non-statin therapies for the management of ldl …non-statin therapies for the management of...

Non-statin Therapies for the Management of LDL-associated ASCVD

RiskPamela B. Morris, MD, FACC, FACP, FACPM, FAHA, FNLA

Chair, American College of Cardiology Prevention of Cardiovascular Disease

Section

Associate Professor of Medicine

Director, Seinsheimer Cardiovascular Health Program

Co-Director, Women's Heart Care

Medical University of South Carolina

Disclosures

• Advisory board—Amgen, AstraZeneca, Sanofi-Regeneron

Discussion Objectives

1. Describe mechanism of action of new and emerging

agents for LDL-C lowering based on targets in

lipoprotein synthesis, transport, and regulation

2. Outline clinical trial data on the efficacy and safety of

novel agents for lowering LDL-C

High, Moderate, and Low-intensity

Statin Therapy Used in Clinical Trials

High-Intensity

Statin Therapy

Moderate-Intensity

Statin Therapy

Low-Intensity

Statin Therapy

Daily dose lowers LDL-C

on average, by

approximately ≥50%


on average, by

approximately 30 to <50%


on average, by

approximately <30%

Atorvastatin 40*-80* mg

Rosuvastatin 20*-40** mg

Atorvastatin 10* (20**) mg

Rosuvastatin (5**) 10* mg

Simvastatin 20*-40* mg

Pravastatin 40* (80**) mg

Lovastatin 40* mg

Fluvastatin XL 80** mg

Fluvastatin 40 mg BID*

Pitavastatin 2-4** mg

Simvastatin 10** mg

Pravastatin 10*-20* mg

Lovastatin 20* mg

Fluvastatin 20**-40** mg

Pitavastatin 1** mg

*Statins demonstrated reduction in major CVD events.**FDA approved doses not tested in clinical trials.

FDA = Food and Drug Administration.Goff DC, et al. Circulation. 2014;129(25 Suppl 2):S49-73.Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

Are there unmet clinical needs?

• High absolute ASCVD risk and inadequate

response/elevated LDL-C despite maximally

tolerated statin therapy

• Familial hypercholesterolemia

• Statin intolerance and high ASCVD risk or

known ASCVD

Lowering LDL-C: Treatment options

• Reduce absorption

– Ezetimibe

– Bile acid sequestrants

• Reduce production

– Mipomersen

– Lomitapide

• Increase clearance

– Statins

– PCSK9 inhibition

Approaches to additional LDL-C lowering

Ray KK, et al. Lancet. 2015:386:412-15

Ezetimibe

8

IMProved Reduction of Outcomes: Vytorin Efficacy

International Trial (IMPROVE IT): Design

Cannon CP, et al. Am Heart J. 2008;156:826-32.

Patients stabilized post-ACS ≤ 10 days

LDL-C ≤ 125 mg/dL (or ≤ 100 mg/dL if prior statin)

Double-blind

N ~ 18,000

ASA + Standard Medical Therapy

Simvastatin 40 mg*Ezetimibe/Simvastatin

10/40 mg*

Follow-up visit day 30, every 4 months

Duration: Minimum 2.5 year follow-up (5250 events)

Primary Endpoint: CV death, MI, Hospitalization for UA, Revascularization

(> 30 days after randomization), or Stroke

*uptitrated to

80 mg if LDL-C

> 79 mg/dL

IMProved Reduction of Outcomes: Vytorin Efficacy

International Trial (IMPROVE IT)

Cannon CP et al. N Engl J Med 2015;372:2387-2397.

100

90

80

70

60

50

40

QE R 1 4 8 12 16 24 36 48 60 72 84 96

Time since randomization (months)

Number at risk

EZ/Simva 53.2 125.8 120.4 48.7 3.3

Simva 9009 8921 8306 7843 7289 6939 6607 6192 5684 5267 4395 3387 2569 1068

Mean

LD

L-C

(m

g/d

L)

Median Time avg

69.5 vs. 53.7 mg/dL

Simva 69.9 145.1 137.1 48.1 3.8

Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5

1 yr mean LDL-C TC TG HDL-C hs-CRP

Ez/Simva 8990 8899 8230 7701 7264 6864 6583 6256 5734 5354 4508 3484 2608 1078


IMPROVE-IT: Kaplan–Meier Curves for the Primary

Efficacy End Point

34.7%

2742 events

32.7%

2572 events


Plot of the IMPROVE-IT Trial Data and Statin Trials for Change in

Low-Density Lipoprotein (LDL) Cholesterol versus Clinical Benefit.

The size of the box is proportional to the number of end points in the study.

Post-hoc analysis: Is it safe to achieve very low

levels of LDL-C?

Giugliano RP, et al., ESC 2015

Post-hoc analysis: Is it safe to achieve very low

levels of LDL-C?


Myalgia w/CK AE->D/c ALT/AST > 3x

ULN

Gallbladder

AENeurocognitive

Post-hoc analysis: Primary efficacy endpoint (CV death, MI, hospitalization for UA, coronary revascularization, stroke)


Myalgia w/CK AE->D/c ALT/AST > 3x

ULN

Gallbladder

AENeurocognitive

Mipomersen

16

Mipomersen: Mechanism of Action

1. Kastelein JJ, et al Circulation. 2006;114(16):1729-35;

2. Crooke ST, ed. Antisense Drug Technology: Principles, Strategies and Applications. 2nd ed. 2008:601-39;

3. Yu R, et al. Drug Metab Dispos. 2007;35(3):460-8.

Mipomersen (apoB)

antisense strand G C C T C A G T C T G C T T C G C A C C

Phosphorothioate

backbone

2′ MOE2′ MOE

2′ deoxy

(supports RNase H activity)

Mipomersen crosses the

hepatocyte and nuclear

membranes to target

apoB mRNA

Nucleus

apoB mRNA

DNA

mRNA–antisense duplex

RNase H recognizes

duplex

RNA is cleaved

Hepatocyte cell

membrane

Cytoplasm

Summary of mipomersen efficacy in combination

with maximally-tolerated lipid-lowering therapy

Raal FJ, et al. Lancet. 2010;375(9719):998-1006; McGowan MP, et al. PLoS One. 2012;7(11):e49006; Stein EA, et al. Circulation. 2012;126(19):2283-92;

Cromwell W, et al. J Am Coll Cardiol. 2011;57:Poster 1011-304.

% change from baseline

Patient

population

Baseline

LDL-C

(mmol/L)

LDL-CMean

ApoBMean

Lp(a)Median

TG Median

HDL-CMean

HoFH 11.4 –25% –27% –32% –18% 19%

Severe HC 7.2 –36% –36% –39% –15% 6%

HeFH with

CAD4.0 –28% –26% –21% –14% 3%

HC at high

risk for CAD3.2 –37% –38% –26% –26% 2%

Percentage change from baseline in LDL-C, apoB, Lp(a), TG and HDL-C

in patients treated with mipomersen

Phase 3: SafetyOn-Treatment Adverse Events and Clinical Findings

• Adverse Events

– Most common AEs were mild to moderate injection site reactions & flu-like

symptoms

• Clinical Findings

– Transaminase increases

– No effect on liver synthetic function, i.e. total bilirubin, albumin, PT

– Modest median increase in hepatic fat, which was reversible after cessation

of dosing

• No clinically significant drug-drug interactions

• No interactions with warfarin

• No QTc changes in dedicated ECG study

Santos RD, et al. Eur Heart J. 2013 [Epub Ahead of Print].

Microsomal Triglyceride

Transfer Protein Inhibition

↑TG results in ↑ hepatic fat

↑TG contributes to

GI tolerability issues

Predicted Effects of MTP Inhibition

Liver Cell

Intestinal

Epithelial

Cell

TG

ER

Lumen

Cytoplasm

Apo B100Degraded

MTP

TG

Apo B48Degraded

MTP

Blood Vessel

Lower

VLDL, LDL,

chylomicrons,

and

chylomicron

remnants

ER

Lumen

Cytoplasm

Hussain et al. J Lipid Res. 2003:44;22-32.

10

0

–10

–20

–30

–40

–50

–60

–70

Mea

n %

ch

ange

in

LDL-

C (±

95

%C

I)

0 10 18 26 36 46 56 66 78 90 102 114 126Week

17 17 16 17 17 17 17 17 17 17 17 17 17

Phase 3 Long-Term Extension

n:

–80

Phase 3 Long-Term Extension Trial:

Mean percent change from baseline in LDL-C by study

visit (week 126 completers population)

Cuchel et al. Circulation. 2013; 128: A16516.

Hepatic Safety: Hepatic Fat (N=19 safety population)*

WeekN

Median, %Mean, %Range, %

Baseline170.70.8

0, 2.4

126137.710.2

1.6–24.7

78176.57.9

0.6–19.0

26175.96.5

1.1–16.3

Week

Med

ian

hep

atic

fat

, % (±

IQR

)

1747

7.67.3

0.6–15.6

150127.6

11.1 0.7–35.2

Cuchel et al. Circulation. 2013; 128: A16516

Lomitapide

• Dose titration schedule can limit GI side effects

• Due to its mechanism of action it may reduce absorption of fat-soluble

vitamins

– Supplements of vit E 400 IU, linoleic acid 200 mg, ALA 210 mg, EPA

110 mg, DHA 80 mg provided

• Low-fat (<20%) diet to minimize GI side effects

• Limit alcohol to one serving daily

• Inhibitors of CYP3A4 may increase exposure to lomitapide

– Do not exceed 30 mg in patients on weak CYP3A4 inhibitors

• Use only low-dose simvastatin and lovastatin

• Lomitapide increases plasma concentrations of warfarin

Mipomersen and Lomitapide

• Orphan Drugs: available for patients with rare genetic

diseases

– Both associated with increase in intrahepatic fat

– Long-term consequences unknown

• Available through a REMS (Risk Evaluation and

Mitigation Strategy) program

• Prescriber training and certification

• Controlled distribution through certified pharmacies

• Prescription authorization forms

PCSK9 Inhibition

PCSK9-mediated degradation of the LDLR:

Schematic of the major domains of PCSK9

Jay D. Horton et al. J. Lipid Res. 2009;50:S172-S177

• Member of the family of proteases

involved in degradation of LDL

receptor

• Secreted by a variety of cells but

primarily in the liver

• Cleavage of the prodomain is

necessary for maturation and

secretion

• PCSK9 binds the EGF-A domain of

the LDL-R and promotes

degradation of the LDL-R within the

lysosome

• Prevents dissociation of the LDL-R

and lipoproteins before and during

the endosomal pathway toward the

lysosome

PCSK9 Regulates the Surface Expression of

LDLRs by Targeting for Lysosomal Degradation

Qian YW, et al. J Lipid Res. 2007;48(7):1488-1498Horton JD, et al. J Lipid Res. 2009;50:S172-S177

Zhang DW, et al. J Biol Chem. 2007;282(55):18602-18612

Genetic variants of PCSK9 demonstrate

its importance in regulating LDL levels

Swiss Med Wkly. 2015;145:w14094

n=301n=9223

11.8

6.3

Peterson AS, Fong LG, Young SG. J Lipid Res. 2008;49(7):1595-1599 Cohen J, et al. Nature Genetics. 2005;37(2):161-165

Cohen JC, et al. N Engl J Med. 2006;354(12):1264-1272

PCSK9 Loss-of-Function Mutations Resulted in

Low LDL-C Levels and Reduced CHD Rates

• Wild-type PCSK9 degrades

LDL receptors.

• Loss-of-function mutations

increase hepatic LDL-R

expression, reducing LDL-C

levels by 15%-40%.

• CHD was reduced 47% to

88% in PCSK9 loss-of-

function mutation carriers

compared with normal

individuals.

Black Subjects

0

12

CH

D (

%)

2

8

10

6

White Subjects

Normal Subject

Mutation Carrier

n=85n=3278

9.7

1.2

4

P=.008 P=.008

Mode of Action Drug Company Phase

PCSK9 binding:

Monoclonal antibodies Alirocumab (REGN727/SAR236553)

Evolocumab (AMG 145)

Bococizumab (RN316)

LY3015014

RG7652

LGT209

Sanofi/Regeneron

Amgen

Pfizer

Eli Lilly

Roche/Genentech

Novartis

3

3

3

2

2 (terminated)

2 (terminated)

Modified binding protein

(adnectin)

(small molecule)

BMS-962476 Bristol-Myers

Squibb/Adnexus

1

PCSK9 synthesis:

RNA interference ALN-PCS02 Alnylam 1

LNA antisense

oligonucleotide SPC-5001 Santaris 1 (terminated)

RNA antisense BMS-844421 Isis/Bristol-Myers Squibb

1 (terminated)

Approaches to PCSK9 Inhibition

Adapted from Stein, Swergold. Curr Atheroscler Rep. 2013;15:310.

J Am Coll Cardiol 2015;65:2638–51

[2914 patients]

J Am Coll Cardiol 2015;65:2638–51[11,598 patients]

Total of 14,512 patients in Phase

2 and Phase 3 Studies

PCSK9 inhibitors: Cardiovascular Outcomes Trials

Alirocumab Evolocumab Bococizumab

Sponsor Sanofi/Regeneron Amgen Pfizer

Trial ODYSSEY Outcomes FOURIER SPIRE I SPIRE II

Sample Size 18,000 22,500 12,000 6300

Patients 4-16 weeks post-ACS MI, stroke, or PAD High risk of CV event

Statin Evidence-based RxAtorvastatin ≥20 mg or

equivalentLipid-lowering Rx

LDL-C ≥70 mg/dL ≥70 mg/dL 70-99 mg/dL ≥100 mg/dL

PCSK9i

DosingEvery 2 weeks Every 2 or Every 4 weeks Every 2 weeks

Endpoint

CHD death, MI,

ischemic stroke, or UA

hospitalization

Primary: CV death, MI,

stroke, UA hospitalization or

coronary revascularization

Key Secondary: CV death,

MI, or stroke

CV death, MI, stroke, or urgent

revascularization

Completion March 2018 December 2017 August 2017

58,800 patients in long-term

cardiovascular outcomes trials

Change in Calculated LDL-C at 2 Weekly

Intervals from Baseline to Week 12

JACC. 2012;59:2344-2353

Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12

in the modified intent-to-treat (mITT) population, by treatment group.

Week 12 estimation using LOCF method.

∆ -5.1% Placebo

-80

-20

-30

0

-10

-40

-50

-60

-70

LD

L-C

Mean

(±S

E)

% C

han

ge f

rom

Baselin

e

Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12

∆ -39.6% SAR236553

50 mg Q2W

∆ -43.2% SAR236553

200 mg Q4W∆ -47.7% SAR236553

300 mg Q4W

∆ -64.2% SAR236553

100 mg Q2W

∆ -72.4% SAR236553

150 mg Q2W

(A) Percentage Changes from Baseline in Levels of LDL-C (calculated) for Patients Treated Every 2 Weeks

(Q2W), (B) Treated Every 4 Weeks

Stein et al. Eur Heart J 2014;35:2249-59.

Evolocumab (AMG-145)

Mean percentage change from baseline in LDL-C. Change over time is shown for the (A) Q14 days and (B)Q28 days

placebo and bococizumab dose groups.

American Journal of Cardiology. 2015;115:1212-21

Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase

Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study

in Statin-Treated Subjects With Hypercholesterolemia

OSLER Trial: Effect of Evolocumab on

Cardiovascular Outcomes

Evolocumab plus standard of care(n=2976)

1

2

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

Standard of care alone

(n=1489)

0.95%

2.18%

3

Days Since Randomization

Cu

mu

lati

ve

Inc

ide

nc

e(%

)

.

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

0 30 60 90 120 150 180 210 240 270 300 330 365

Post hoc Analysis of Adjudicated

Major Adverse Cardiovascular Events*

Placebo + maximally

tolerated statin ± other LLT

Alirocumab + maximally

tolerated statin ± other LLT

Cu

mu

lati

ve

pro

ba

bil

ity o

f e

ve

nt

Time (weeks)

Cox model analysis

HR = 0.52 (95% CI 0.31 to 0.90)

Nominal p-value = 0.02

No. at risk:Placebo

Alirocumab

788 776 731 700 670 653 644 597

1550 1533 1445 1392 1342 1306 12661170

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 52 64 78 86

0.06

0.04

0.02

0.00

0 12 24 36 52 64 7886

*Based on primary endpoint for the ODYSSEY OUTCOMES trial, including CHD death,

non-fatal MI, fatal and non-fatal ischemic stroke, and unstable angina requiring

hospitalization. Unstable angina requiring hospitalization was considered based on strict

criteria/clear progression of ischemia.

Robinson JG, et al. N Eng J Med. 2015;372:1489-99.

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With

Hypercholesterolemia: A Systematic Review and Meta-analysis of effects of PCSK9

Antibodies in Adults With Hypercholesterolemia

Ann Intern Med. 2015;163(1):40-51. doi:10.7326/M14-2957

All-cause mortality

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults

With Hypercholesterolemia: A Systematic Review and Meta-analysis of effects

of PCSK9 Antibodies in Adults With Hypercholesterolemia


Analysis of cardiovascular mortality, adjusted for follow-up.


With Hypercholesterolemia: A Systematic Review and Meta-analysis of effects

of PCSK9 Antibodies in Adults With Hypercholesterolemia


Analysis of myocardial infarction, adjusted for follow-up.


With Hypercholesterolemia: A Systematic Review and Meta-analysisEffects of

PCSK9 Antibodies in Adults With Hypercholesterolemia


Analysis of serious adverse events, adjusted for follow-up.

CETP Inhibition

Barter PJ, et al. N Engl J Med. 2007;357(21):2109-2122Qiu X, et al. Nat Struct Mol Biol. 2007;14(2):106-112

CETP Inhibitors and Modulators

CETP

EvacetrapibTorcetrapib Anacetrapib Dalcetrapib

Is the toxicity of torcetrapib related to the mechanism or the molecule?

Torcetrapib: “beneficial” effects on lipoproteins, but increased

cardiovascular and non-cardiovascular morbidity and mortality

Barter PJ, et al. N Engl J Med. 2007;357(21):2109-2122.

0

92

100

96

Pati

ents

wit

ho

ut

Ev

ent

(%)

360 540 8100

Days after Randomization

90

98

94

180 450 72090 270 630

Atorvastatin only

Torcetrapib

plus Atorvastatin

Schwartz GG, et al. N Engl J Med. 2012;367(22):2089-99.

dal-OUTCOMES Results: No ↓CVD

0

30

100

70

Cu

mu

lati

ve I

ncid

en

ce o

f

Pri

mary

Ou

tco

me (

% o

f P

ati

en

ts)

2 30

10

90

50

1

YearNo. at Risk:

Placebo 1743655173867933Dalcetrapib 1736649573727938

Dalcetrapib

Placebo

20

60

80

400

12

2 30

10

1

2

6

8

4

P=.52 by log-rank test

Lipid Effects of CETP Inhibitors/Modulators% Change from Baseline

CETP AgentDose

(Mg/day)HDL-C (%) LDL-C (%) TG (%)

Torcetrapib 60 61 -24 -9

Dalcetrapib 600 31 -2 -3

Anacetrapib 100 138 -40 -7

Evacetrapib 500 129 -36 -11

Adapted from Cannon C et al. JAMA. 2011;306:2153-2155

Nicholls SJ et al. JAMA. 2011;306:2099-2109

Anacetrapib Evacetrapib

Name (ID) REVEAL (NCT01252953 ACCELERATE (NCT01687998

Company Merck (Oxford Trial Sponsor) Eli Lilly

Sample size 30,000 12,092

Inclusion 1) Age >50 years

2) History of MI

3) Stroke or cerebrovascular

revascularization

4) PAD repair/revascularization

5) DM with symptomatic CAD

1) Age >18 years

2) History of ACS (30-365 days)

3) Cerebrovascular disease

4) PAD

5) DM with CAD

Primary end point CHD death, MI, coronary

revascularization

CV death, MI, CVA, coronary

revascularization, hospitalization for

UA

Study duration Median 4 years Median 2 years

Clinical Trials.gov NCT01252953 NCT01687998

Trial Completion January 2017 July 2016

CETP Inhibitors: Ongoing Phase 3 Trials

Conclusions• Current guidelines permit discretion to discern if LDL-C

reduction is adequate. If not, or if patient is statin intolerant or

only tolerates a low dose of a statin, then non-statin therapy may

be used.

• Mipomersen is an anti-sense molecule that increases

degradation of the mRNA for apoB100.

• Lomitapide is a MTP inhibitor that reduces lipidation and

maturation of apoB100 in the endoplasmic reticulum.

• Mipomersen and lomitapide are only indicated for the treatment

of HoFH.

Conclusions

• Monoclonal antibodies directed against PCSK9 are promising class of

LDL-C lowering agent.

– Being tested in large-scale outcomes trials vs statin background in

patients with stable ischemic heart disease and s/p ACS.

– Alirocumab and evolocumab now FDA approved

• In addition to increasing HDL-C, CETP inhibitors reduce LDL-C, non-

HDL-C, apo B, and Lp(a).

– Anacetrapib and evacetrapib have a favorable safety profiles and

are being tested for clinical efficacy vs statin background in

REVEAL and ACCELERATE trials.

• Adjuvant therapies will ultimately have to demonstrate incremental

benefit against a statin background.

non-statin therapies for the management of ldl …non-statin therapies for the management of...

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