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?

G.K. Hovingh MD PhD MBA dept of vascular medicine Academic Medical Center the Netherlands g.k.hovingh@amc.uva.nl PACE ESC Barcelona 2017

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 Nobel Prize to Konrad Bloch for elucidating cholesterol biosynthesis pathway Goldstein and Brown, the LDL receptor and regulation

• f cholesterol and lipoprotein metabolism

Endo, discovery of the first effective statin drug (statins not marketed until 1987) Merck, discovery of mevinolin (lovastatin), later to become the first statin to reach the market Innerarity, discovery of ApoB implication in FH The statin era: (4S) showing that treatment with simvastatin reduces coronary heart disease mortality 1913 1939 1949 1961 1964 1974 1976 1980 1985 1994

A CENTURY

2003 Abifadel, discovery of PCSK9 implication in FH 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

• Lower LDL-C targets over time1
• Low tolerance to available therapy3

– 7-15% of statin users experience muscle complaints

• Absence of effective therapy1,2

– 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.

LDL-C

Evolocumab produces rapid suppression

• f PCSK9 and LDL-C levels

Stein et al. Drugs of the Future 2013;38:451–459.

Study day

14 28 42 56 70 84 50 75 100 125 150 175 100 200 300 400

Evolocumab PCSK9 LDL-C LDL-C (mg/dL) Free PCSK9 concentration (ng/mL) Free evolocumab concentration (ng/mL × 0.01)

Evolocumab reduces LDL-C by app 60% by 1 injection per 2-4 weeks

• 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 140mg Q2W Placebo Q2W Primary hypercholesterolaemia or mixed dyslipidaemia HeFH High-intensity statin1 (atorvastatin 80mg) Statin + ezetimibe2 Moderate-intensity statin1 (simvastatin 40mg)

Evolocumab reduces LDL-C by app 60% by 1 injection per 2-4 weeks

• 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 140mg Q2W Placebo Q2W Primary hypercholesterolaemia or mixed dyslipidaemia HeFH High-intensity statin1 (atorvastatin 80mg) Statin + ezetimibe2 Moderate-intensity statin1 (simvastatin 40mg)

Similar figures for alirocumab

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 time1
• Low tolerance to available therapy3

– 7-15% of statin users experience muscle complaints

• Absence of effective therapy1,2

– 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.

LDL-C

DUTCH EXPERIENCE: FH undertreated

Pijlman et al Athersoclerosis 2009

Raal Hovingh. Lancet 2015;385:331–340.

Evolocumab significantly reduces LDL-C in patients with heterozygous FH

Placebo Q2W (n=54) Evolocumab 140 mg Q2W (n=110)

Study week Mean % change in LDL-C from baseline

10 8 12 20

• 20
• 40
• 60
• 80

Baseline 2

60% vs placebo

• 1%
• 61%

Long term follow up in heFH

Kastelein, Hovingh Eur Heart J 2015

Non-apheresis (n = 72) Apheresis (n = 34) All patients (N = 106) LDL-C* Baseline, mean (SD), mmol/L 8.9 (3.8) 7.4 (2.6) 8.4 (3.5) 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 9,420 no history of CHD

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

• Lower LDL-C targets over time1
• Low tolerance to available therapy3
• 7-15% of statin users experience muscle complaints
• Absence of effective therapy1,2
• 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.

LDL-C

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

Per-protocol dose ↑ possible depending on W8 LDL-C

N=100

Ezetimibe 10 mg PO QD + placebo SC Q2W

N=100 W8 W16 Primary endpoint (LDL-C % change from baseline, ALI and EZE only) Safety analysis (all groups) W4 W12 W24

Per-protocol dose increase if Week 8 LDL-C ≥70 or ≥100 mg/dL (depending on CV risk)

*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

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)

†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.

Assessments W0 W -4

Patients discontinued if muscle-related AEs reported with placebos during run-in

R

Placebo PO QD + Placebo SC Q2W†

Atorvastatin 20 mg PO QD + placebo SC Q2W

N=50

OLTP/8 week FU

Moriarty, AHA 2014

Moriarty et al. J Clin Lipidol 2015; 9: 758-69

ODYSSEY ALTERNATIVE : Alirocumab Significantly Reduced LDL- C from Baseline to Week 24 vs Ezetimibe

LS mean (SE) % change from baseline to Week 24

LS mean difference (SE) vs ezetimibe:

• 30.4 (3.1); P<0.0001

n=122

Alirocumab

n=126

Ezetimibe

% change from baseline to Week 24 in LDL-C

†49.5% of 109 patients who received at least one injection after Week 12 had dose increase.

ITT (primary endpoint) 49.5%† received 150 mg Q2W at W12 Absolute change of

• 84 (4.1) mg/dL

Absolute change of

• 33 (4.2) mg/dL

n=118 n=123

On-treatment (key secondary endpoint)

LS mean difference (SE) vs ezetimibe:

• 35.1 (2.8); P<0.0001

Absolute change of

• 96 (3.9) mg/dL

Absolute change of

• 38 (4.2) mg/dL

Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin

0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00

Cumulative probability of event Week Atorvastatin Alirocumab

4 8 12 16 20 24 28 32 36

Kaplan-Meier estimates for time to first skeletal muscle event†

†Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.

ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe.

Cox model analysis: HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042 Ezetimibe HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096

Moriarty, AHA 2014

Recent studies with PCSK9i

ODYSSEY DM-DYSLIPIDEMIA: design and study procedures

24

Usual care – optional addition of one of the following: ezetimibe, fenofibrate, omega-3 fatty acids, nicotinic acid, or no other LLT Safety observation period (8 weeks) n=276 n=137 Primary endpoint: % change from baseline in non-HDL-C W 24 W 0 Screening period (up to 3 weeks) W 12 Visits: W–3 W 8 W 4 W 20 W 32

Randomization Screening visit 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)

Open-label treatment period (24 weeks; N=413) ALI 75 mg SC Q2W R ALI dose increase to 150 mg SC Q2W at Week 12 if Week 8 non-HDL-C ≥100 mg/dL (2.59 mmol/L)

Diet and maximum tolerated statin (or no statin if intolerant)

Randomization was stratified by the investigator’s selection of usual care therapy prior to randomization. Usual care also includes the

• ption 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.

2:1

% change in non-HDL-C from baseline to Week 24 vs usual care (primary efficacy endpoint; ITT†)

25

LS mean difference (SE) versus usual care: LS mean (SE) % change in non-HDL-C 36.4% (94/275) 63.6% (182/275) Alirocumab dose at Week 12, % (n) Dose increase to 150 mg Q2W Maintained at 75 mg Q2W –37.3 –4.7 –32.5% (2.5) P<0.0001

†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 – 3rd generation chemically synthesized siRNA
• Enhanced stabilization chemistry results in long duration
• f action
• Low total exposure (600 to 900 mg/yr)

Phase II ORION-1 Study

Study design

Completed (n=483) Screening (Day -14 to Day -1) Treated (n=497)

Day 1 Study drug given Day 14 1st follow-up visit Monthly follow-up visits Day 30 Day 90 Day 180 Day 210 End of study visit Primary evaluation Day 360 Extended follow-up

One dose starting regimen 200 mg

N=60

Placeb

• N=65

500 mg

N=65

300 mg

N=61

Day 1 Study drug given Day 14 1st follow-up visit Monthly follow-up visits Day 30 Day 90 Day 180 Day 210 End of study visit Primary evaluation Day 360 Extended follow-up

Two dose starting regimen 100 mg

N=61

Placeb

• N=62

300 mg

N=61

200 mg

N=62

Study drug given

Randomized (n=501)

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 7 (3.8) 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

End of study if LDL-C back to baseline P-value for all comparisons to placebo <0.0001

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

Mean 52.6% Max 80.9%

Placebo Percent reduction Inclisiran 300 mg Percent reduction All patients responded

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?