Le nuove terapie dell ipercolesterolemia e il loro impatto sull aderenza. Riccardo Candido S.S. Centro Diabetologico Distretto 3 A.S.S.

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1 Le nuove terapie dell ipercolesterolemia e il loro impatto sull aderenza Riccardo Candido S.S. Centro Diabetologico Distretto 3 A.S.S. 1 Triestina

2 Il dr. Riccardo Candido dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Novartis, Roche Diagnostics, Johnson & Johnson Medical, Eli Lilly Italy, Boehringer Ingelheim, Astra Zeneca-Bristol Myers Squibb, Merck Sharp & Dohme, ForFarma, Novo Nordisk, Sanofi Aventis

3 Terapie farmacologiche esistenti Statine Fibrati Ezetimibe Resine a scambio ionico Acidi grassi Omega 3

4 -23% every 40 mg/dl LDL-C

5 N Engl J Med 2010; 362:

6 SHARP: Major Atherosclerotic Events Event Simv/Eze (n=4650) Placebo (n=4620) Risk ratio & 95% CI Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularisation procedure 284 (6.1%) 352 (7.6%) Major Atherosclerotic Event 526 (11.3%) 619 (13.4%) 16.6% SE 5.4 reduction (p=0.0021) Simv/Eze better Placebo better Lancet 2011;377(9784):

7 Residual Cardiovascular Risk Residual CV risk is defined as the risk of CV events that persists in people despite achievement of treatment goals for low-density lipoprotein (LDL) cholesterol, blood pressure, and glycaemia according to current standards of care Coronary heart disease and stroke still account for 25% of all deaths. Reiner Ž and Tedeschi-Reiner E. Croat Med J. 2013;54:339-45

8 DM1 DM2

9 DM1 DM2

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11 Ali MK et al. N Engl J Med 2013;368:

12 Riduzione del colesterolo LDL con le statine disponibili a vari dosaggi Modified from ESC/EAS Guidelines for the Management of Dyslipidaemias: Addenda, European Heart Journal 2011

13 Danni da Statine <2% danno epatico transitorio The rate of statin discontinuation owing to adverse events, observed in clinical trials and clinical practice, ranges from 4% 3-5% sindrome dolorosa muscolare + aumento del CPK to 13%, and is mainly caused by myalgias. 0.08% Miopatia grave (CK>10 volte) < 0.01% Rabdomiolisi, fatale nel 8% JACC 2002; 40:567

14 Persistence and determinants of statin therapy among middle-aged patients free of cardiovascular disease. RESULTS Persistence with statin therapy fell to 67% in the first 6 months after treatment and continued to decline over the next 3 years to 39%. We observed lower persistence in patients who used the greatest number of pharmacies and prescribing physicians Perreault S et al. Eur J Clin Pharmacol 2005; 61:667-74

15 Pazienti che hanno raggiunto il target di colesterolemia LDL (%) Compliance alla terapia con statine ed eventi cardiovascolari Wei L et al. Heart 2002; 88: Re-infarto Mortalità per tutte le cause Compliance alla terapia con statine <39% (n=67) Compliance alla terapia con statine tra 40-79% (n=88) Compliance alla terapia con statine tra % (n=272)

16 Nutr Metab Cardiovasc Dis.2014 Oct;24(10): Resistance and intolerance to statins. Reiner Z RESULTS: The resistance to statins has been associated with polymorphisms in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA-R), P-glycoprotein (Pg-P/ABCB1), breast cancer resistance protein (BCRP/ABCG2), multidrug resistance-associated proteins (MRP1/ABCC1 and MRP2/ABCC2), organic anion transporting polypeptides (OATP), RHOA, Nieman-Pick C1-like1 protein (NPC1L1), farnesoid X receptor (FXR), cholesterol 7alpha-hydroxylase (CYP7A1), Apolipoprotein E (ApoE), proprotein convertase subtilisin/kexin type 9 (PCSK9), low density lipoprotein receptor (LDLR), lipoprotein (a) (LPA), cholesteryl ester transfer protein (CETP), and tumor necrosis factor α (TNF-α) genes. However, currently, there is still not enough evidence to advocate pharmacogenetic testing before initiating statin therapy. Patients with inflammatory states and HIV infection also have diminished LDL-C lowering as a response to statin treatment. Pseudo-resistance due to nonadherence or non-persistence in real-life circumstances is probably the main cause of insufficient LDL-C response to statin treatment.

17 Terapie farmacologiche innovative Oligonucletoidi antisenso (Mipomersen, anti ApoB) Inibitori di proteina MTP* (Lomitapide) Anticorpi contro PCSK9 Oligonucleotidi antisenso (Anti ApoCIII) Inibitori di CETP *MTP = proteina microsomiale che trasferisce i trigliceridi

18 Gli oligonucleotidi antisenso (ASO) Geary RS et al. Antisense therapy for cardiovascular metabolic disease. Drug Discovery Today: Therapeutic Strategies

19 Meccanismo d azione di Mipomersen

20 Mipomersen Il Mipomersen è un oligonucleotide antisenso di seconda generazione contro l apolipoproteina B 100 (apob100) umana. L uso di mipomersen riduce i livelli epatici di mrna per l apob100 in maniera dose-dipendente. Riduzione dei livelli ematici di LDL-C, numero di particelle LDL, Trigliceridi e lipoproteina (a). Il mipomersen viene somministrato per iniezione sottocutanea una volta alla settimana e la concentrazione massima viene raggiunta in circa 3-4 ore

21 Thomas GS et al. J Am Coll Cardiol 2013;62:

22 Thomas GS et al. J Am Coll Cardiol 2013;62:

23 PLoS One. 2012;7(11)

24 Expert Opin Pharmacother 2013 Apr;14(6):691-7 The potential of mipomersen, an ApoB synthesis inhibitor, to reduce necessity for LDL-apheresis in patients with heterozygous familial hypercholesterolemia and coronary artery disease. Vogt A, Parhofer KG Mipomersen ha ridotto ulteriormente i livelli di LDL-C del 28% e di Lp(a) del 21% Mipomersen ha ridotto la necessità di aferesi nel 50% di questi pazienti

25 Am J Cardiovasc Drugs 2014 Oct;14(5): Mipomersen is a Promising Therapy in the Management of Hypercholesterolemia: A Meta-Analysis of Randomized Controlled Trials. Li N, Li Q, Tian XQ, Qian HY, Yang YJ. RESULTS: Six randomized controlled trials with 444 patients were included in the analysis. Compared with the placebo group, patients who received mipomersen therapy had a significant reduction in LDL-C (33.13 %), as well as a reduction in non-hdl-c (31.70 %), ApoB (33.27 %), and LP(a) (26.34 %). Mipomersen therapy was also associated with an obvious increase in injection-site reactions with an odds ratio (OR) of 14.15, flu-like symptoms with an OR of 2.07, and alanine aminotransferase levels 3 the upper limit of normal with an OR of CONCLUSIONS: Mipomersen therapy is effective for lowering ApoB-containing lipoproteins in patients with severe hypercholesterolemia. Future studies exploring how to minimize side effects of mipomersen therapy are needed.

26 Altri ASO sono in via di sviluppo Oligonucleotidi contro: apo CIII Lp(a) proteina 3 simile all angiopoietina PCSK9 CETP

27 Meccanismo d azione di Lomitapide

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29 Vuorio A et al. Vascular Health and Risk Management 2014:

30 Lancet Jan 5;381(9860):40-6 Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Cuchel M et al Phase 3 HoFH Lomitapide Study investigators FINDINGS: 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI - 62 to -39) from baseline (mean 8 7 mmol/l [SD 2 9]) to week 26 (4 3 mmol/l [2 5]; p<0 0001). Levels of LDL cholesterol were lower than 2 6 mmol/l in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0 0001) at week 56 and 38% (-52 to -24; p<0 0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.

31 Nat Clin Pract Cardiovasc Med 2008; 5:

32 Am J Health Syst Pharm Jun 15;71(12): Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia. Davis KA, Miyares MA CONCLUSION: Lomitapide is an oral MTP inhibitor approved for the treatment of HoFH. This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or cannot tolerate statin therapy.

33 Interazione della proproteina convertasi subtilisina/kexin tipo 9 (PCSK9) con LDL-R Capacità di PCSK9 di ridurre il riciclo del LDLR sulla superficie della cellula favorendone la sua degradazione.

34 Varianti del gene che codifica per la proteina PCSK9 siano associate a variazioni dei livelli circolanti di LDL-C. Mutazioni geniche che comportano un aumentata attività di PCSK9 (gain of function) caratterizzano alcune forme di ipercolesterolemia familiare autosomica dominante con una normale espressione del LDL-R e LDL con normale affinità per il recettore, ma elevati livelli di LDL-C ed un aumentato rischio cardiovascolare HUMAN MUTATION, Vol. 30, No. 4, , 2009

35 Major targeting points of the known PCSK9 pathway 1. Reducing the expression of PCSK9 mrna 2. Reducing the expression of PCSK9 protein (inhibition of autocatalytic processing) 3. Inhibiting PCSK9 binding to the LDL-R 4. Inhibiting PCSK9-mediated LDL-R degradation Hedrick JA, Curr Opin Investig Drugs 2009; 10:

36 Anti-PCSK9 therapeutic agents Inhibition of PCSK9 binding to LDLR - Monoclonal antibodies (mab) - Small peptide molecules - Adnectins Inhibition of PCSK9 synthesis (gene silencing) - Antisense oligonucleotides (ASO) - Small interfering RNA (sirna) Inhibition of PCSK9 autocatalytic processing - Small molecule inhibitors

37 Il legame dell anticorpo monoclonale a PCSK9 impedisce la degradazione del LDL-R

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40 Effetto di mab contro PCSK9 sui livelli plasmatici di LDL-C. Riduzione del LDL-C osservato (-55-70%) in pazienti ipercolesterolemici non a target dopo trattamento con alte dosi di statine +/- ezetimibe Stein EA et al. Lancet 2012, 380(9836):29-36

41 Efficacy of Alirocumab mab 150 mg every 2 weeks (data from phase 2 trials) 1. Mc Kenney et al. J Am CollCardiol 2012; 59: Roth et al. N EnglJ Med 2012; 367: Stein et al. Lancet 2012; 380: 29-36

42 Efficacy of Evolocumab (140 mg every 2 weeks and 420 mg every 4 weeks) (data from phase 2 trials) 1.Giugliano et al. Lancet 2012; 380: Raal et al. Circulation 2012; 126: Koren et al. Lancet 2012; 380: Sullivan et al; JAMA 2012; Nov5

43 AMG 145: Phase 1a/b Safety Adapted from Dias CS et al. J Am Coll Cardiol 2012; 60:

44 Lancet Oct 1. pii: S (14)61374-X. doi: /S (14)61374-X. [Epub ahead of print] Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebocontrolled trial. Raal FJ et al. INTERPRETATION: In patients receiving stable background lipid-lowering treatment and not on apheresis, evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo (-30.9%). Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. Lancet Oct 1. pii: S (14) doi: /S (14) [Epub ahead of print] PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Raal FJ et al., for the RUTHERFORD-2 Investigators INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo.

45 Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebocontrolled, phase 1 trial. RESULTS 70% reduction in circulating PCSK9 plasma protein (p<0.0001) mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0.0001). Fitzgerald K et al. Lancet 2014;383(9911):60-8

46 X Landmesser U. Eur Heart J 2013, 34,1254 (modificata)