[PPT] - Novel strategies targeting residual risk: the promise of PCSK-9 PowerPoint Presentation

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Novel strategies targeting residual risk: the promise of PCSK-9 inhibiting therapies

Erik Stroes, MD Academic Medical Center Amsterdam, The Netherlands

ESC August 29th, Rome

SLIDE 2

Faculty Disclosure

I I have received a research grant(s)/ in kind support

A From current sponsor(s) YES B From any institution YES

II I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) YES B From any institution YES

III I have been a consultant/strategic advisor etc

A For current sponsor(s) YES B For any institution YES

IV I am a holder of (a) patent/shares/stock ownerships

A Related to presentation NO B Not related to presentation NO

Declaration of financial interests For the last 3 years and the subsequent 12 months:

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Faculty Disclosure

Declaration of non-financial interests:

Department of Vascular Medicine, AMC, Amsterdam, The

Netherlands

Professor of Medicine
List of scientific or other organisations:
Chair Dutch Atherosclerosis Society
Member Lipid-evaluation committee of Dutch Internal

medicine society

Member of ATVB council American Heart Association

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Outline

Why LDL-c as target to reduce residual risk ?
The Promise of PCSK-9 inhibiting therapies
PCSK9-inhibiton and the Inflammation-Paradox

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Genetic and Pharmacologic trials show causal role for LDLc in CVD

Ference et al. J Am Coll Cardiol 2015;65:1552–1561.

Lower LDL-C (mg/dL)

Proportional reduction in CHD risk (log scale) 30% 20% 10%

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0

GISSI-P A to Z SEARCH ALLHAT-LLT LDLR rs6511720 NPC1L1 LDL-C score HMGCR LDL-C score

Genetically lower LDL-C Pharmacologically lower LDL-C

IMPROVE-IT

HMGCR LDL-C score NPC1L1 LDL-C score

18.2% reduction in CHD risk for each 1mmol/L (38mg/dL) lower LDL-C 54.5% reduction in CHD risk for each 1mmol/L (38mg/dL) lower LDL-C

LDLR rs2228671 NPC1L1 rs217386 PCSK9 rs2479409 ABCG5/8 rs4299376 HMGCR rs12916

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Why further LDL-c lowering to reduce residual risk?

I. Achieved very low LDL-C equals lower CV-risk

Boekholdt SM, JACC 2015

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Why further LDL-c lowering to reduce residual risk?

II. No evidence for lower LDLc limit in CV-benefit
1. LaRosa et al. Am J Cardiol 2007;100:747–752.
2. Hsia et al. J Am Coll Cardiol 2011;57:1666–1675.
3. Wiviott et al. J Am Coll Cardiol 2005;46:1411–1416.

TNT1 Rate of major CV events JUPITER2 Risk of primary endpoint* PROVE-IT3 Risk of primary endpoint†

≤40 >40–60 >60–80 >80–100 0.80 (0.59, 1.07) 0.67 (0.50, 0.92) 0.61 (0.40, 0.91)

Lower LDL-C Better Higher LDL-C Better

Referent

1 2 2 4 6 8 10 12 14

P for trend across LDL-C <0.0001

% of patients with major CV events

<64 64–<77 77–<90 90–<106 ≥106 0.76 (0.57–1.00) 0.35 (0.25–0.49) 0.39 (0.26–0.59)

Lower LDL-C Better Higher LDL-C Better

0.1 1 10

<50 vs not <50 <50 vs placebo Not <50 vs placebo Placebo

Achieved LDL-C (mg/dL)

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Why do we need further LDL-C lowering therapies ?

I. Guidelines set LDL-C goals in high risk patients II. Special populations do not achieve LDL-C goals

III. More patients with adverse effects on statins

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I. post-ACS, 1:5 patients achieve LDL-C <70mg/dL

despite statin prescription and good adherence

EUROASPIRE IV

Kotseva et al. Eur J Prev Cardiol 2015;Feb 16. pii:2047487315569401. www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/EUROASPIRE-IV-reveals-success-and- challenges-in-secondary-prevention-of-CVD-acro. Accessed 22 Jan 16.

87 58 21

10 20 30 40 50 60 70 80 90 100

Lipid-lowering drugs LDL-C <100mg/dL LDL-C <70mg/dL

Prevalence (%)

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II. In patients with Familial Hypercholesterolemia
nly 1 : 5 achieves target LDLc
Of 1,249 HeFH patients, 21% achieved

LDL-C <2.6 mmol/L (100 mg/dL)

100 80 60 40 20

LDL-C target (mmol/L) Attainment of target (%)

1 2 3 4 5 6 7 8 9 10

Of those not achieving LDL-C

<2.6mmol/L, 73% were not receiving maximal lipid lowering therapy

Pijlman et al. Atherosclerosis 2010;209:189–194.

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III. Statin-associated side effects often lead to

discontinuation and reduced survival

Side effects are the most common reason patients discontinue statins1
Survival is reduced in patients who discontinue,

even compared to those on non-daily statin doses2

1. Cohen et al. J Clin Lipidol 2012;6:208-15.
2. Mampuya et al. Am Heart J 2013;166:597–603.

Survival (%) Years

Statin continued/daily dose Statin continued/non-daily dose Statin discontinued

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Outline

Why LDL-c as target to reduce residual risk ?
The Promise of PCSK-9 inhibiting therapies
PCSK9-inhibiton and the Inflammation-Paradox

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PCSK9 monoclonal antibodies binding PCSK9

Chan et al. Proc Nat Acad Sci USA 2009;106:9820–9825.

PCSK9-mab Increased LDLR concentration LDLR LDLR recycling restored

Presence of PCSK9-mab = absence of PCSK9  more LDLR  lower plasma LDL-C

LDL particles PCSK9 bound to mab LDL/LDLR complex

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Genetic variants of PCSK9 demonstrate its importance in regulating LDL levels

1. Abifadel et al. Hum Mutat 2009;30:520–529. 2. Dadu et al. Nat Rev Cardiol 2014;11:563–575.
3. Benn et al. J Am Coll Cardiol 2010;55:2833–2842.

PCSK9 gain of function (GOF) = Fewer LDLRs1 (rare2)

GOF variant Population Characteristics D374Y British, Norwegian families, 1 Utah family Premature CHD, tendon xanthomas, severe hypercholesterolaemia S127R French, South African, Norwegian patients Tendon xanthomas; CHD, early MI, stroke D129G New Zealand family Brother died at 31 from MI; strong family history of CVD

PCSK9 loss of function (LOF) = More LDLRs3 (more common2)

LOF variant Population LDL-C CHD risk R46L ARIC, DHS ↓ 15% ↓ 47% Y142X or C679X ARIC, DHS ↓ 28%–40% ↓ 88% R46L CGPS ↓ 11% ↓ 46%

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Genetics support cumulative effect of PCSK9-inhibition on top of statins

Absolute magnitude of lower LDL-C (mg/dL) Proportional reduction in CHD risk (log scale) 30% 20% 10%

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0

PCSK9 46L rs11591147 LDLR rs6511720 NPC1L1 LDL-C score HMGCR LDL-C score LDLR rs2228671

Genetically Lower LDL-C

Combined NPC1L1 & HMGCR LDL-C score

HMGCR LDL-C score NPC1L1 LDL-C score NPC1L1 rs217386 PCSK9 rs2479409 PCSK9 rs11206510 ABCG5/8 rs4299376 HMGCR rs12916

Ference et al. J Am Coll Cardiol 2012;60:2631–2639. Ference et al. J Am Coll Cardiol 2015;65:1552–1561.

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Combination therapy Monotherapy Statin intolerant HeFH HoFH/Severe FH Long-term safety and efficacy Open-label extension Atherosclerosis Secondary Prevention Neurocognition Phase 3 (n=2,067) Phase 3 (n=615) Phase 3 (n=307) Phase 3 (n=511)* Phase 3 (n=331) Phase 2/3 (n=300) Phase 3 (n=905) Phase 3 (n=3,671)* Phase 3 (n=970) Phase 3 (n=27,564) Phase 3 (n=1,971)* Phase 2 (n=631) Phase 2 (n=411) Phase 2 (n=160) Phase 2 (n=168) Phase 2/3 (n=58) Phase 2 (n=1,104)

*Data are planned numbers of randomised patients Completed trials >35,000 patients

Evolocumab in phase III PROFICIO programme

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Evolocumab rapidly reduces LDL-C within 2 weeks

1. Stroes et al. J Am Coll Cardiol 2014;63:2541–2548.
2. Raal et al. Lancet 2015;385:331–340.

HeFH patients on maximally- tolerated statin dose2 Patients unable to tolerate an effective dose of statin1

Mean LDL-C % change from baseline

Time (weeks) Time (weeks)

10
40
50
60
70
20
30
80
90
100

2 4 6 8 10 12

10
40
50
60
70
20
30
80
90
100

2 4 6 8 10 12

Placebo Q2W Evolocumab 140mg Q2W Ezetimibe 10mg QD + placebo Q2W 2 weeks n = 100 n = 110 n = 51 n = 54

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Evolocumab persistently reduces LDLc > 52 weeks

Sabatine et al. N Engl J Med 2015;372:1500–1509.

LDL–C (mg/dL) Standard therapy Weeks Evolocumab

1,219 2,508

n =

394 864 Standard therapy Evolocumab

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Evolocumab reduces LDL-C

irrespective of baseline characteristics

Raal et al. Lancet 2015;385:331–340. Every 2 weeks dosing

Overall Male patients Female patients Age ≥65 years Age <65 years BMI ≥30kg/m2 BMI >25 to <30kg/m2 BMI ≤25kg/m2 Non-intensive statin therapy Intensive statin therapy No ezetimibe use Ezetimibe use LDL-C ≥4.1mmol/L (158mg/dL) LDL-C <4.1mmol/L (158mg/dL)

80
60
40
20

Change from baseline in LDL-C

(treatment differences of evolocumab vs placebo)

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Evolocumab is well tolerated

even in patients with statin intolerance

70
60
50
40
30
20
10

2 4 6 8 10 12 14 16 18 20 22 24 26 Percent Change in LDL-C (%)

Weeks Following Randomization in Phase B

Ezetimibe Evolocumab

Mean reduction 16.7% (LDL-C = 181 mg/dL) Mean reduction 53.0% (LDL-C = 104 mg/dL)

Nissen S, Stroes E, et al. JAMA 2016

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Evolocumab and safety

in subjects with very low LDLc - OSLER

Evolocumab subjects stratified by minimum achieved LDL-C

All EvoMab (n=2976) SOC Alone (n=1489) <25 mg/dL (n=773) 25 to <40 mg/dL (n=759) <40 mg/dL (n=1532) ≥40 mg/dL (n=1426)

Adverse Events (%) Any 70.0 68.1 69.1 70.1 69.2 64.8 Serious 7.6 6.9 7.2 7.8 7.5 7.5 Muscle-related 4.9 7.1 6.0 6.9 6.4 6.0 Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3 Lab results (%) ALT/AST >3×ULN 0.9 0.8 0.8 1.3 1.0 1.2 CK >5×ULN 0.4 0.9 0.7 0.5 0.6 1.2

Sabatine MS et al. N Engl J Med 2015;372:1500-1509

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Sabatine MS et al. N Engl J Med 2015;372:1500-1509

Evolocumab and Cardiovascular Events

OSLER

1 2 30 60 90 120 150 180 210 240 270 300 330 365 HR 0.47 95% CI 0.28-0.78 P=0.003

Composite Endpoint: Death, MI, UA  hosp, coronary revasc, stroke, TIA, or CHF  hosp

3 Days since Randomization Cumulative Incidence (%) Evolocumab plus standard of care (N=2976) Standard of care alone (N=1489)

0.95%* 2.18%**

*29/2976 **31/1489

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Alirocumab ODYSSEY Phase 3 programme

Completed trials. Combination therapy (n = 2484) Monotherapy/no statin (n = 336) Statin intolerant (n = 314) HeFH (n = 841) Long-term safety and efficacy (n = 2341) Open-label extension (n = 1000) Secondary prevention (n = 18,000)

Total, n = 24,316 ODYSSEY FH I*

(n = 486)

ODYSSEY FH II*

(n = 249)

ODYSSEY HIGH FH†

(n = 106)

ODYSSEY LONG TERM† (n = 2341) ODYSSEY OLE (n = 1000) ODYSSEY ALTERNATIVE* (n = 314) ODYSSEY OUTCOMES* (n = 18,000) ODYSSEY MONO* (n = 103) ODYSSEY COMBO I*

(n = 316)

ODYSSEY COMBO II*

(n = 720)

ODYSSEY OPTIONS I*

(n = 355)

ODYSSEY OPTIONS II*

(n = 305)

ODYSSEY CHOICE I‡

(n = 803)

ODYSSEY CHOICE II§ (n = 233)

HoFH Atherosclerosis Neurocognition

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Alirocumab

Alirocumab lowers LDLc persistently

in hyperlipidemic CV-patients

Week

118.9 mg/dL (+0.8%) 48.3 mg/dL (−61.0%) 123.0 mg/dL (+4.4%) 53.1 mg/dL (−56.8%) Placebo Calculated LDL-C, LS mean (SE), mg/dL Achieved LDL-C Over Time All patients on background of maximally tolerated statin ± other lipid-lowering therapy Difference −61.9%

4 8 12 16 24 36 52

Difference −61.3% Robinson J et al. N Engl J Med 2015

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62.1%
56.3%
0.5%

7.0%

70
60
50
40
30
20
10

10 20 HeFH Non-HeFH

Alirocumab effective

in Familial hypercholesterolemia

All patients on background of maximally tolerated statin

Placebo Alirocumab

n=271 n=145 n=1259 n=635

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

62.3%
52.3%

9.3%

8.7%
80
60
40
20

20 ≥160 mg/dL <160 mg/dL

n=84 n=35 n=187 n=110

HeFH population by baseline LDL-C

20 −10 −20 −30 −40 −60 −50 10 −70

Robinson J, et al. N Engl J Med 2015

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Alirocumab and Cardiovascular Events¶

Robinson JG et al. N Engl J Med 2015;372:1489-1499

Time (weeks)

0.06 0.02 0.04 52 78 86 0.03 0.05 0.01

Placebo Alirocumab*

Cumulative Probability of Event

64 12 24 36

Cox model analysis HR = 0.52 (95% CI, 0.31-0.90) Nominal P-value = .02

*27/1550 **26/788

3.3%** 1.7%*

¶post-hoc analysis not specified in the study protocol

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Ongoing Phase 3 Trials:

Alirocumab, Evolocumab, Bococizumab

Patient Pop’n Evolocumab (PROFICIO program) Alirocumab (ODYSSEY program) Bococizumab (SPIRE program) Trial N PP Tx Dur’n (m) Predicted Pt Exposure (Pt-Y)* Min B/L LDL-C (mg/dL) Trial N PP Tx Dur’n (m) Predicted Pt Exposure (Pt- Y)* Min B/L LDL-C (mg/dL) Trial N PP Tx Dur’n (m) Predicted Pt Exposure (Pt-Y)* Min B/L LDL-C (mg/dL) Combo Therapy LAPLACE-2 1896 3 286 ≥80 COMBO I 311 12 205 ≥ 70 HR 711 12 356 >70 COMBO II 707 24 934 ≥70 OPTIONS I 345 6 51 ≥70 LDL 2139 12 1070 >70 OPTIONS II 298 6 51 ≥70 CHOICE I 803 12 573 None APPRISE 1300 30 3250

‡

≥100 Mono MENDEL-2 614 3 77 ≥100 MONO 103 6 26 ≥70 AI 299 3 56 ≥70 HeFH RUTHERFORD-2 329 3 55 ≥100 FH I 485 18 483 ≥70 FH 370 12 185 >70 FH II 247 18 249 ≥70 HIGH FH 107 18 107 ≥160 HAUSER (paed) 150 6 50† ≥130 Apheresis 50 1.5 4† ≥100 ESCAPE 63 4 11 None HoFH TESLA 49 3 8 ≥130 TAUSSIG (OL) 300 60 1500

‡

≥100 Statin Intolerance GAUSS-2 307 3 51 None ALTERNATIVE 310 6 63 ≥70 SI 184 6 37 ≥70 GAUSS-3 491 6 73 ≥100 CHOICE II 233 6 88 >70 Long term DESCARTES 901 12 599 ≥75 LONG-TERM 2310 18 2295 ≥70 LL 746 12 497 ≥100 OSLER-2 (OL) 3681 24 4908

†

None OLE (OL) 1000 40 3400 None Atheroma GLAGOV 968 18 726 ≥60 Lp(a) NCT02729025 120 4 27

†

≥100 DM NCT02739984 400 3 67

†

None DM 500 6 167† ≥70 NCT02662569 900 3 150

†

≥100 TOTALS Patients: 7575 Predicted Pt Yrs: 8825 Patients: 7485 Predicted Pt Yrs: 11,627 Patients: 4202 Predicted Pt Yrs: 2561 CVD Outcomes FOURIER 27,564 Event driven NA ≥70 OUTCOMES 18,000 Event driven NA ≥70 SPIRE-1 17,000 Event driven NA ≥70 SPIRE-2 11,000 NA ≥100 Neurocog events EBBINGHAUS 1972 in FOURIER End of FOURIER N/A ≥70

*Predicted exposure to investigational product; †When randomisation not stated, assumed 2:1 in favour of investigational product; ‡Single-arm study. PP = per protocol; Tx = treatment; Dur’n = Duration; Pt Y = patient years

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Including ACS-patients

1. Sabatine MS, et al. Am Heart J 2016;173:94–101.
2. Schwartz GG, et al. Am Heart J 2014;168:682–9.

History of MI n = 22,356

PAD n = 3640 History of stroke* n = 5330

ODYSSEY OUTCOMES2 N ~ 18,000 FOURIER1 N = 27,564

Recent MI < 1 year

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Outline

Why LDL-c as target to reduce residual risk ?
The Promise of PCSK-9 inhibiting therapies
PCSK9-inhibiton and the CRP-paradox

SLIDE 30

Inflammation vs LDLc in post-ACS patients

Re-events after ACS

Days Inzitari, N Engl J Med 2000 Raal FJ, et al. Lancet 2014; (14)61399-4.

50%

0% 50% 100%

Placebo Q2W (N = 54) Placebo QM (N = 55) Evolocumab 140 mg Q2W (N = 110) Evolocumab 420 mg QM (N = 110)

CRP (% change)

CRP change following PCSK9-ab

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Plaque rupture is caused by arterial wall macrophages

Patients with recent infarctions

are characterized by vascular ‘inflammation’ on PET/CT

Rogers JIMG 2010

Atherosclerotic plaques with high

number of macrophages are prone to rupture, causing acute vessel occlusion

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Rapid white blood cell influx in atherosclerotic lesions in patients

CV patient Control subject

* **

Rapid WBC accumulation Correlation SPECT - PET F van der Valk, Stroes E. J Am Coll Cardiol 2014

SLIDE 33

2 4 6 8 10 12 500 1000 1500 r2 = 0.503 p = 0,0045 LDL (mmol/L) CCR2 (MFI) classical intermediate non-classical 200 400 600 800 Control FH

***

CCR2

CCR2 (MFI)

Circulating monocytes activated in hypercholesterolemia

CCR2

MARKERS AORTA TBRMAX P-VALUE CAROTIDS TBRMAX P-VALUE CCR2 0.025* 0.220 CCR5 0.140 0.146 CD11B 0.585 0.595 CD11C 0.785 0.849 CD18 0.768 0.868 CD36 0.363 0.102

CCR2-expression on monocytes independently correlates with Arterial wall inflammation in CVD patients

Verweij S, Stroes. Data on file

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Control Familial hypercholesterolemia

cell membrane neutral lipids

Increased lipid droplet content in monocytes with high cholesterol

SLIDE 35

CCR2high-expressing monocytes show increased migration which is reversible following PCSK9-ab

Control CVD patient untreated CVD patient treated Data On file

SLIDE 36

Take Home

LDL-c is causal factor in cardiovascular disease
Whereas Lower LDL-C is better, Very low LDL-C is even better
PCSK9-antibodies reduce LDLc
Rapidly, consistently and potently
Independent of baseline characteristics & comorbidities
Side effects at placebo level
PCSK9-antibodies also reduce monocyte activation
By reducing intracellular lipid accumulation
CV-endpoint data expected 2017