New developments in lipid managementCGR 0800 h 11 May 2015

Rob Hegele MD FRCPC FACPDistinguished Professor of Medicine and Biochemistry

Western UniversityLondon, Canada

hegele@robarts.ca

Financial disclosure: speaker and ad board member for Aegerion, Amgen, Merck, Pfizer, Sanofi, Valeant

Overview

existing drugsnew drugs

Overview

existing drugsnew drugs:

PCSK9 inhibitors

LDL-C and CHD risk

≥4.52 3.88-<4.52 3.23-<3.88 2.58-<3.23 1.94-<2.58 1.29-<1.94 <1.290

5

10

15

20

25

30

35

Major cardiovascular eventsMajor coronary eventsMajor cerebrovascular events

Achieved LDL-C concentration in mmol/L

% in

cide

nce

of e

vent

s

Boekholdt SM et al. JACC 2014; 64:5485-94

Lower on-Rx LDL-C and reduced risk

Reduced all-cause mortality with statins

4S Investigators Lancet 2004; 364:771-7.

Second line drugs

1. Bile acid sequestrants

2. Ezetimibe

3. Fibrates

4. Niacin

Bile acid sequestrantsLipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT)

Lipid Research Clinics. JAMA 1984;251:351-364.

Life-table cumulative incidence of primary end point (definite CHD death and/or definite nonfatal MI) in treatment groups, computed by Kaplan-Meier method.

1 2 3 4 5 6 7 8 90

2

4

6

8

10

12

Years of Follow up

Life

-Tab

le C

umul

ative

Inci

denc

e (%

)

Placebo

Cholestyramine resin

8

LDL-C and Lipid ChangesM

ean

LD

L-C

(m

mo

l/L

)

1.0

1.25

1.5

1.75

2.0

2.25

2.5

QE R 1 4 8 12 16 24 36 48 60 72 84 96Time since randomization (months)Number at risk:

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 1.81 3.75 1.55 1.24 3.8 mg/dl

EZ/Simva 1.38 3.25 1.36 1.26 3.3 mg/dl

Δ in mmol/L

-0.43 -0.50 -0.19 +0.2 -0.5mg/dl

median time avg1.8 vs. 1.4 mmol/L

AHA Scientific Sessions, 17 Nov 2014

Primary Endpoint — ITT

Simva — 34.7% 2742 events

EZ/Simva — 32.7% 2572 events

HR 0.936 CI (0.887, 0.988)

p=0.016

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

NNT= 50

AHA Scientific Sessions, 17 Nov 2014

    Simva* EZ/Simva* p-value

Primary   34.7 32.7 0.016 CVD/MI/UA/Cor Revasc/CVA       Secondary #1   40.3 38.7 0.034 All D/MI/UA/Cor Revasc/CVA       Secondary #2   18.9 17.5 0.016 CHD/MI/Urgent Cor Revasc       Secondary #3   36.2 34.5 0.035 CVD/MI/UA/All Revasc/CVA

0.936

Ezetimibe/Simva Better

Simva Better

UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization (≥30 days after randomization); All D, all-cause death; CHD, coronary heart disease death; All Revasc, coronary and non-coronary revascularization (≥30 days)

*7-year event rates (%)

Primary and 3 Prespecified Secondary Endpoints — ITT

0.8 1.0 1.1

0.948

0.912

0.945

AHA Scientific Sessions, 19 Nov 2014

Safety — ITT

No statistically significant differences in cancer or muscle- or gallbladder-related events

Simva n=9077

%

EZ/Simvan=9067

% p

ALT and/or AST≥3x ULN 2.3 2.5 0.43

Cholecystectomy 1.5 1.5 0.96

Gallbladder-related AEs 3.5 3.1 0.10

Rhabdomyolysis* 0.2 0.1 0.37

Myopathy* 0.1 0.2 0.32

Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64

Cancer* (7-yr KM %) 10.2 10.2 0.57

* Adjudicated by Clinical Events Committee % = n/N for the trial duration

IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit

CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.

IMPROVE-IT

Fibrates: Gemfibrozil Reduced MCVEin Patients with CAD by 22%

Rubins HB et al. NEJM 1999; 341: 410-8

ACCORD-Lipid: MACE

16

Possible role for fibrates

Sacks F et al. N Engl J Med 2010; 363:692-695

High TG, low HDL-C subgroups Normolipidemic subgroups

Coronary Drug Project:Effect of Niacin in Post-MI Patients

The Coronary Drug Project Research Group. JAMA. 1975;231:360-381.

Cumulative Rate of Nonfatal MI in Post-MI Patients Treated With Niacin or PlaceboCu

mul

ative

Eve

nt R

ate

(%)

(P < 0.004)

27%

Recurrent nonfatal MI

0 12 34 36 48 60

15

10

5

PlaceboNiacin

Patients receiving niacin (n=1119) vs patients receiving placebo (n=2789). Total mortalitywas similar between the 2 groups at 5 years.

Months of Follow-up

HPS2-THRIVE: Major Vascular Events on Niacin/Laropiprant (ERN/LRPT)

0 1 2 3 4 Years of follow-up

0

5

10

15

20

Pat

ient

s s

uffe

ring

even

ts (

%)

15.0% 14.5%

Placebo ERN/LRPT

Risk ratio 0.96 (95% CI 0.90–1.03) Logrank P=0.29

Armitage J, et al "HPS2-THRIVE: Randomized placebo-controlled trial of ER Niacin and laropriprant in 25,673 patients with pre-existing cardiovascular disease" ACC 2013.

CVD end point reduction

Drug class No background statin

With background statin

Bile acid sequestrants

Yes (LRC-CPPT) Not done

Ezetimibe Not done Yes (SHARP; IMPROVE-IT)

Fibrates Yes (HHS, VA-HIT) No (ACCORD, FIELD)

Niacin Yes (CDP) No (AIM-HIGH, HPS2)

20

Combination treatment: safety

Very safe: statin + bile acid sequestrantstatin + ezetimibe

Quite safe: statin + niacinstatin + fenofibratestatin + bezafibrate

Riskier statins: lova, simva

Reduce dose: fenofibrate if creatinine > 150

Avoid: statin + gemfibrozil

Compound Dose % LDL lowering Evidence level

Isoflavones (soy protein powder) 50-100 mg 3-11% A-I

Soluble fibre 5-15 g 5-20% A-I

Oatmeal 60 g 2-6% A-I

Plant sterols 1.3 g 4-13% A-I

AHA Step 2 diet 5-10% A-I

Mediterranean diet 5-10% A-I

Portfolio diet 10-20% A-I

Almonds 50-80 g 5% B-I

Green tea extract 1.2 g 10% B-I

High carb diet 60% of calories 5-10% B-I

High protein diet 25% of calories 5-10% B-I

Red yeast rice 1-2 g 7-20% A-IIa

Guggulipid 100 mg 12% A-IIb

Huang et al. Can J Cardiol 2011: 488-505

Non-pharmacological LDL-lowering

• keep LDL-C targets

• combination Rx

• non-statin LDL-C lowering

• non-HDL-C as alternate

• non-fasting lipids

• ongoing RCTs – PCSK9i lower LDL-C < 1.0 mmol/L

• ongoing RCTs – CETP inhibitors

Looking forward to the 2015 guidelines

Emerging lipid therapies

effect- lomitapide lowers LDL-C by 40% - mipomersen lowers LDL-C by 40%- anti-PCSK9 lowers LDL-C by 60%- CETP inh (ana, eva) lowers LDL-C by 30%

- alipogene tiparvovec lowers TG by 30%- anti-APOC3 lowers TG by 50%- anti-ANGPTL lowers TG by 50%

Four Mechanisms for Reducing LDL-C

Lilly SM, Rader DJ. Curr Opin Lipid. 2007;18:650–655.; Shinkai H. Vasc Health Risk Manag. 2012;8:323-331.

Emerging lipid therapies

Emerging lipid therapies

Proprotein

Emerging lipid therapies

ProproteinConvertase

Emerging lipid therapies

ProproteinConvertaseSubtilisin

Emerging lipid therapies

ProproteinConvertaseSubtilisinKexin

Emerging lipid therapies

ProproteinConvertaseSubtilisinKexin9

PCSK9 inhibitors

- very potent LDL-C reduction: up to 70%- non-statin mechanism- mAbs: sc q2 or q4 wk- competitive environment- signal for 50% reduced MCVE

Loss-of-Function Mutations in PCSK9 are Associated with Lower Serum LDL-C and Lower Incidence of CHD

Cohen JC et al. N Engl J Med. 2006;354:1264-72.

PCSK9 mutations were associated with a 28% reduction in mean LDL-C and an 88% reduction in the lifetime risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95% CI, 0.02 to 0.81; P = 0.03)

30

20

10

0

Fre

quen

cy (

%)

1.3 2.6 5.2 6.5 7.8

Plasma LDL-C in Black Subjects (mmol/L)

0

No Mutation(N=3 278) 50th Percentile

30

20

10

01.3 2.6 3.9 5.2 6.5 7.80

PCSK9142X or PCSK9679X

(N=85)

12

8

4

0No Yes

PCSK9142X or PCSK9679X

Cor

onar

y H

eart

Dis

ease

(%

)

3.9

Loss-of-Function Mutations in PCSK9 are Associated with Lower Serum LDL-C and Lower Incidence of CHD

PCSK9 mutations were associated with a 28% reduction in mean LDL-C and an 88% reduction in the lifetime risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95% CI, 0.02 to 0.81; P = 0.03)

30

20

10

0

Fre

quen

cy (

%)

1.3 2.6 5.2 6.5 7.8

Plasma LDL-C in Black Subjects (mmol/L)

0

No Mutation(N=3 278) 50th Percentile

30

20

10

01.3 2.6 3.9 5.2 6.5 7.80

PCSK9142X or PCSK9679X

(N=85)

12

8

4

0No Yes

PCSK9142X or PCSK9679X

Cor

onar

y H

eart

Dis

ease

(%

)

3.9

• PCSK9 LOF mutations found in 1% to 4% of population• Associated with

- Lower serum LDL-C- Lower incidence of coronary heart disease

Cohen JC et al. N Engl J Med. 2006;354:1264-72.

In the Presence of PCSK9, the LDL-R Is Degraded and Does Not Cycle Back to Cell Surface

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

Serum LDL-Cholesterol Binds to LDL-Receptors. Following Internalization, LDL is Degraded and the Receptor Recycled

Monoclonal Antibody binds to PCSK9 and inhibits Binding to the LDL-Receptor

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

Blocking PCSK9 Activity Inhibits Intracellular Degradation of LDL-R

PCSK9-Directed Therapies in DevelopmentCompany Drug Agent Indication Phase

Inhibition of PCSK9 binding to LDLR

Amgen Evolocumab Fully Human mAb Hypercholesterolemia 3

Sanofi/Regeneron Alirocumab Fully Human mAb Hypercholesterolemia 3

Pfizer/Rinat Neuroscience

Bococizumab mAb Hypercholesterolemia 3

Novartis LGT209 mAb Hypercholesterolemia 2

Roche/ Genentech RG7652 mAb Hypercholesterolemia 2

Eli-Lilly LY3015014 mAb Hypercholesterolemia 2

PCSK9 protein binding fragment

BMS/ Adnexus BMS-962476 Adnexins Hypercholesterolemia 1

Inhibition of PCSK9 synthesis (gene silencing)

Alnylam ALN-PCS02 siRNA oligonucleotides Hypercholesterolemia 2

Idera TBDAntisense

oligonucleotideHypercholesterolemia Preclinical

Inhibition of PCSK9 autocatalytic processing

Seometrix SX-PCK9 Small peptide mimetic Hypercholesterolemia Preclinical

Shifa Biomedical TBD Small molecule Metabolic Disorders Preclinical

Cadila Healthcare TBD Small molecule Preclinical

Adapted from Rhainds D, et al. Clin Lipidol. 2012;7:621-640.;Lambert G, et al. J Lipid Res. 2012;53:2515-24;clinicaltrials.gov; Stein EA. Swergold GR. Curr Atheroscler Rep. 2013:15:310.

mAb: monoclonal antibody; CVD: cardiovascular disease

Terminology of Monoclonal Antibodies

1. Weiner LM. J Immunother. 2006;29:1-9.; 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.; 3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125.; 4. Gerber DE. Am Fam Physician. 2008;77:311-319.

Mouse(0% human)

Human(100% human)

Humanized (> 90% human)

Chimeric (65% human)

-umab-zumab-ximab-omabGeneric suffix:

Source (% human protein)

High LowPotential for immunogenicity

Alirocumab: Phase II/III LDL-C Lowering Summary

*P<0.0001 vs. Placebo 1. Stein EA, et al. Presented at ACC 2014. Abstract 1183-126.2. McKenney JM, et al. J Am Coll Cardiol. 2012;59(25):2344-53.3. Roth EM, et al. Poster presentation at ACC 2014. Abstract 1183-125..

Placebo Alirocumab

0

-10

-20

-30

-40

-50

-60

-70LS

Me

an

% C

ha

ng

e in

LD

L-C

Le

vel

at

We

ek

8/1

2 L

OC

F

HeFH12 wk RCT+ 52 wk open-label extension

add-on therapy, Mean LDL-C 3.9 mmol/L

Open-label extension1

Placebon=15

Q2Wn=45

150 mg

-67.9%

Hypercholesterolemia12 weeks

N=88, add-on therapy, inclusion LDL-C ≥2.6 mmol/L

Dose Ranging

Q2W†

n=30Placebo

n=31

*

150 mg

Alirocumab was well tolerated with no evidence of any liver or creatine kinase elevations. Injection site bruising the most frequently reported adverse event.

Hypercholesterolemia24 weeks

N=103, monotherapyInclusion LDL-C 2.6-4.9 mmol/L

ODYSSEY MONO3

150 mg

Q2Wn=52

EZEn=51

Ezetimibe

10 mg

-47%

-16%

150 mg 100 mg 50 mg

Q2Wn=29

Q4Wn=30

Q4Wn=28

Q2Wn=31

-5.0%

200 mg 300 mg

-40.0%

-64%

-72%

-48%

-43%

*

*

*

* † LDL-C reductions with SAR236553 weresimilar among atorvastatin doses (10, 20, 40 mg)

-10.7%

Q2Wn=54

-59.5%

150 mg

Bococizumab: Efficacy as add-on therapy in hypercholesterolemia 24 week study

Phase 2 StudyHypercholesterolemiaN=354, add-on therapy,

inclusion LDL-C ≥2.1 mmol/L

LS Mean % Change in LDL-C Levelat Week 8/12 LOCF

0

-10

-20

-30

-40

-50

-60

-70

150 mg

Q2WQ2W

150 mg 150 mg

50 mg 100 mg 150 mg

Q2W Q4W

-34%

-45%

-53%

-28%

200 mg

-45%

300 mg

Q4W

Ballantyne CM, et al. Poster presentation at ACC 2014. Abstract 1183-129

• Incidence and profile of adverse events similar across groups.

Sabatine M et al. NEJM Mar 2015 online

Evolocumab: effect on LDL-C

LDL-C 3.1 mmol/L

LDL-C 1.24 mmol/L

Evolocumab: CVD reduction

Sabatine M et al. NEJM Mar 2015 online

Evolocumab: adverse events

Sabatine M et al. NEJM Mar 2015 online

Alirocumab: effect on LDL-C

Robinson J et al. NEJM Mar 2015 online

Alirocumab: CVD reduction

Robinson J et al. NEJM Mar 2015 online

Alirocumab: adverse events

Robinson J et al. NEJM Mar 2015 online

Four Mechanisms for Reducing LDL-C

Lilly SM, Rader DJ. Curr Opin Lipid. 2007;18:650–655.; Shinkai H. Vasc Health Risk Manag. 2012;8:323-331.

Proprietary. ©2014 Aegerion Pharmaceuticals, Inc. All Rights Reserved. Juxtapid is a trademark of Aegerion Pharmaceuticals, Inc. Licensed User Aegerion Pharmaceuticals (Canada) Ltd.

10

0

–10

–20

–30

–40

–50

–60

–70

Me

an

% c

ha

ng

e in

LD

L-C

(±9

5%

CI)

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

Lomitapide: LDL-C change from baseline

48

(Week 126 Completers Population)

APOB antisense: mipomersen in HoFH

Raal D et al. Lancet 2010; 375:998-1006.

CETP inhibition: effect on LDL-C

Kastelein J et al. Lancet 2015 75:998-1006.

CETP inhibition: effect on HDL-C

Kastelein J et al. Lancet 2015 75:998-1006.

Summary

- statins are good- LDL-C targets will remain in guidelines- second line drugs work – depends on context- novel Rx for LDL-C:

- PCSK9 inhibitors- lomitapide- APOB antisense- CETP inhibitors