lipids and beyond - amazon s3 · 2016-05-10 · lipids and beyond ? erik stroes, md academic...

PCSK-9 antibodies:Lipids and Beyond ?

Erik Stroes, MD Academic Medical Center

Amsterdam, The Netherlands

May 21st, 2016

Disclosures: Lecturing fees from

• Amgen, Sanofi, Merck, Chiesi, Novartis, Cerenis

No stocks

No patents

2

Outline

Best lipid target

Need for more LDL-c lowering

‘Study’ evidence

Competition

Lipoprotein Pathways for MI

Epidemiology Genetics Therapy

HDL-raising therapy

Common variants: no effect on MI

Rare variants: no effect on MI Failed

Plasma Level

TG

MI R

isk

Plasma Level

HDL

MI R

isk

LDLRPCSK9NPC1L1

StatinsPCSK9 AbsEzetimibe

Common variants: Yes

Rare variants: LPL, APOC3,

APOA5, ANGPTL4

?

Plasma Level

LDL

Courtesy S Katherisan

Lower lifetime LDL provides more protection than later LDL lowering

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

0

Lower LDL-C (mg/dL)

Prop

ortio

nal r

educ

tion

in C

HD

risk

(log

scal

e) 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 46Lrs11591147

GISSI-PA to Z

SEARCH

ALLHAT-LLT

LDLRrs6511720

NPC1L1 LDL-C scoreHMGCR LDL-C score

Genetically lower LDL-C

Pharmacologically lower LDL-C

IMPROVE-IT

Combined NPC1L1 & HMGCR LDL-C score

HMGCR LDL-C scoreNPC1L1 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

LDLRrs2228671

NPC1L1 rs217386

PCSK9 rs2479409

ABCG5/8rs4299376

HMGCR rs12916

PCSK9rs11206510

Outline

Best lipid target



Competition for LDL-c lowering

Need for additional 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

I. ESC guidelines: LDL-c target levels

Ray KK et al.

Eur Heart J 2014

I. After a CV event, 1:5 patients achieve LDL-C <70mg/dLdespite 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

210

10

20

30

40

50

60

70

80

90

100

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

Prev

alen

ce (%

)

II. Heterozygous Familial Hypercholesterolemia is a common disease

HeFH is characterised by:

Markedly elevated LDL-C levels from before birth1

Atherosclerotic plaque formation at an early age2–4

High incidence of MI and stroke2–5

HeFH is caused by mutations in genes involved in LDLR endocytic and recycling pathways1,6

LDLR (most common)

APOB and PCSK9

1. Nordestgaard et al. Eur Heart J 2013;34:3478–3490. 2. Versmissen et al. BMJ 2008;337:a2423. 3. Elis et al. Am J Cardiol 2011;108:223–226. 4. Raal et al. Circulation 2011;124:2022–2027. 5. Reiner et al. Eur Heart J 2011;32:1769–1818. 6. De Backer et al. Atherosclerosis 2015;241:169–175.

HeFH worldwide prevalence

14 to 34 million1

1:2001

Individuals are affected

II. Familial hypercholesterolaemia patients reach LDL-C threshold levels for CHD at an early age

Cuchel et al. Eur Heart J 2014;35:2146–2157.Nordestgaard et al. Eur Heart J 2013;34:3478–3490.

Without FH

55 years

12.5 years

35 years

Heterozygous FHHomozygous FH

0

Age in years

Cum

ulat

ive

LDL-

C (m

mol

) 200

150

100

50

0

Threshold for CHD

603 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

mmol/L

mg/dL

LDL-C

10

1315

390

500580

0

5

0

190

111

3444

61213

1943

71

0 20 40 60

MexicoBrazilChile

JapanCanada

USAOman

ItalyTaiwanFrance

Hong KongAustralia

South AfricaDenmarkSlovakiaBelgium

SpainUK

SwitzerlandIcelandNorway

Netherlands

Based onprevalence 1 in50021%

of HeHF patients achieved the LDL-C treatment goal of <2.5mmol/L1

II. HeFH is under-diagnosed and undertreated

In many countries

<10%of patients are

diagnosed2

1. Pijlman et al. Atherosclerosis 2010;209:189–194.2. Nordestgaard et al. Eur Heart J 2013;34:3478–3490.

<

Diagnosed FH (estimated) as % of estimated number in each country

0.40.40.41.21.61.61.62.4

4.85.2

7.617.2

28.40 20 40 60

MexicoBrazilChile

JapanCanada

USAOman

ItalyTaiwanFrance

Hong KongAustralia

South AfricaDenmarkSlovakiaBelgium

SpainUK

SwitzerlandIcelandNorway

Netherlands

Based onprevalence 1 in500Based onprevalence 1 in200

21%of HeHF patients achieved the LDL-C treatment goal of <2.5mmol/L1

II. HeFH is under-diagnosed and undertreated

In many countries

<10%of patients are

diagnosed2

1. Pijlman et al. Atherosclerosis 2010;209:189–194.2. Nordestgaard et al. Eur Heart J 2013;34:3478–3490.

Diagnosed FH (estimated) as % of estimated number in each country

II. FH and Cardiovascular risk

Nordestgaard, Eur Heart J 2013

III. Special populations ‐ Statin intoleranceDiscontinuation due to Statin‐Associated Side Effects

Observational studies: Most frequent: statin‐attributed muscle symptoms (SAMS)

Gastro‐intestinal discomfort

Fatigue

Peripheral neuropathy

Insomnia

Neurocognitive symptoms

Carter AA et al. BMJ. 2013;346:f2610; Mancini GB et al. Can J Cardiol. 2013;29(12):1553‐68; Richardson K et al. Ann Intern Med. 2013 Nov 19;159(10):688‐97

III. Muscle symptoms associated with statins are common in observational studies

Bruckert et al. Cardiovasc Drugs Ther 2005;19:403–414.

10.914.9

18.2

5.1

0

10

20

Pravastatin Atorvastatin Simvastatin Fluvastatin

Patie

nts

with

mus

cula

r sy

mpt

oms

(%)

PRIMO: 7,924 patients with hyperlipidaemia receiving high-dosage statin therapy

III. Statin intolerance may be less common than suggested by observational data

STOMP was powered to assess statin-associated muscle symptoms2

Trial details1 Myalgia1

Trial Total No. Agent Dose, mg Duration, yr Statin Placebo

4S 4,444 Simvastatin 20–40 5.4 3.7% 3.2%WOSCOPS 6,595

Pravastatin 404.9 3.5% 3.7%

PROSPER 5,804 3.2 1.2% 1.1%CARDS 2,838

Atorvastatin10

3.9 4.0% 4.8%ASPEN 2,410 4.0 3.0% 1.6%SPARCL 4,731 80 4.9 5.5% 6.0%JUPITER 17,802 Rosuvastatin 20 1.9 7.9% 6.9%

1. Newman et al. JAMA 2015;313:1011–1012. 2. Parker et al. Circulation 2013;127:96–103.

No imbalance

Trial details2 Myalgia2

Trial Total No. Agent Dose, mg Duration, yr Statin PlaceboSTOMP 440 Atorvastatin 80 0.5 19 10 P=0.05

III. Successful statin re-challengein vast majority

Blinded challenge1

361 patients intolerant to ≥ 2 statins

Randomized to ezetimibe, alirocumab, atorvastatin

Results:atorva challenge: 22% muscle symptoms 75% free of AE’sezetimibe challenge: 20% muscle symptoms 75% free of AE’salirocumab challenge: 16% muscle symptoms 82% free of AE’s

Statin rechallenge2

From 107.835 records – 18.778 statin-attributed AE (40% muscle s.)

From 11.124 discontinued – 6.579 rechallenged

Results:92% successfully used ‘a statin’ for > 12 months after rechallenge

1. Moriarty, AHA 2014; 2. Zheng, Ann Int Med 2013;

Exclude other causes of muscle symptoms and interactions

Statin rechallenge Continue statin

Establish highest tolerable statin dose:very low dose, different statin, more potent

statin, alternate day dosing

Add ezetimibe and option for PCSK9 inhibitor

2–4 weeks statin washout

III. Algorithm for treating patients with statin-associated muscle symptoms

Stroes et al. Eur Heart J 2015;36(17):1012–22.

No symptomsSymptoms recur

Not at recommended LDL-C

III. Statin discontinuation leads to 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.

Surv

ival

(%)

Years

Statin continued/daily doseStatin continued/non-daily doseStatin discontinued

Outline

Best lipid target


‘Study’ evidence for PCSK9 antibodies


LDLR

PCSK9

3. C-terminus2. Prodomain1. Catalytic domain

PCSK9

A serine proprotein convertase1

Expressed in hepatocytes, kidney mesenchymal cells, intestinal ileum and colon epithelia, CNS2

Regulates hepatic LDLRs, which bind and internalise LDL particles2

1. Abifadel et al. Hum Mutat 2009;30:520–529.2. Seidah et al. Proc Natl Acad Sci USA 2003;100:928–933.3. Horton et al. J Lipid Res 2009;50:S172–S177.

1

2

3

Plasma LDL-C is controlled by hepatic low density lipoprotein receptor (LDLR) levels

Brown et al. Proc Natl Acad Sci USA 1979;76:3330–3337.

Recycling of LDL-R

Increased LDL-R surface concentration

LDL particles

LDL-R

PCSK9 reduces LDLR recycling, thereby increasing plasma LDL-C

Horton et al. J Lipid Res 2009;50:S172–S177.

LDL particles

LDL-R

PCSK9 secretion

PCSK9 routes LDL-R for lysosomal degradation

LDL-R recycling blocked

Loss-of-function variants in PCSK9, with lifetime low LDL-C, are associated with a lower risk of CV events

Serum LDL-C

GeneticPCSK9 LDL-R

Yes

12

No

8

4CH

D(%

)

0

CHD

88%

P=0.008Plasma LDL-C in black subjects (mg/dL)

Cohen et al. N Engl J Med 2006;354;1264–1272.

30

20

10

(N=85)

50th percentile with no nonsense mutation

Freq

uenc

y (%

)

050 100 300150 200 250

Nonsense mutation

Nonsense mutation

PCSK9 is a new therapeutic targetType Compound Company

mAb

Evolocumab (Repatha®)AMG145 Amgen

Alirocumab (Praluent®)REGN7272/SAR236553 Sanofi/Regeneron

BococizumabRN-316/PF-04950615 Pfizer/Rinat

RG7652 (MPSK3169A) Roche/GenentechLY3015014 Eli Lilly

Adnectin Ad. BMS-962476 BMS-AdnexussiRNA ALN-PCS Alnylam Pharmaceuticals

Vaccine AFFITOPE AT04A+adjuvantAFFITOPE AT06A+adjuvant AFFiRiS AG

Small molecule – Shifa Biomedical Corp

Mimetic peptideEGF-A peptide Merck & Co.

Prodomain and C-terminal domain interaction disruption

School of Medicine, University of South Carolina, USA

Antibody-based therapeutics have a long history

www.nobelprize.org/nobel_prizes/medicine/laureates/1901/behring-article.html. Accessed 10 Jan 2016. www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ehrlich-bio.html. Accessed 10 Jan 2016.Zhou et al. Annu Rev Pharmacol Toxicol 2011;51:359–372. www.nobelprize.org/nobel_prizes/medicine/laureates/1972/. Accessed 10 Jan 2016.Caravella et al. Curr Comput Aided Drug Des 2010;6:128-138.www.nobelprize.org/nobel_prizes/medicine/laureates/1984/. Accessed 10 Jan 2016.Ecker et al. MAbs 2015;7:9–14.

1890 1901 1962 1984 19861908

Serum therapy used as treatment against diphtheria and tetanus

• Side-chain theory predicted substances todaycalled antibodies

• First idea of a "magic bullet"

Discovery of antibody chemical structure

Development of hybridoma technology

Production of first monoclonal antibody

César Milstein

Emil Adolf von Behring

Gerald Edelman

Rodney Porter

Paul Ehrlic

hGeorges Köhler

>40 Ab-based therapies approved in the EU

>300 in development

1972 1975

Nobel prizes

Discovery milestones

2015

0

Study Day28 56

0

50

500

100

300

400

200

14 70 8442

LDL-C

Mean C

hange (%)

0

150

350

450

250

Total evolocumab

Free PCSK9

LDL-C

Free

PC

SK9

conc

entr

atio

n (n

g/m

L)Fr

ee E

volo

cum

abco

ncen

trat

ion

(ng/

mL

x 0.

01)

Pharmacokinetics and pharmacodynamics of PCSK9-ab: changes in PCSK9 and LDL-C levels

in response to evolocumab

Stein EA , Annu. Rev. Med. 2014. 65:417–31.

160

140

120

100

80

60

40

20

0

Overview of the ODYSSEY Phase 3 Program (Alirocumab)

Fourteen global Phase 3 trials including >23,500 patients across >2000 study centers

ODYSSEY FH II (NCT01709500; CL1112)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=249; 18 months

HeFH population HC in high CV-risk population Additional populations

ODYSSEY HIGH FH (NCT01617655; EFC12732)LDL-C ≥160 mg/dL n=107; 18 months

ODYSSEY ALTERNATIVE (NCT01709513; CL1119)Patients with defined statin intoleranceLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=314; 6 months

ODYSSEY OPTIONS II (NCT01730053; CL1118)Patients not at goal on moderate-dose rosuvastatinLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=305; 6 months

ODYSSEY MONO (NCT01644474; EFC11716)Patients on no background LLTsLDL-C ≥100 mg/dLn=103; 6 months

ODYSSEY OPTIONS I (NCT01730040; CL1110)Patients not at goal on moderate-dose atorvastatinLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=355; 6 months

ODYSSEY COMBO I (NCT01644175; EFC11568)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=316; 12 months

ODYSSEY FH I (NCT01623115; EFC12492)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=486; 18 months

ODYSSEY LONG TERM (NCT01507831; LTS11717)LDL-C ≥70 mg/dL n=2341; 18 months

ODYSSEY OUTCOMES (NCT01663402; EFC11570)LDL-C ≥70 mg/dLn=18,000; 64 months

Add-on to max tolerated statin (± other LLT)

Add-on to max tolerated statin (± other LLT)

*ODYSSEY COMBO II (NCT01644188; EFC11569)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=720; 24 months

*For ODYSSEY COMBO II other LLT not allowed at entry

ODYSSEY CHOICE I (NCT01926782; CL1308)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=700; 12 months

ODYSSEY CHOICE II (NCT02023879; EFC13786)Patients not treated with a statinLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=200; 6 months

ODYSSEY OLE (NCT01954394; LTS 13463) Open-label study for FH from EFC 12492,CL 1112, EFC 12732 or LTS 11717n ≥1000; 30 months

FamilialHypercho-lesterolemia

High-risk ‘progressive’

CV-disease

Statinintolerance

Alirocumab

Alirocumab 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

Cal

cula

ted

LDL-

C, L

S m

ean

(SE)

, mg/

dL

Achieved LDL-C Over Time All patients on background of maximally tolerated statin ± other lipid-lowering therapy

Difference

−61.9%

0 4 8 12 16 24 36 52

Difference

−61.3%

Robinson J, N Engl J Med 2015

-62.1%-56.3%

-0.5%

7.0%

-70-60-50-40-30-20-10

01020

HeFHNon-HeFH

Alirocumab in Familial hypercholesterolemia

All patients on background of maximally tolerated statin± other lipid-lowering therapy

PlaceboAlirocumab

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

LS m

ean

(SE)

% c

hang

e fr

om

base

line

to W

eek

24

-62.3%

-52.3%

9.3%

-8.7%

-70

-60

-50

-40

-30

-20

-10

0

10

20

≥160 mg/dL<160 mg/dL

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

HeFH population by baseline LDL-C

20

0−10−20−30−40

−60−50

10

−70

Robinson J, N Engl J Med 2015

Alirocumab in statin-intolerance

Moriarty PM, et al. AHA 2014

Alirocumab*

0

-60

-50

-10

-40

-20

-30

LS M

ean

(SE)

% C

hang

e fr

om

Bas

elin

e to

Wee

k 24

LS Mean Difference (SE) vs Ezetimibe:-30.4 (3.1); P<0.0001

-14.6%

-45.0%

n=122n=126

% Change from Baseline to WK 24 in LDL-C(ITT, primary endpoint)

Ezetimibe

Alirocumab and safetySubanalysis in patients with LDLc < 25mg/dl

% of patientsAll pts on background of maximally tolerated statin ± other LLT

ALI (n=1550)

ALI with2 consecutive

LDL-C <25 mg/dL

(n=562, 37%)

PBO (n=788)

Nasopharyngitis 12.6 10.0 12.7

URTI 7.0 5.7 8.0

Injection-site reaction 5.7 3.6 3.4

Influenza 5.4 4.1 5.5

Diarrhea 5.3 3.9 5.1

Urinary tract infection 5.2 5.5 6.2

Bronchitis 5.2 5.2 4.7

Myalgia 4.9 3.0 3.0

Headache 4.8 1.8 5.6

Back pain 4.7 5.0 6.0

Arthralgia 4.5 3.2 6.0

Muscle spasms 3.7 2.8 3.2

Fatigue 3.0 3.0 3.8

Pain in extremity 3.0 2.1 4.4

Hypertension 3.5 2.0 3.4Robinson J, N Engl J Med 2015

Alirocumab and Incidence of Cardiovascular Events¶

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

0Time (weeks)

0

0.06

0.02

0.04

52 78 86

0.03

0.05

0.01

PlaceboAlirocumab*

Cum

ulat

ive

Prob

abili

ty o

f Eve

nt

6412 24 36

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

*27/1550

**26/7883.3%**

1.7%*

¶post-hoc analysis not specified in the study protocol

Combo-therapy

Statin-intolerant

Mono-therapy

HeFH

Long-term safety and

efficacyOpen-labelextension

HoFH

Phase 2(N = 168)

Phase 3(N = 300)

Phase 2(N = 629)

Phase 3(N = 1700)

Phase 2(N = 1400)

Phase 2/3(N ≤67)

Phase 2/3(N = 125)

Phase 2(N = 406)

Phase 3(N = 600)

Phase 3(N = 905)

Phase 3(N = 27,500)

Secondary

prevention Phase 3

(N = 950)

Phase 2(N = 157)

Phase 3(N = 300)

Athero

Phase 3(N ≥3500)

Phase 3(N = 500)

PROFICIO Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations

FamilialHypercho-lesterolemia

High ‘progressive’ CV-disease

Statinintolerance

Evolocumab in hyperlipidemic CV-patients DESCARTES

UC

LD

L-C

per

cent

cha

nge

from

bas

elin

e, m

ean

(±SE

)

Baseline Week 12 Week 52

-80-70-60-50-40-30-20-10

01020

Number of patients:

Study week

599 582 542302 294 264

Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599)

-50.1%

6.8%

Treatment difference57%

Blom et al. N Engl J Med 2014;370:1809–19

Evolocumab in statin intoleranceGAUSS3

511 patients with a history of intolerance to multiple statins due to muscle-related adverse effects

Atorvastatin 20 mg Placebo

PlaceboAtorvastatin 20 mg

Participants entered Phase B only if they had muscle symptoms on atorvastatin, but not placebo, or CK ≥ 10 x ULN during statin

treatment

PhaseA

PhaseB

Daily oral ezetimibe 10 mgMonthly SC evolocumab 420 mg

2 1

10 weeks

10 weeks

24 weeks

Nissen S, Stroes E, et al. JAMA 2016

Baseline Characteristics

Characteristic Phase A(n=491)

Phase B (n=218)Ezetimibe

(n=73)Evolocumab (n=145)

Age (years) 61 59 59

Male Gender 50% 47% 54%

Coronary Heart Disease 35% 29% 33%

NCEP-ATP III High Risk 63% 52% 58%

Intolerance to ≥ 3 statins 82% 82% 82%

Total Cholesterol (mg/dL) 301 308 307

LDL-C (mg/dL) 212 222 219

HDL-C (mg/dL) 51 50 50Nissen S, Stroes E, et al. JAMA 2016

Phase A: Study Drug Discontinuation Events

Intolerable Muscle Symptoms N = 491

On atorvastatin, but not placebo 209 (42.6%)*

On placebo, but not atorvastatin 130 (26.5%)

On both placebo and atorvastatin 48 (9.8%)

No symptoms on either treatment 85 (17.3%)

Did not complete Phase A 20/511

Bypassed Phase A due to CK elevation≥ 10 x ULN 19 (3.9%)*


LDL-C Values Over Time During Phase BLDL-C Values Over Time During Phase B

-70

-60

-50

-40

-30

-20

-10

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Perc

ent C

hang

e in

LD

L-C

(%)

Weeks Following Randomization in Phase B

Ezetimibe

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

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


Achievement of Common LDL-C Target LevelsAchievement of Common LDL-C Target Levels

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

1.4%

29.9%

0%

20%

40%

60%

80%

100%

Ezetimibe Evolocumab

Perc

ent o

f Pat

ient

s (%

)

1.8%

64.1%

0%

20%

40%

60%

80%

100%

Ezetimibe Evolocumab

Perc

ent o

f Pat

ient

s (%

)


Conclusion

GAUSS-3 demonstrates that muscle-related intolerance is reproducible during blinded statin rechallenge in more than 40% of patients with a history of symptoms

Development of alternative approaches to LDL-C reduction for these patients is an important medical priority

Evolocumab and safetyOSLER

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)

<40mg/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

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

Evolocumab and Cardiovascular Events¶

OSLER

0

1

2

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

HR 0.4795% CI 0.28-0.78P=0.003

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

3

Days since Randomization

Cum

ulat

ive

Inci

denc

e (%

)

Evolocumab plus standard of care(N=2976)

Standard of care alone(N=1489)

0.95%*

2.18%**

*29/2976

**31/1489

¶CVD clinical outcomes (prespecified, exploratory): adjudicated by TIMI Study Group CEC, blinded to treatmentIncluded death, myocardial infarction, unstable angina requiring hospitalization, revascularization, stroke or transient ischemic attack and Heart failure requiring hospitalization

Evolocumab Alirocumab Bococizumab

Sponsor Amgen Sanofi / Regeneron Pfizer

Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II

Sample size 27,500 18,000 17,000 9,000

Patients MI, stroke or PAD 4-52 wks post-ACS High risk of CV event

Statin Atorva ≥20 mg or equiv Evid-based med Rx Lipid-lowering RxLDL-C

mg/dL(mmol/L) ≥70 (≥1.8) ≥70 (≥1.8) 70-99 (1.8-2.6) ≥100 (≥2.6)

PCSK9i Dosing Q2W or Q4W Q2W Q2W

Endpoint 1: CV death, MI, stroke, revasc or hosp for UA,

Key 2: CV death, MI, or stroke

CHD death, MI, ischemic stroke, or hospfor UA

CV death, MI, stroke, or urgent revasc

Recruitment Status Completed June 2015 Projected for Dec 2015 ?

Completion Q4 /2016 Q3 /2017 ? /2017

PCSK9 Inhibitor CVD Outcomes Trials

www.clinicaltrials.gov

Outline

Best lipid target




The competitive landscape for LDLc lowering

• Apo B mRNA antisense

• Microsomal Triglyceride Transfer Protein inhibitors

• Cholesteryl-ester transfer protein inhibitors

ApoB antisense reduces LDL-c in patients with statin intolerance

–2%

–47%

Akdim, Stroes, Eur H J 2012

Safety and tolerability issuesfor apoB antisense

Injection site reactions (target-independent)

Hepatic steatosis (target-dependent)

Heterogeneity of response (target-dependent)

the competitive landscape of LDLc lowering

• Apo B mRNA antisense drugs



Efficacy and safety of lomitapide in HoFH open-label phase 3 study (n=29)

Dose escalation biweekly: 5–60 mg

LDL-C 50%, ApoB 49%, TC 45% (23/29 completer population)

Change in LDL-C (%) Percentage of hepatic fat in the liver

Mean (98% CI)0 42 6 8 10 12 14 16 18 20 22 24 26

20

0

–20

–40

–60

–80

–100

Study week

LDL-CTCApoB

Baseline Week 26 Week 56 Week 78

25

20

15

10

5

0

Study week

Hep

atic

fat (

%)

Mea

n (

SD) %

ch

ange

from

bas

elin

e

Cuchel M et al. Lancet 2013; 381: 40–6.

Safety and tolerability issuesfor MTP-inhibition using Lomitapide

Gastrointestinal complaints Reported by 27 (93%) of 29 patients Decreased by maintaining strict fat-restriction

Transaminase elevations 10 (34%) of 29 patients had elevation in ALT/ AST ≥3x ULN

Hepatic fat 18 (78%) of patients exhibited increase in hepatic fat > 5%

3 (13%) of patients exhibited increase in hepatic fat >20%

The competitive landscape of LDLc lowering

• Apo B mRNA antisense drugs



CETP inhibition by Anacetrapib lowers LDL-cin patients with Heterozygous FH

Kastelein JJ et al. Lancet 2015Kastelein JJ et al. Lancet 2015

Mea

n %

cha

nge

from

bas

elin

e

ACCELERATEEvacetrapib reduces LDLc by 37%

55Nicchols S, ACC 2016

ACCELERATEEvacetrapib does not reduce CV-events

56Nicchols S, ACC 2016

There is a need for additional LDL-c lowering therapies getting to targetFamilial hypercholesterolemiaStatin intolerance

PCSK9-antibodies lower LDLcPotently and prolongedFew side effectsBeneficial CV-signal in post-hoc analyses

Other options less attractive due toSide effects: ISRs, liver fat, gastro-intestinal, … Lack of potency

Summary: PCSK9 antibodies: Lipids and beyond

Take Home

LDL-c lowering is currently best target in CV therapy

Statin/ezetimibe is always number ‘1’ option

PCSK9-antibodies offer potent and safe LDLc loweringin patient groups currently facing residual LDLc-burden

Keeping CVD-therapy affordable necessitates restricteduse of PCSK9-ab in selected patient groups:Fam hypercholesterolemia, statin-intolerance and …very high CV risk with residual LDLc burden

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lipids and beyond - amazon s3 · 2016-05-10 · lipids and beyond ? erik stroes, md academic...

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