PCSK9 inhibition across a wide spectrum of patients: One size fits all?

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

A CENTURY Milestones on the roadmap towards acceptance of the LDL-C hypothesis Anitschkow, the cholesterol-fed rabbit model Muller, familial hypercholesterolemia, xanthomatosis Gofman, lipoproteins in plasma correlate with CHD risk Framingham Study, CHD risk is highest in groups with highest blood cholesterol levels 1961 Nobel Prize to Konrad Bloch for elucidating cholesterol biosynthesis pathway 1913 1939 1949 1964 Goldstein and Brown, the LDL receptor and regulation of cholesterol and lipoprotein metabolism Endo, discovery of the first effective statin drug (statins not marketed until 1987) 1974 1976 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. LDL-C 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 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.

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

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

% change in LDL-C from baseline at mean of Weeks 10 and 12 Evolocumab reduces LDL-C by app 60% by 1 injection per 2-4 weeks Moderate-intensity statin 1 (simvastatin 40mg) High-intensity statin 1 (atorvastatin 80mg) Statin + ezetimibe 2 Similar figures for alirocumab Primary hypercholesterolaemia or mixed dyslipidaemia HeFH 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. LDL-C 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 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

Mean % change in LDL-C from baseline Evolocumab significantly reduces LDL-C in patients with heterozygous FH 20 0-1% -20 60% vs placebo -40-60 - 61% -80 Baseline 2 8 10 12 Study week Placebo Q2W (n=54) Evolocumab 140 mg Q2W (n=110) 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 26,167 patients with heterozygous familial hypercholesterolemia 20,206 adult patients with heterozygous familial hypercholesterolemia 10,479 eligible for analysis: 1,059 history of CHD 9,420 no history of CHD 65 excluded: homozygous familial hypercholesterolemia 7,439 excluded: complete lipid profile with LDL-C unavailable 5,961 excluded: children below 18 years Rhartgers et al sumbitted

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 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.

OLTP/8 week FU ODYSSEY ALTERNATIVE Study Design Statin intolerant patients* (by medical history) with LDL-C 70 mg/dl (very-high CV risk) or 100 mg/dl (moderate/ high risk) Placebo PO QD + Placebo SC Q2W R N=100 Double-Blind Treatment Period (24 Weeks) Alirocumab 75/150 mg SC Q2W + placebo PO QD administered via single 1 ml injection using prefilled pen for self-administration N=100 N=50 Per-protocol dose possible depending on W8 LDL-C Ezetimibe 10 mg PO QD + placebo SC Q2W Atorvastatin 20 mg PO QD + placebo SC Q2W Assessments W -4 W0 W4 W8 W12 W16 W24 Patients discontinued if muscle-related AEs reported with placebos during run-in Per-protocol dose increase if Week 8 LDL-C 70 or 100 mg/dl (depending on CV risk) Primary endpoint (LDL-C % change from baseline, ALI and EZE only) 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

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

Cumulative probability of event Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin Kaplan-Meier estimates for time to first skeletal muscle event 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Atorvastatin Ezetimibe Alirocumab Cox model analysis: 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 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

ODYSSEY DM-DYSLIPIDEMIA: design and study procedures Screening period (up to 3 weeks) Open-label treatment period (24 weeks; N=413) Safety observation period (8 weeks) Participants: T2DM with non-hdl-c 100 mg/dl (2.59 mmol/l), TG 150 and <500 mg/dl (1.70 5.65 mmol/l) + ASCVD/other CV risk factor(s) n=276 R 2:1 n=137 ALI 75 mg SC Q2W ALI dose increase to 150 mg SC Q2W at Week 12 if Week 8 non-hdl-c 100 mg/dl (2.59 mmol/l) Usual care optional addition of one of the following: ezetimibe, fenofibrate, omega-3 fatty acids, nicotinic acid, or no other LLT Diet and maximum tolerated statin (or no statin if intolerant) Visits: W 3 W 0 W 4 W 8 W 12 W 20 W 24 W 32 Screening visit Randomization Primary endpoint: % change from baseline in non-hdl-c 24 Randomization was stratified by the investigator s selection of usual care therapy prior to randomization. Usual care also includes the option to continue on max tolerated statin without the addition of another LLT at randomization. Phone-call visits at Weeks 4 and 32. N numbers indicate the final sample sizes. Müller-Wieland D et al. Cardiovasc Diabetol. 2017;16:70.

LS mean (SE) % change in non-hdl-c % change in non-hdl-c from baseline to Week 24 vs usual care (primary efficacy endpoint; ITT ) 4.7 37.3 LS mean difference (SE) versus usual care: 32.5% (2.5) P<0.0001 Alirocumab dose at Week 12, % (n) Dose increase to 150 mg Q2W 36.4% (94/275) Maintained at 75 mg Q2W 63.6% (182/275) 25 Mixed effect model with repeated measures analysis. ITT, intention-to-treat analysis.

Ongoing / planned studies with PCSK9i

PCSK9; anything else?

Approaches to target PCSK9 Bind PCSK9 in plasma - Monoclonal antibodies (Regeneron/Sanofi, Amgen, Pfizer, Lily) - Adnectins (Adnexis/BMS) - Vaccine (VLP) Reduce PCSK9 synthesis - sirna (Alnylam/Medicine Co) - Small molecule (Serometrix)

Background of Inclisiran Inclisiran 3 rd generation chemically synthesized sirna Enhanced stabilization chemistry results in long duration of action Low total exposure (600 to 900 mg/yr)

Phase II ORION-1 Study Study design Screening (Day -14 to Day -1) One dose starting regimen Randomized (n=501) Two dose starting regimen Placeb o N=65 200 mg N=60 300 mg N=61 500 mg N=65 Treated (n=497) Placeb o N=62 100 mg N=61 200 mg N=62 300 mg N=61 Day 1 Day 14 Day 30 Day 90 Study drug given 1 st follow-up visit Monthly follow-up visits Day 1 Day 14 Day 30 Day 90 Study drug given 1 st follow-up visit Monthly follow-up visits Study drug given Day 180 Day 210 Primary evaluation End of study visit Completed (n=483) Day 180 Day 210 Primary evaluation End of study visit Day 360 Extended follow-up Day 360 Extended follow-up

Patients High-risk CV patients, balanced by randomization One dose starting regimen Two dose starting regimen Placebo Inclisiran Placebo Inclisiran N=65 N=186 N=62 N=184 Age Mean years 62 63 63 64 Male sex % 64.6 67.7 53.2 66.3 Prior ASCVD % 69.2 67.9 74.2 68.3 Statin Rx % 70.3 74.4 77.0 70.2 LDL-C Mean mg/dl 128.5 125.9 125.2 133.0 Non-HDL-C Mean mg/dl 157.8 156.5 157.1 165.6 Apo-B Mean mg/dl 102.4 103.2 104.6 107.7 Lipoprotein(a) Median nmol/l 27.0 34.0 50.5 40.0 PCSK9 Mean ng/ml 404.7 428.7 431.3 416.2

Safety No safety concerns: Adverse events similar to placebo Safety population One dose starting regimen Two dose starting regimen Placebo Inclisiran Placebo Inclisiran N=65 N=186 N=62 N=184 n(%) n(%) n(%) n(%) Any TEAE 46 (70.8) 140 (75.3) 50 (80.6) 142 (77.2) Serious 3 (4.6) 17 (9.1) 6 (9.7) 24 (13.0) Severe 2 (3.1) 11 (5.9) 7 (11.3) 19 (10.3) Related 12 (18.5) 39 (21.0) 18 (29.0) 51 (27.7) Injection site reaction 0 7 (3.8) 0 12 (6.5) TEAEs (treatment emergent adverse events) - similar incidence placebo vs inclisiran: One dose starting regimen: Nasopharyngitis, myalgia, back pain, cough, arthralgia, headache Two dose starting regimen: Myalgia, headache, diarrhea, nasopharyngitis, arthralgia, back pain

Efficacy: Two dose starting regimen PCSK9 level P-value for all comparisons to placebo <0.0001 End of study if LDL-C back to baseline

Efficacy: Two dose starting regimen Robust, sustained LDL-C reductions optimal start regimen 300 mg x2 55.5% 52.6% P-value for all comparisons to placebo <0.0001

Efficacy: Two dose starting regimen Individual patient responses (%) at day 180 Placebo Percent reduction Inclisiran 300 mg Percent reduction Mean 52.6% All patients responded Max 80.9%

Copied from Nat Rev Drugs Discovery DOI 10.1038

PCSK9 inhibition... - PCSK9 antibody Rx: ahead of the game - Inclisiran: ORION trials will tell - Vaccin - orals?