PCSK9 inhibition across a wide spectrum of patients: One size fits - PowerPoint PPT Presentation

PCSK9 inhibition across a wide spectrum of patients: One size fits all? PACE ESC Barcelona 2017 G.K. Hovingh MD PhD MBA dept of vascular medicine Academic Medical Center the Netherlands g.k.hovingh@amc.uva.nl

Milestones on the roadmap towards acceptance of the LDL-C hypothesis Anitschkow, the cholesterol-fed rabbit model 1913 Muller, familial hypercholesterolemia, xanthomatosis 1939 Gofman, lipoproteins in plasma correlate with CHD risk 1949 Framingham Study, CHD risk is highest in groups with highest blood cholesterol levels 1961 Nobel Prize to Konrad Bloch for elucidating cholesterol biosynthesis pathway 1964 Goldstein and Brown, the LDL receptor and regulation A CENTURY of cholesterol and lipoprotein metabolism 1974 Endo, discovery of the first effective statin drug 1976 (statins not marketed until 1987) Merck, discovery of mevinolin (lovastatin), later to become the first statin to reach the market 1980 Innerarity, discovery of ApoB implication in FH 1985 The statin era: (4S) showing that treatment with simvastatin reduces coronary heart disease mortality 1994 Abifadel, discovery of PCSK9 implication in FH 2003 Improve-it, adding Ezetimibe: beneficial effect on CVD 2015 PCSK9 ab outcome trial FOURIER...effect on CVD 2017

The new LDL century

Reasons why ‘Lipid’ targets are not achieved • Lack of potency. – app 80% of patients with Familial Hypercholesterolemia do not reach target LDL-C despite maximal lipid-lowering therapy LDL-C • Lower LDL-C targets over time 1 • Low tolerance to available therapy 3 – 7-15% of statin users experience muscle complaints • Absence of effective therapy 1,2 – Triglyceride-rich remnants, Lipoprotein(a) 1.Béliard et al. Atherosclerosis 2014;234:136 – 141. 2.NCEP Expert Panel. Circulation 2002;106:3143 – 3421. 3.Cohen et al. J Clin Lipidol 2012;6:208 – 215. 4.Kuklina et al. MMWR Morb Mortal Wkly Rep 2011;60:109 – 114.

Evolocumab produces rapid suppression of PCSK9 and LDL-C levels 175 Evolocumab Free evolocumab concentration (ng/mL × 0.01) PCSK9 400 LDL-C Free PCSK9 concentration (ng/mL) 150 300 LDL-C (mg/dL) 125 200 100 100 75 0 50 0 14 28 42 56 70 84 Study day Stein et al. Drugs of the Future 2013;38:451 – 459.

Evolocumab reduces LDL-C by app 60% by 1 injection per 2-4 weeks Moderate-intensity High-intensity statin 1 Statin + statin 1 (atorvastatin 80mg) ezetimibe 2 (simvastatin 40mg) % change in LDL-C from baseline at mean of Weeks 10 and 12 Primary hypercholesterolaemia or HeFH mixed dyslipidaemia Evolocumab 140mg Q2W Placebo Q2W 1. Robinson et al. JAMA 2014;311:1870 – 1882. 2. Raal et al. Lancet 2015;385:331 – 340

Evolocumab reduces LDL-C by app 60% by 1 injection per 2-4 weeks Moderate-intensity High-intensity statin 1 Statin + statin 1 (atorvastatin 80mg) ezetimibe 2 (simvastatin 40mg) % change in LDL-C from baseline at mean of Similar figures for Weeks 10 and 12 alirocumab Primary hypercholesterolaemia or HeFH mixed dyslipidaemia Evolocumab 140mg Q2W Placebo Q2W 1. Robinson et al. JAMA 2014;311:1870 – 1882. 2. Raal et al. Lancet 2015;385:331 – 340

Reasons why ‘Lipid’ targets are not achieved • Lack of potency. – app 80% of patients with Familial Hypercholesterolemia do not reach target LDL-C despite maximal lipid-lowering therapy LDL-C • Lower LDL-C targets over time 1 • Low tolerance to available therapy 3 – 7-15% of statin users experience muscle complaints • Absence of effective therapy 1,2 – Triglyceride-rich remnants, Lipoprotein(a) 1.Béliard et al. Atherosclerosis 2014;234:136 – 141. 2.NCEP Expert Panel. Circulation 2002;106:3143 – 3421. 3.Cohen et al. J Clin Lipidol 2012;6:208 – 215. 4.Kuklina et al. MMWR Morb Mortal Wkly Rep 2011;60:109 – 114.

DUTCH EXPERIENCE: FH undertreated Pijlman et al Athersoclerosis 2009

Evolocumab significantly reduces LDL-C in patients with heterozygous FH Mean % change in LDL-C from baseline 20 -1% 0 -20 60% vs placebo -40 - 61% -60 -80 Baseline 2 8 10 12 Study week Evolocumab 140 mg Q2W (n=110) Placebo Q2W (n=54) Raal Hovingh. Lancet 2015;385:331 – 340.

Long term follow up in heFH Kastelein, Hovingh Eur Heart J 2015

Non-apheresis (n Apheresis (n All patients (N = 72) = 34) = 106) LDL-C* Baseline, mean (SD), 8.9 (3.8) 7.4 (2.6) 8.4 (3.5) mmol/L Change at Week 12, mean (SE) Absolute, mmol/L -1.7 (0.2) -1.0 (0.3) -1.5 (0.2) Percent -22.2 (2.7) -17.3 (4.9) -20.6 (2.4) Change at Week 48, mean (SE) Absolute, mmol/L -2.1 (0.3) -1.1 (0.3) -1.8 (0.2) Percent -26.7 (4.2) -15.8 (4.9) -23.3 (3.3) Raal et al. Lancet 2017  5)4:280

Raal et al. Lancet 2017  5)4:280

Real world evaluation of potential effect of PCSK9i in heFH 64,171 underwent molecular screening for familial hypercholesterolemia mutations 37,939 excluded: no pathogenic mutation 26,232 included: patients with a pathogenic mutation 65 excluded: homozygous familial hypercholesterolemia 26,167 patients with heterozygous familial hypercholesterolemia 5,961 excluded: children below 18 years 20,206 adult patients with heterozygous familial hypercholesterolemia 7,439 excluded: complete lipid profile with LDL-C unavailable 10,479 eligible for analysis: 1,059 history of CHD Rhartgers et al sumbitted 9,420 no history of CHD

Consistent LDL-C lowering?

Dadu and Ballantyne. Nat Card Rev 2014

Reasons why ‘Lipid’ targets are not achieved • Lack of potency. • app 80% of patients with Familial Hypercholesterolemia do not reach target LDL-C despite maximal lipid-lowering therapy • Lower LDL-C targets over time 1 LDL-C • Low tolerance to available therapy 3 • 7-15% of statin users experience muscle complaints • Absence of effective therapy 1,2 • Triglyceride-rich remnants, Lipoprotein(a) 1.Béliard et al. Atherosclerosis 2014;234:136 – 141. 2.NCEP Expert Panel. Circulation 2002;106:3143 – 3421. 3.Cohen et al. J Clin Lipidol 2012;6:208 – 215. 4.Kuklina et al. MMWR Morb Mortal Wkly Rep 2011;60:109 – 114.

ODYSSEY ALTERNATIVE Study Design Double-Blind Treatment Period (24 Weeks) Statin intolerant N=100 patients* OLTP/8 week FU Alirocumab 75/150 mg SC Q2W + placebo PO QD (by medical administered via single 1 mL injection using prefilled pen for self-administration history) Per-protocol dose ↑ possible depending on W8 LDL-C Placebo with LDL-C PO QD N=100 ≥70 mg/ dL + Ezetimibe 10 mg PO QD + placebo SC Q2W Placebo R (very-high SC CV risk) or Q2W † N=50 ≥100 mg/ dL Atorvastatin 20 mg PO QD + placebo SC Q2W (moderate/ high risk) Assessments W -4 W0 W4 W8 W12 W16 W24 Primary endpoint Per-protocol dose increase if Patients discontinued if (LDL-C % change from baseline, Week 8 LDL- C ≥70 or ≥100 mg/ dL muscle-related AEs reported ALI and EZE only) (depending on CV risk) with placebos during run-in Safety analysis (all groups) *Unable to tolerate at least two different statins, including one at the lowest dose, due to muscle-related symptoms *Unable to tolerate at least two different statins, including one at the lowest dose, due to muscle-related symptoms † 4-week single-blind placebo run-in follows 2-week washout of statins, ezetimibe and red yeast rice. OLTP: Alirocumab open-label treatment period; W, Week. Moriarty, AHA 2014

ODYSSEY ALTERNATIVE : Alirocumab Significantly Reduced LDL- C from Baseline to Week 24 vs Ezetimibe % change from baseline to Week 24 in LDL-C On-treatment (key secondary endpoint) ITT (primary endpoint) n=123 n=118 n=126 n=122 LS mean (SE) % change from baseline to Week 24 49.5% † received 150 mg Q2W at W12 Absolute Absolute change of change of -33 (4.2) mg/dL -38 (4.2) mg/dL Alirocumab Ezetimibe Absolute Absolute change of change of -84 (4.1) mg/dL -96 (3.9) mg/dL LS mean difference (SE) vs ezetimibe: LS mean difference (SE) vs ezetimibe: -30.4 (3.1); P <0.0001 -35.1 (2.8); P <0.0001 † 49.5% of 109 patients who received at least one injection after Week 12 had dose increase. Moriarty et al. J Clin Lipidol 2015; 9: 758-69

Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin Kaplan-Meier estimates for time to first skeletal muscle event † Atorvastatin 0.50 Ezetimibe 0.45 Alirocumab Cumulative probability of event 0.40 0.35 0.30 0.25 0.20 0.15 Cox model analysis: 0.10 HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P =0.042 HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P =0.096 0.05 0.00 0 4 8 12 16 20 24 28 32 36 Week † Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe. Moriarty, AHA 2014

Recent studies with PCSK9i