Treatment of severe Familial Hypercholesterolemia

PCSK9 inhibitors

Dr. Khalid Al-Waili, MD, FRCPC, DABCL

Senior Consultant Medical Biochemist & Lipidologist

Sultan Qaboos University Hospital

Identifying and Treating Severe Familial Hypercholesterolemia

October 14-15, 2017

Dubai, UAE

Disclosure

• Honoraria for consulting, research and

speaker activities from:

– Astra Zeneca, Pfizer, Sanofi/Regeneron.

Cardiovascular Disease (CVD) remains the biggest killer

worldwide

Reducing levels of low-density lipoprotein (LDL) cholesterol is

a cornerstone of the prevention of CVD.

Despite the proven efficacy of statins in lowering CV events,

many patients fail to reach recommended LDL-C goals

Background

Putting Into Perspective the Hazards of Untreated Familial Hypercholesterolemia

Paul N. Hopkins, J Am Heart Assoc. 2017;6:e006553

Focus on treatment of blood cholesterol to reduce ASCVD risk

in adults

No LDL-C (and non–HDL-C) treatment goals

Statin centric

Identification of 4 patient groups most likely to benefit from

statin therapy

2013 ACC/AHA Guideline on the

Treatment of Blood Cholesterol

ACC=American College of Cardiology; AHA=American Heart Association; ASCVD=arteriosclerotic cardiovascular disease;

HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol.

Stone NJ et al. Circulation. 2013; doi:10.1161/01.cir.0000437738.63853.7a/-/DC1.

2013 ACC/AHA Guideline on the Treatment of

Blood Cholesterol

Clinical ASCVD

LDL > 190 mg/dL

DM 1 or 2 and age 40-

75

ASCVD 10 y risk > 7.5 %

and age 40-75

High intensity statin

unless > 75 years old or

intolerant

High intensity statin

unless intolerant

High intensity statin

unless 10 year ASCVD <

7.5 %

Moderate to high

intensity statin

The Actual Evidence

At that time Statin drugs are the only class with actual mortality and morbidity

benefits studied in randomized controlled trials

No RCT evidence that adjuncts to statin therapy add clinical benefit

Actually evidence to the contrary:

AIM HIGH: niacin added to statin when LDL < 80 mg/dL provides no benefit

ACCORD: adding fenofibrate to statin in patients with DM provides no

benefit

Focus Shift from LDL lowering to mortality and morbidity benefit

No evidence for target LDL levels in terms of ASCVD event risk reduction

High intensity statin therapy ( > 50 % LDL reduction) provides more clinical

benefit than moderate intensity therapy ( 30-50 % LDL reduction)

Are Statins Enough?

Statins are effective, potent, inexpensive and

generally well tolerated

Residual Risk

Achieving LDL-c target with Statins

Wiviott SD et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005 Oct 18;46(8):1411-6

0.10.51.7

8.2

15.2

19.218

13.3

8.3

5.6

3.22.11.4

3.2

0

5

10

15

20

25

Pe

rce

nt

(%)

of

sub

ject

s

Achieved LDL (mg/dL)

Residual Risk

Major lipid trials

Is a low LDL better and is a low LDL-C safe ?

How low is too low LDL-c?

Persons born with defective PCSK9 gene have very low LDL

They are protected from CVD

No depression

No cognitive abnormalities

They are generally healthy

They have LDL-c <30mg/dL

Have no particular side effects

Appear to benefit from low LDL-c

Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C

and Low Prevalence of CHD Events

Adapted from Cohen JC. N Engl J Med 2006;354:1264-72 ARIC=Atherosclerosis Risk in the Community

30

20

10

09.7%

PCSK9142x or PCSK9679X

No Yes

12

8

4

0

0 50 100 150 200 250 300

30

20

10

00 50 100 150 200 250 300

No Nonsense Mutation

(N = 3278)50th Percentile

Plasma LDL Cholesterol in Black Subjects (mg/dL)

Fre

quency (

%)

1.2%

PCSK9142x or PCSK9679X

(N=85)

Coro

nary

Heart

Dis

ease (

%)

Mean 138 mg/dL

Mean 100 mg/dL

(-28%)

88% reduction in the risk of CHD

events during 15-year follow-up

The Role of PCSK9 in the Regulation

of LDL Receptor Expression

1) Tibolla G et al. Nutr Metab Cardiovasc Dis 2011;21:835-43.2) Akram ON et al. Arterioscler Thromb VascBiol 2010;30:1279-81.3) Duff CJ et al. Expert Opin Ther Targets 2011;15:157-68.4) Horton JD et al. J Lipid Res 2009;50 Suppl:S172-7.5) Cariou B et al. Atherosclerosis 2011;216:258-65.

Impact of a PCSK9 mAb on LDL Receptor Expression

1) Tibolla G et al. Nutr Metab Cardiovasc Dis 2011;21:835-43.2) Akram ON et al. Arterioscler Thromb VascBiol 2010;30:1279-81.3) Duff CJ et al. Expert Opin Ther Targets 2011;15:157-68.4) Horton JD et al. J Lipid Res 2009;50 Suppl:S172-7.5) Cariou B et al. Atherosclerosis 2011;216:258-65.

McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353

McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353

McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353

>70% decrease in LDL-C and 90-100% of patients reach predefined levels with150 mg Q2W + 80 mg atorvastatin

SAR236553 + atorva 80 mg resulted in 73% reduction in mean LDL-C vs 17% for atorva 80 mg onlySAR236553 + stable dose of atorva 10 mg resulted in 66% LDL-C reductionSAR236553 was generally well tolerated

% of LDL-C change % of patients at predefined LDL-C target

• p<0.0001 vs Placebo + A80

-80

-60

-40

-20

0

Baseline Week 2 Week 4 Week 6 Week 8 LOCF

-17.3%

66.2%

-73.2%

Placebo + Atorvastatin 80 mg

SAR236553 150 mg Q2W + atorvastatin 10 mg (N=29)

SAR236553 150 mg Q2W + atorvastatin 80 mg (N=30)

Mean P

erc

ent C

han

ge in

LD

L-C

51.7

17.2

100 96.6100

90

0

20

40

60

80

100

120

LDL-C <100 mg/dL LDL-C <70 mg/dL

Placebo + A80 SAR236553 + A10 SAR236553 + A80

**

Most heFH Patients Receiving Alirocumab on Background Statin Other LLT

Achieved LDL-C Goals

72.2%

81.4%

2.4%

11.3%

0

10

20

30

40

50

60

70

80

90

P<0.0001

% p

atie

nts

Placebo

†Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy.

Proportion of patients reaching LDL-C goal† at Week 24

FH I FH II

Alirocumab

Intent-to-treat (ITT) Analysis

Most of These High CV-Risk Patients Receiving Alirocumab

on Background Statin Achieved LDL-C Goal

Proportion of Patients Reaching LDL-C <1.8 mmol/L (70 mg/dL) at Week 24All patients on background of maximally-tolerated statin

% p

atie

nts

77.0%

45.6%

0

10

20

30

40

50

60

70

80

90

P<0.0001Intent-to-treat (ITT) analysis

Ezetimibe

Alirocumab

Who Needs Benefit?

Very High LDL-C levels FH

Insufficient effects from statins

Statin side effects

Progression of Atherosclerosis

Alirocumab in Patients with Heterozygous

Familial Hypercholesterolemia Undergoing

Lipoprotein Apheresis: the ODYSSEY

ESCAPE Trial

Patrick M. Moriarty,1† Klaus G. Parhofer,2† Stephan P. Babirak,3 Marc-Andre Cornier,4

P. Barton Duell,5 Bernd Hohenstein,6 Josef Leebmann,7 Wolfgang Ramlow,8 Volker

Schettler,9 Vinaya Simha,10 Elisabeth Steinhagen-Thiessen,11 Paul D. Thompson,12

Anja Vogt,13 Berndt von Stritzky,14 Yunling Du,15 Garen Manvelian16

1Department of Internal Medicine, Division of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA; 2Medical Department II - Grosshadern, University of Munich, Munich, Germany; 3Metabolic Leader, LLC, Scarborough, MA, USA; 4Division

of Endocrinology, Metabolism, and Diabetes, Anschutz Health and Wellness Centre, Anschutz Medical Campus, Aurora, CO, USA; 5Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA; 6Extracorporeal Treatment and Lipoprotein

Apheresis Center, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden,

Germany; 7Apherese Zentrum Passau, Passau, Germany; 8Apheresis Center Rostock, Rostock, Germany; 9Apheresis centre,

Nehologisches Zentrum Göttingen GbR, Göttingen, Germany; 10Mayo Clinic, Rochester, MN, USA; 11Charite, Universitätsmedizin Berlin-

Campus Virchow-Klinikum, Berlin, Germany; 12Cardiology, Hartford Hospital, Hartford, CT, USA; 13Medizinische Klinik und Poliklinik IV,

LMU Klinikum der Universität München, Munich, Germany; 14Medical Department, Sanofi-Aventis Deutschland GmbH, Berlin, Germany; 15Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 16Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.†These joint authors contributed equally to this manuscript

Moriarty PM et al. Eur Heart J. 2016 (in press).

Key Inclusion Criteria

Diagnosis of HeFH by genotyping or clinical criteria (Simon Broome criteria or the WHO/Dutch

Lipid Network criteria)

Stable lipoprotein apheresis QW for ≥4 weeks or Q2W for ≥8 weeks

Background LLT, diet and exercise level stable for ≥8 weeks

Lipoprotein apheresis techniques: double membrane filtration, immunoadsorption, heparin-

induced LDL precipitation, direct adsorption of lipids, dextran sulfate adsorption (plasma) and

dextran sulfate adsorption (whole blood)

Key Exclusion Criteria

Diagnosis of homozygous FH

Lipoprotein apheresis schedule other than QW and Q2W

Key Inclusion and Exclusion Criteria

2

5

Moriarty PM et al. Eur Heart J. 2016 (in press).

WHO, World Health Oranisation.

Pre-apheresis LDL-C Over Time

Raw mean values are provided for baseline. SE, standard error.

26

Moriarty PM et al. Eur Heart J. 2016 (in press).

0

20

40

60

80

100

120

140

160

180

200

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

0 2 4 6 8 10 12 14 16 18

mg

/dL

Ave

rag

e L

DL

-C v

alu

e

(pre

-ap

here

sis

), m

ea

n (

SE

), m

mo

l/L

Week

Alirocumab 150 mg Q2W (n=41)

Placebo (n=21)

Apheresis rate varied from Week 7 onwards

192

mg/dL

175

mg/dL

185

mg/dL

90

mg/dL

110

mg/dL

191

mg/dL

LDL-C % change from baseline, LS mean (SE), %:

Week 6

Week 18

Alirocumab

-53.7 (2.3)

-42.5 (4.7)

Placebo

1.6 (3.1)

3.9 (6.3)

p-value versus placebo

<0.0001

<0.0001

Time-Averaged Cholesterol Concentrations†

(Kroon Formula1)

†Time-averaged concentrations are widely regarded to provide the best estimate of the physiologically effective plasma cholesterol concentrations

during long-term treatment with lipoprotein apheresis. Data labels are expressed in both measurements.1Kroon AA et al. Atherosclerosis. 2000;152:519–526.

0

50

100

150

200

250

0

1

2

3

4

5

6

7

8–10 10–12 12–14 14–16 16–18

mg

/dL

Ave

rag

e L

DL

-C v

alu

e (

inte

rva

l), m

ea

n,

mm

ol/L

Interval (weeks)

Alirocumab 150 mg Q2W (n=41)

Placebo (n=21)

Moriarty PM et al. Eur Heart J. 2016 (in press).

27

166.0 174.7 172.6165.0

175.2

94.395.296.398.192.1

Standardized Apheresis Treatment

Rates from Week 7–18

63.4

17.112.2

2.4 2.4 2.40 0

14.3

23.8

33.328.6

0

20

40

60

80

100

0 >0 and ≤25% >25% to ≤50% >50% to ≤75% >75% to <100% 100%

% o

f p

ati

en

ts

Standardized Apheresis Rate from Week 7 to Week 18†

Alirocumab 150 mg Q2W (n=41) Placebo (n=21)

†An apheresis rate of 0 indicates that the patient skipped all planned aphereses and an apheresis rate of 1 indicates that the patient received all planned aphereses;

between Week 7 and Week 18 (apheresis rate of 0.75:, the patient received 75% of planned aphereses).

Moriarty PM et al. Eur Heart J. 2016 (in press).

2

8

Sabatine MS, et al. N Engl J Med. 2017 Mar 17. [Epub ahead of print]

Study Design

LDL-C Levels

LDL CholesterolEvolocuma

bPlacebo

≤ 70 mg/dL 87% 18%

≤ 40 mg/dL 67% 0.5%

≤ 25 mg/dL 42% < 0.1%

Primary Endpoint

Key Secondary Efficacy Endpoint

Safety: Adverse Events

Study Conclusions

When added to statin therapy, evolocumab lowered LDL

cholesterol levels by 59% from baseline compared to placebo,

from a median of 92 mg/dL to 30 mg/dL

risk of the primary composite endpoint by 15% and risk of

the key secondary endpoint by 20%

Magnitude of risk reduction shown to increase over time

No effect of additional LDL-C lowering on cardiovascular death

or all-cause mortality

Injection-site reactions were significantly higher in the

evolocumab group compared to the placebo group

ODYSSEY Outcome Trial

Recommended Use of PCSK9I’s

Based on current guidelines, available evidence, and economic

considerations:

Patients with FH or ASCVD and statin resistance (on max dose) for

additional LDL lowering is a reasonable strategy.

Discuss with patient costs vs clinical benefit

In FH patients to avoid apheresis

2nd line to addition of ezetimibe for statin intolerant patients

No evidence to support use of PCSK9I’s as monotherapy or for arbitrary

reduction of statin dose

In complete statin intolerance, PCSK9I monotherapy should be

considered only after careful risk assessment and patient preference

Questions ?

39