51 e CONGRES DE L A.M.U.B.

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1 51 e CONGRES DE L A.M.U.B. ACTUALITES THERAPEUTIQUES EN LIPIDOLOGIE Dr. P. VAN DE BORNE Cardiologue Service de Cardiologie ULB- Hôpital Erasme Session ACTUALITES DIAGNOSTIQUES ET THERAPEUTIQUES Modérateurs : Drs A. FIRKET, M. MAHIEU, T. PEPERSACK Samedi 9 septembre h00-14h45

2 Conflits d intérêt en rapport avec la présentation Honoraires de conférence : Sanofi Participation à un «Advisory Board» : Sanofi, Amgen, MSD Etudes cliniques sponsorisées en cours : Sanofi, Amgen Consultance : <néant> Voyages-Congrès : Sanofi, Amgen, MSD

3 PLAN : LDL C et pathologie cardiovasculaire Statines : Effets secondaires? PCSK9: mode d action, variations d activité, études cliniques

4 Clinical trial data support achieving lower levels of LDL-C, independent of baseline LDL-C ACS study Stable CAD study 4S pbo PROVE-IT TIMI 22 A80 IMPROVE-IT S40+EZE IMPROVE-IT S40 CARE HPS P40 S40 TNT A80 PROVE-IT TIMI 22 P40 TNT A10 LIPID P40 4S S40 HPS pbo CARE pbo LIPID pbo ACS, acute coronary syndrome; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol. Rosenson RS. Exp Opin Emerg Drugs 2004;9:269 79; LaRosa JC, et al. N Engl J Med 2005;352: ; Cannon CP, et al. N Engl J Med 2015;372:

5 men >55 yrs women > 65 yrs + 1 cv risk factor April 2, 2016

6 Reduction in CV events (%) Every 39 mg/dl reduction in LDL-C reduces annual CV risk by up to 28%, regardless of mechanism 50 More LDL lowering and risk reduction Ezetimibe Fibrate Bile acid resin Niacin Diet/unsaturated fatty acid Ileal bypass 10 IMPROVE-IT CTTC trials (statin)? Reduction in LDL-C (mg/dl) There is no evidence of any lower LDL-C threshold Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists Collaboration (CTTC) 2005 meta-analysis. The IMPROVE-IT trial was adequately powered to show the efficacy on incremental LDL-C lowering on CV outcomes. [To convert, 100 mg/dl=2.59 mmol/l]. CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density lipoprotein cholesterol. CTT Collaboration. Lancet 2005:366; ; CTT Collaboration. Lancet 2010;376: ; Cannon CP, et al. N Engl J Med 2015;372:

7 2 g of extended-release niacin (ie nicotinic acid, vitamin B3 or PP (Pellagra Preventive)) and 40 mg of laropiprant vs. placebo Primary outcome: 1 st major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). LDL = - 10 mg/dl and HDL + 6 mg/dl Expected to produce a 5 % proportional reduction in the risk of major vascular events

8 (mainly China) Great concern: 9% increase in the risk of death (P = 0.08, number needed to harm= 200) HDL cholesterol level: risk marker, not a risk factor Consistency of overall findings with earlier niacin trials suggests niacin is the major problem

9 Vascular Health and Risk Management 2012: SR-B1, scavenger receptor-b1 But if not enough LDL-R: CETP, cholesteryl ester transfer protein secreted from the liver (1) Less CE in reverse cholesterol transport SR-B1, scavenger receptor-b1 (2) Larger return of CE-rich LDL to the liver LPL, Lipoprotein lipase HL, Hepatic lipase Cholesterol eliminated from the body LCAT, lecithin cholesterol acyltransferase small-dense LDL-C CE, cholesteryl ester FC, free cholesterol

10 The cetrapibs form a reversible bond between CETP and HDL-C. Formation of this bond results in the inhibition of CETP-mediated CE and TG transfer SR-B1, scavenger receptor-b1 Vascular Health and Risk Management 2012: (1) More CE in reverse cholesterol transport (2) Less return of CE-rich LDL to the liver LPL, Lipoprotein lipase HL, Hepatic lipase Cholesterol eliminated from the body small-dense LDL-C CE, cholesteryl ester FC, free cholesterol

11 ACCELERATE: Phase 3, multicenter, double blind, randomized trial, patients at high vascular risk: Patients (77% male; age: 65 years) randomly assigned 1:1 to either 130 mg evacetrapib (n=6038) or placebo (n=6054) for at least 1.5 years. Baseline clinical characteristics matched Primary end point: Time to first event of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization). Stopped prematurely for clinical futility (evacetrapib, 12.8% vs placebo, 12.7%; hazard ratio:1.01; P=.85) despite 130% increase in HDL-C (104 mg/dl vs 46 mg/dl) and 37% decrease in LDL-C (55 mg/dl vs 84 mg/dl).

12 ACCELERATE: Phase 3, multicenter, double blind, randomized trial, patients at high vascular risk: Patients (77% male; age: 65 years) randomly assigned 1:1 to either 130 mg evacetrapib (n=6038) or placebo (n=6054) for at least 1.5 years. Baseline clinical characteristics matched Primary end point: Time to first event of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization). Stopped prematurely for clinical futility (evacetrapib, 12.8% vs placebo, 12.7%; hazard ratio:1.01; P=.85) despite 130% increase in HDL-C (104 mg/dl vs 46 mg/dl) and 37% decrease in LDL-C (55 mg/dl vs 84 mg/dl).

13 PLAN : LDL C et pathologie cardiovasculaire Statines : Effets secondaires? PCSK9: mode d action, variations d activité, études cliniques

14 Statin-associated autoimmune myopathy is an exceptionally rare side effect of statin use. Incidence +/- 2 or 3 of every 100,000 patients treated with statins : Class II HLA allele DRB1*11:01 Expression of HMG-CoA reductase markedly increased when muscle exposed to statins Regenerating muscle cells express high levels of HMG-CoA reductase protein??? Binding of statin to HMG-CoA reductase change the conformation of the protein, lead to the generation of cryptic epitopes to which the immune system is not tolerant???

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17 Docteur de Lorgeril chercheur au CNRS

18 Docteur de Lorgeril chercheur au CNRS

19 Despite benefits of current LLTs, many secondary prevention patients do not achieve LDL-C goals EUROASPIRE IV n=7998, all patients with established CHD 87% on LLTs, almost exclusively statins Almost 80% of patients on LLTs failed to reach an LDL-C goal of <1.8 mmol/l (<70 mg/dl) 42% Only 21% of patients on LLTs were at goal 79% of patients on LLTs did NOT achieve 79% NOT an at LDL-C goal goal of <1.8 mmol/l (<70 mg/dl) Data collected from patients <80 years old with established CHD, 25% women, mean age 64 years, one-third <60 years CHD, coronary heart disease; EUROASPIRE, European Action on Secondary and Primary Prevention through Intervention to Reduce Events; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy. [Accessed 11 May 2015].

20 Patients who completed the placebo run-in without experiencing a skeletal muscle related AE were randomized to alirocumab, ezetimibe, or atorvastatin unable to tolerate 2 statins, including one at the lowest starting dose due to muscle symptoms 13% 16% 20% 22% 24% 34% 33%

21 During the open-label treatment period (41 wks), when patients knew they were not receiving statins, rates of skeletal muscle related AEs were lower (24%) than during doubleblind period (33%)

22 PLAN : LDL C et pathologie cardiovasculaire Statines : Effets secondaires? PCSK9: mode d action, variations d activité, études cliniques

23 Clinical Therapeutics Volume 35, Issue 8, August 2013, Pages

24 P= placebo / E= Evolucumab

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26 PLAN : LDL C et pathologie cardiovasculaire Statines : Effets secondaires? PCSK9: mode d action, variations d activité, études cliniques

27 PCSK9 mutations effects on LDL Effects of 3 sequence variations on Coronary Heart Disease incidence in Atherosclerosis Risk in Communities (ARIC) study: longitudinal, biracial cohort study to assess subclinical and clinical atherosclerosis.

28 2 % black subjects have 1 of 2 nonsense mutations in PCSK9 gene: 137G T, encoding R46L [replacement of the arginine at position 46 with leucine] 426C G, encoding Y142X [replacement of the tyrosine at position 142 with a stop codon] 2037C A, encoding C679X [replacement of the cysteine at position 679 with a stop codon] 3% white subjects (vs. 0.6 % black) PCSK9 sequence variation:

29 =9,7% nonsense mutations

30 During the 15-year follow-up period The only carrier in whom CHD developed was a black man, BMI 34 kg/m², BP186/85 mm Hg, smoker, family history of CHD,

31 Familial hypercholesterolemia can be caused by mutations in 4 known genes Circulation LDL particle ApoB acts as ligand, binding LDL particle to receptor Liver cell LDL receptor on hepatocyte,binds to ApoB on LDL particle, inducing endocytosis of LDL 17 33% of FH patients harbour mutations in unknown genes PCSK9 enzyme degrades LDL receptors LDLRAP1(ARH) Mediates internalization via clarithrin coated pits ApoB, apolipoprotein B; FH, familial hypercholesterolemia; GoF, gain of function; LDL, low-density lipoprotein; LDLRAP1, low-density lipoprotein receptor adapter protein 1; PCSK9, proprotein convertase subtilisin/kexin type 9. De Castro-Oros I, et al. Appl Clin Genet 2010;3:53 64.

32 Clear genetic and epidemiological evidence for LDL-C as a risk factor Meta-analysis of 312,321 participants: long-term exposure to lower LDL-C was associated with 54.5% reduction in risk of CHD for each 1 mmol/l (38.7 mg/dl) lower LDL-C 1 Mendelian randomization analysis 2 [To convert, 100 mg/dl=2.59 mmol/l]. CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LLT, lipid-lowering therapy; PCSK9, proprotein convertase subtilisin/kexin type 9; SE, standard error. 1. Ference BA, et al. J Am Coll Cardiol 2012;60: Ference BA, et al. J Am Coll Cardiol 2015;65:

33 PLAN : LDL C et pathologie cardiovasculaire Statines : Effets secondaires? PCSK9: mode d action, variations d activité, études cliniques

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35 Long-term Low-Density Lipoprotein Cholesterol Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of HypercholesterolemiaResults Up to 4 Years From the Open-Label OSLER-1 Extension Study 4,3 années de traitement

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37 PRIMAIRE : DECES CARDIOVASCULAIRES, INFARCTUS MYOCARDIAQUE, HOSPITALISATION POUR ANGINE DE POITRINE INSTABLE OU REVASCULARISATION CORONAIRE revascularisation SECONDAIRE : DECES CARDIOVASCULAIRES, INFARCTUS MYOCARDIQUE, ACCIDENT CEREBROVASCULAIRE

38 Baseline Characteristics Characteristic An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Pooled data; no differences between treatment arms Median time from most recent event ~3 yrs Rate of secondary preventive therapies high: 92% taking antiplatelet therapy, 76% taking betablockers, and 78% taking an ACE/ARB/aldosterone antagonist,

39 Lipid Lowering Therapy & Lipid Levels at Baseline Characteristic Statin use (%)* An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Value High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 ( ) HDL-C 44 (37-53) Triglycerides 133 ( ) *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. 10% of patients had alterations in their background lipid-lowering therapy Pooled data; no differences between treatment arms

40 LDL Cholesterol (mg/dl) LDL Cholesterol Placebo Cohort of 11,077 patients who had all measurements through 120 weeks did not discontinue study drug did not D concomitant background lipid-lowering Rx Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Evolocumab Similar data out to 4 years in OSLER-1 (JAMA Cardiology online)

41 LDL Cholesterol At 48 weeks, LDL cholesterol level was reduced to: Evolocumab group: <70 mg per deciliter (1.8 mmol per liter) in 87% of the patients, <40 mg per deciliter (1.0 mmol per liter) in 67% of the patients, <25 mg per deciliter (0.65 mmol per liter) in 42% of the patients, Placebo group: <70 mg per deciliter (1.8 mmol per liter) in 18% of the patients, <40 mg per deciliter (1.0 mmol per liter) in 0.5% of the patients, <25 mg per deciliter (0.65 mmol per liter) in 0.1% of the patients, P<0.001 for all comparisons of evolocumab vs. placebo). An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Confidential

42 CV Death, MI, Stroke, Hosp for UA, or Cor Revasc Primary Endpoint 16% 14% 12% 10% 8% 6% 4% 2% Hazard ratio 0.85 (95% CI, ) P< % Placebo Primary end point occurred in 1344 patients (9.8%) in the evolocumab group and in 1563 patients (11.3%) in the placebo group Evolocumab 14.6% Magnitude of risk reduction tended to increase over time, from 12% (95% CI, 3 to 20) in the first year to 19% (95% CI, 11 to 27) beyond the first year. 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization

43 CV Death, MI, or Stroke Key Secondary Endpoint 10% 9% 8% 7% 6% 5% 4% Hazard ratio 0.80 (95% CI, ) P< Key secondary end point in 816 patients (5.9%) in evolocumab group and in 1013 patients (7.4%) in the placebo group. Placebo Evolocumab 9.9% 7.9% 3% 2% 1% Risk reduction increased from 16% (95% CI, 4 to 26) in the first year to 25% (95% CI, 15 to 34) beyond the first year. 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization

44 Types of CV Outcomes Endpoint An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CV death, MI, or stroke ( ) Cardiovascular death 2.5 No effect ( ) Death due to acute MI ( ) Death due to stroke ( ) Other CV death ( ) MI 4.4-2% ( ) Stroke 2.2-0,5% ( ) Evolocumab had no observed effect on cardiovascular mortality, and hence P values for other outcomes should be considered exploratory. Overall, 74 patients would need to be treated over a period of 2 years to prevent a cardiovascular death, myocardial infarction, or stroke.

45 More Intensive LDL-C Lowering Trial Year More Intensive Rx Arm & CV Death No clear benefit on CV mortality # of CV Deaths Less Intensive Rx Arm HR (95% CI) PROVE-IT TIMI ( ) A2Z ( ) TNT ( ) IDEAL ( ) SEARCH ( ) IMPROVE-IT ( ) Summary ( ) NEJM 2004;350: JAMA 2004;292: NEJM 2005;352: JAMA 2005;294: Lancet 2010;376: NEJM 2015;372: More intensive therapy better Less intensive therapy better An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

46 Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CVD, MI, stroke, UA, or revasc ( ) CV death, MI, or stroke ( ) Cardiovascular death ( ) MI ( ) Stroke ( ) Hosp for unstable angina ( ) Coronary revasc ( ) Urgent ( ) Elective ( ) Death from any cause ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

47 Comparison to Cholesterol Treatment Trialists Collaboration Hazard Ratio (95% CI) per 1 mmol/l reduction in LDL-C Major Coronary Events 0.78 ( ) 0.80 ( ) Stroke Coronary revascularization Urgent Elective 0.77 ( ) 0.77 ( ) 0.75 ( ) 0.73 ( ) 0.84 ( ) CTTC Meta-analysis Year 2 FOURIER Year 2 Major Vascular Events 0.77 ( ) 0.83 ( ) 0.5 Lipid-lowering therapy better 1.0 Lipid-lowering therapy worse 2.0 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School CTTC data from Lancet 2010;376:

48 Lower LDL-C Is Better Patients divided by quartile of baseline LDL-C and by treatment arm The magnitude of benefit of evolocumab in largely consistent with the benefit with statins on a per millimole-per-liter basis P< of LDL cholesterol lowering Q3 Q4 Q3 Q4 Q1 Q2 Q1 Q2 Placebo Evolocumab An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

49 Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any Serious Allergic reaction Injection-site reaction Treatment-related and led to d/c of study drug Muscle-related Cataract Diabetes (new-onset) Neurocognitive Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

50 Conclusions In patients with known cardiovascular disease: 1. PCSK9 inhibition with evolocumab significantly & safely major cardiovascular events when added to statin therapy 2. Benefit was achieved with lowering LDL cholesterol well below current targets An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Overall, 74 patients would need to be treated over a period of 2 years to prevent a cardiovascular death, myocardial infarction, or stroke.

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52 PCSK9 Therapeutic Hypothesis: Phase 1 RNAi therapeutic targeting PCSK9 protein synthesis LDLR LDL Anti- PCSK9 Mabs Transiently block PCSK9 Endosome binding to LDL receptor (LDLR) Lysosomal degradation PCSK9 Synthesis Inhibitors Durably block PCSK9 synthesis and all intracellular and extracellular PCSK9 functions 52 ALN-PCS LDLR synthesis PCSK9 synthesis PCSK9 mrna Nucleus PCSK9 Khvorova A. N Engl J Med 2017;376:4-7.

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54 In the multiple-dose phase, the most common adverse events (occurring in 10% of the participants in the inclisiran group) were headache (in 6 of 33 participants [18%]), back pain and diarrhea (in 5 [15%] each), and 54 nasopharyngitis (in 4 [12%])

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57 PLAN : LDL C et pathologie cardiovasculaire Statines : Effets secondaires? PCSK9: mode d action, variations d activité, études cliniques