (ACP-501 Lyon 2013) - Improving Cellular Cholesterol Extraction B. Blocking HDL Cholesterol Exchange (CETP Inhibitors)
11 Mipomersen (previously ISIS ,, trade name Kynamro) Is a cholesterol-reducing reducing drug It is an antisense oligonucleotide inhibitor of apob100 Crosses the hepatocyte & nuclear membranes that targets the m-rna for apob100 apolipoprotein B Is significally distributed to liver where apob100 synthesised 100 is Kynamro (mipomersen) Now FDA Approved - January 29, 2013
12 ASOs Cross Cell and Nuclear Membranes and Target a Specific mrna Antisense Oligonucleotide (ASO) Strand Hepatocyte Cell Membrane mrna-antisense duplex Apo B mrna RNase H 1 recognizes duplex DNA RNA is cleaved Nucleus Cytoplasm Adapted from Crooke. Antisense Drug Technology: Principles, Strategies, and Applications, 2 nd ed. 2008
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16 PLoS One. 2012;7(11):e49006 Epub 2012 Nov Randomized, placebo-controlled controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering lowering therapy McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, Wagener G, Chasan-Taber S.
17 PLoS One. 2012; 7(11. Published online 2012 November
18 PLoS One. 2012; 7(11): e Published online 2012 November
19 PLoS One. 2012
20 PLoS One. 2012
21 PCSK-9 inhibitors (proprotein convertase subtilin/kexin 9) PCSK-9 blinds to LDL-Receptors leading to their accelerated degradation Increase LDLc levels The PCSK-9 inhibitors decrease the LDL-Rs degradation
22 LDL Receptor Function and Life Cycle
23 The Role of PCSK9 in the Regulation of LDL Receptor Expression
24 PCSK9 Inhibitors Under Development Company Agent Stage Comments Reference SA-Regeneron mab Phase 2 REGN727 IgG Phase 1 results May 2010, LDL decreased 60% ID= Pfizer-Rinat mab Phase 1 RN316 IgG Clinical trial started Merck mab In development 1D05-IgG Rhesus PoC, AHA Nov Amgen mab In development mab1-igg Cyno PoC, PNAS May BMS-Isis ASO Preclinical BMS Phase 1 Areas/Cardiovascular.htm#BMS-PCSK9Rx Santaris ASO In development SPC5001, LNA class ASO pharma-a-s-advances-rna-targeted-drug-development- candidate-against-pcsk9-an-important-new-target-for- the-treatment treatment-of-high-cholesterol/default.aspx Alnylam/UT-SW ASO In development ALN-PCS, Liposome formula, Cyno PoC, PNAS Aug Pipeline/Programs/Hypercholestoralemia.php BMS-Adnexus Adnectin Preclinical development BMS Brautbar A and Ballantyne CM. Nat Rev Cardiol. 2011
25 PCSK9 Inhibitors - Clinical Trials
26 Effect of a monoclonal antibody to PCSK-9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial Prof, Dr Evan A Stein, MD, et al LANCET July 2012, Pages 29 36
27 Multicentre, randomised, placebo-controlled phase 2 trial done at 16 lipid clinics in the USA and Canada (Jan 18, 2011& Nov 7, 2011) Adults with heterozygous familial hypercholesterolaemia and LDL- C concentrations of 2 6 mmol/l or higher on stable diet and statin dose, with or without ezetimibe Pts were randomly assigned to receive REGN mg, 200 mg, or 300 mg / 4 weeks, or 150 mg/ 2 weeks, or placebo / 2 weeks (ratio 1:1:1:1:1) Randomisation was stratified by concomitant use of ezetimibe at baseline Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing The primary endpoint was mean % in LDL-C from baseline at week 12 Was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group
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29 LDLc apob LANCET July 2012, Mean % change in baseline LDL-C (A) & ApoB (B) vs week during treatment & follow-up period. Data are mean % LDL-C & ApoB
30 SAR236553/REGN727 in Patients With Hypercholesterolemia On Atorvastatin Therapy Screening Period (7 weeks) Treatment Period (12 weeks) Follow-up Period (8 weeks) N=31 Placebo Q2W LDL-C 100 mg/dl at Wk-1 while taking atorva 10, 20, or 40 mg for 6wks N=30 N=31 N=31 N=30 SAR mg Q2W SAR mg Q2W SAR mg Q2W SAR mg Q4W w/alt placebo Primary Endpoint % calculated LDL-C from baseline to week 12 Secondary Endpoints % in other lipoproteins and apolipoproteins and % patients reaching prespecified LDL-C levels N=30 SAR mg Q4W w/alt placebo Diet* W-7 V1a W-1 V1 W0 V2 *NCEP ATP-III TLC or equivalent diet W2 V3 W4 V4 W6 V5 W8 V6 W10 V7 W12 V8 W16 V9 McKenney JACC 2012 W20 V10
31 Changes in LDL-C from Baseline to Week 12 by Treatment Group (mitt Population) Intervention Baseline LDL-C (mg/dl) % Change LDL-C 1 Placebo (3.1) SAR mg Q2W (3.2)* SAR mg Q2W (3.1)* SAR mg Q2W (3.2)* SAR mg Q4W (3.3)* SAR mg Q4W (3.2)* *P< for % change SAR vs. placebo 1 LS mean (SE), using LOCF method McKenney JACC 2012
32 PCSK9 Inhibition in Subjects on Atorvastatin NEJM, Halloween 2012
33 Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects (GAUSS): Results from a Randomized, Double-blind, blind, Placebo and Ezetimibe Controlled Study Study objective: Evaluate the safety, tolerability, and efficacy of AMG 145 compared to ezetimibe in adult patients, years, at cardiovascular risk unable to tolerate effective doses of statins due to muscle-related side effects. Evan Stein et al JAMA Nov. 2012
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35 MTP inhibitors MTP (microsomal TG transfer protein) mediates TGs absorption, chylomicron secretion from the intestine & VLDL secretion from the liver by linking lipid molecules with apolipoprotein B (apob). including LDL
36 Phase 3 study of lomitapide (AEGR-733) to lower LDL-c for the treatment of pts with (HoFH ) November 16, 2009 Aegerion Pharmaceuticals 22 pts enrolled in the ongoing Phase 3 trial 14 of the pts for a min of 26 & 7 pts for 56 weeks Pts are titrated >to a max tolerated dose of lomitapide (up to 60 mg/day) The 14 pts treated with lomitapide for 26 weeks experienced a mean reduction in LDL-C of 49% on top of maximum tolerated background therapy. Average baseline LDL-C levels in this trial were 351 mg/dl &6 of the 14 patients achieved an LDL-C level below 100 mg/dl At 26 weeks, pts experienced a modest in hepatic fat from 1.0% to 7.8% All pts that have reached 56 weeks have seen their hepatic fat levels 7% at 56 weeks Mild -moderate gastrointestinal adverse events have been the most commonly reported side effect 2 of the 14 pts experienced transaminase which required a dose None of the ps required drug discontinuation due to liver function test elevations
37 Lomitapide (INN, marketed as Juxtapid) ) is a drug for the treatment of FH It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe & fenofibrate The US Food and Drug Administration (FDA) approved lomitapide on 21 December 2012, as an orphan drug to reduce LDL-C, total cholesterol, apolipoprotein B, & non-hdl HDL-C in patients with (HoFH)
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39 Analysis of Off-target Effects of CETP Inhibitors Characteristic Torcetrapib Anacetrapib Dalcetrapib Evacetrapib Clinical evidence of increased BP Yes 1 No 2 No 3 No 7 Preclinical evidence of increased aldosterone production* Preclinical evidence of aldosterone synthase (CYP11B2) mrna induction* Preclinical evidence of RAASassociated gene induction* Yes 3 No 4 No 3 No 8 Yes 3? No 3? Yes 5? No 5? L-type Ca 2+ channel activation* Yes 6? No 6? 1. Barter et al. N Engl J Med. 2007;357: Masson D. Curr Opin Invest Drugs. 2009;10: Stein et al. Am J Cardiol. 2009;104: Forrest et al. Br J Pharmacol. 2008;154: Stroes et al. Br J Pharmacol. 2009;158: Clerc et al. J Hypertens. 2010: in press. 7. Nicholls et al. JAMA 2011;306: Cao et al. J Lipid Research. 2011;52:
40 Anacetrapib Effects on LDL-C and HDL-C 100 LDL-C 120 HDL-C LDL-C (mg/d dl) (SE) % (P<0.001) % (P<0.001) HDL-C (mg/d dl) (SE) Anacetrapib Placebo 20 Anacetrapib Placebo 0 Baseline Study Week 0 Baseline Study Week Anacetrapib n = Placebo n = Anacetrapib n = Placebo n = Cannon CP et al. N Engl J Med. 2010;363:
41 Dalcetrapib Phase IIb Trial HDL-C Increase at Week 12 *P < vs placebo * Change From Baseline (%) * * placebo n = 73 dalcetrapib 300 mg n = 75 dalcetrapib 600 mg n = 67 dalcetrapib 900 mg n = 72 NOTE: Dalcetrapib 600 mg is the dose used in phase III Stein EA. Am J Cardiol. 2009;104:82-91.
42 Termination of Dalcetrapib Clinical Trial The dal-outcomes trial evaluated the efficacy and safety profile of dalcetrapib when added to existing standard of care in patients with stable coronary heart disease following an acute coronary syndrome. Following the results of the second interim analysis of the dalcetrapib dal-outcomes Phase III trial the Independent Data and Safety Monitoring Committee (DSMC) has recommended stopping the trial due to a lack of clinically meaningful efficacy (did not improve endothelial function).. No safety signals relating to the dal-outcomes trial were reported from the DSMC. As a result, Roche has decided to terminate the dal-outcomes trial, as well as all other on-going studies in the dal-heart program, including dal-plaque 2 and dal-outcomes 2. Additional information will be provided in due course as data become available. Excerpt from letter to dal-outcomes Investigators from Roche (July 2012)
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