Are PCSK 9 Inhibitors

Poised for Breakthrough? A Perspective Based on the Most

Recent Information

Robert P Giugliano, MD, SM, FACC, FAHA

Senior Investigator, TIMI Study Group

Physician, CV Medicine, Brigham and Women’s Hospital

Associate Professor of Medicine, Harvard Medical School

PCSK9: Proprotein convertase subtilisin/kexin type 9

Proprotein Convertases (PCs) are proteolytic enzymes that

activate precursor proteins into biologically active forms

• PCSK9 : plays an important role in

degradation of the LDL-receptor (LDL-R)

• A circulating protein that binds the LDL-R and is

cleared via this mechanism

• It can bind other proteins (annexin, resistin, etc)

• May target other lipoprotein receptors

• It is up-regulated by statins, ezetimibe, and insulin

• It is down-regulated by fasting

Abifadel M, et al. Curr Atheroscler Rep (2014) 16:439

Discovery of PCSK9 as a Regulator of

Cholesterol Homeostasis

Family HC92 Pedigree

Affected family members with:

• Total chol in 90th percentile

• Tendon xanthomas

• CHD, Early MI

• Stroke

Gain-of-function mutations in PCSK9 cause

autosomal dominant hypercholesterolemia (ADH)

Abifadel M, et al. Nature Genet. 34: 154-156, 2003.

Loss-of-Function PCSK9 Mutations in Blacks Are Associated

with Low LDL-C and Low Prevalence of CHD Events

Adapted from Cohen JC. N Engl J Med 2006;354:1264-72

30

20

10

0

PCSK9142x or PCSK9679X

No Yes

12

8

4

0

0 50 100 150 200 250 300

30

20

10

0 0 50 100 150 200 250 300

No Nonsense Mutation

(N = 3278) 50th Percentile

Plasma LDL Cholesterol in Black Subjects (mg/dL)

Fre

qu

en

cy (

%)

PCSK9142x or PCSK9679X

(N=85)

Co

ron

ary

He

art

Dis

ea

se

(%

)

Mean 113 mg/dL

Mean 100 mg/dL

(-28%)

88% reduction in risk of CHD

during 15-year follow-up

4

PCSK9-Directed Therapies in Development Company Drug Agent Indication Phase

Sanofi/Regeneron Alirocumab

(SAR 2236553/REGN727)

Fully Human IgG1 monoclonal antibody

Hypercholesterolemia 3

Amgen Evolocumab (AMG 145)

Fully Human IgG1 monoclonal antibody

Hypercholesterolemia 3

Pfizer/Rinat Bococizumab

(RN316) Humanized IgG1

Monoclonal antibody Hypercholesterolemia 3

Novartis LGT-209 Monoclonal antibody Hypercholesterolemia 2

Eli Lilly LY3015014 Monoclonal antibody Hypercholesterolemia 2

Roche/Genentech RG7652, MPSK3169A, Monoclonal antibody Hypercholesterolemia 2

Alnylam Pharma ALN-PCS02 siRNA oligonucleotide Hypercholesterolemia 1

Adnexus Therapeutics / Bristol-Myers Squibb

BMS-962476 Fusion protein using Adnectin technology

Cardiovascular disease

Preclinical

Idera Pharmaceuticals TBD Antisense oligonucleotide Hypercholesterolemia Preclinical

Serometrix SX-PCK9 Small peptide mimetic;

LDLR antagonist Hypercholesterolemia Preclinical

Shifa Biomedical Corp. TBD Small molecule PCSK9

modulator Metabolic disorders Preclinical

Adapted from Sheridan C, et al. Biotechnology. 2013;V31:1058.

Alirocumab: Dynamic Relationship

Between mAb Levels, PCSK9 and LDL-C

-70

-60

-50

-40

-30

-20

-10

0

0

20

40

60

80

100

120

140

160

180

200

0 500 1000 1500 2000 2500

LDL-

-C m

ean

% c

han

ge

Fre

e/T

ota

l PC

SK9

Co

nc.

(n

g/m

L)

Tota

l Alir

ocu

mab

(n

g/m

L) X

0.0

1

Time (hours)

Free PCSK9, Total Alirocumab Concentration and Mean % Change LDL-C vs Time

free PCSK9 LDL-cTotal Alirocumab

Swergold G et al. Circulation. 2011;124:A16265.

Alirocumab: First in Man LDL-C Dose Response Atorvastatin Combo-Rx, HeFH & Non-FH Combined and Diet Control

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

1 15 29 43 57 71 85 99 113 127 141 155

Mean P

erc

ent

Change f

rom

B

aselin

e in C

alc

LD

Lc (

%)

Study Days

Combined placebo Combined 150mg Diet placebo Diet 150mg

Mean % Change from Baseline

Swergold G et al. Circulation. 2011;124:A16265.

= Dose administered

PCSK9-010813004

Alirocumab Phase 2 Data:

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

8

*Alirocumab=SAR236553/REGN727

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

Primary Endpoint: Evolocumab Reduced LDL-C at 12 wks

LDL-C measured

using

ultracentrifugation 70 mg

N = 79

105 mg

N = 79

140 mg

N = 78

280 mg

N = 79

350 mg

N = 79

420 mg

N = 80

Evolocumab Q2W Evolocumab Q4W

* p < 0.0001 for each dose vs placebo

LDL-C at 12 wks Mean (mg/dL) (SD)

73 (25)

53 (21)

44 (25)

69 (28)

60 (23)

58 (26)

Giugliano RP et al. Lancet 2012;380:2007-17.

Bococizumab (Phase 2 Data)

Ballantyne CM et al. JACC 2014:63:A1374 (abstr)

• 351 pts with HC treated for 24 weeks

• LDL-C > 80 mg/dL on statin

• Double-blind, placebo-controlled, SC injections 3 doses Boco v pbo q2W; 3 doses Boco vs pbo q4W

• Dose reduced if LDL-C < 25 mg/dL

Boco 50

mg q2W

(n=50)

Boco 100

mg q2W

(n=51)

Boco 150

mg q2W

(n=49)

Boco200

mg q4W

(n=50)

Boco 300

mg q4W

(n=51)

Baseline

LDL-C (mg/dL)

108 113 106 106 105

Dose-reduced 0 16% 35% 44% 39%

LDL-C (mg/dL)

at week 12

-35 -52 -54 -21 -38

% change v. placebo -34% -45% -53% -28% -45%

AE -> D/C (n) 1 0 4 0 2

Monoclonal Antibodies to PCSK9 Markedly

Lower LDL-C in a Variety of Patients

1. Background of low or high dose statin

2. As monotherapy

3. Statin intolerant patients

4. Heterozygous FH

5. Homozygous FH (most variants)

6. Long-term (>1 year)

Aliro Evolo

√ √

√ √

√ √

√ √

√ √

P √

√ √

Changes in Other Lipids with

Top 2 Evolocumab Doses

P < 0.0001 versus placebo for all parameters

Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error

-43%

-33%

-61%

-48% -44%

-32%

-48%

-36%

-56%

-42%

-53%

-43%

Giugliano RP et al. Lancet 2012:380:2007-17.

Results: Mean % Change in Lp(a)

at Week 12: Evolocumab v. Placebo

P<0.001 for each dose v. placebo

P<0.001 for each

dose v. placebo

Me

an

% C

ha

nge

in

Lp

(a)

at

We

ek

12

Co

mp

are

d t

o P

lace

bo

Evolocumab Q2W Evolocumab Q4W

Achieved Lp(a) at

week 12, nmol/L,

median (IQR)

30.0

(9-116)

27.0

(7-148)

29.0

(7-97)

21.5

(7-125)

17.0

(7-155)

40.0

(9-167)

Desai NR et al. Circulation 2013; 128: 962-969

Safety: Evolocumab (DESCARTES)

Blom DJ et al. NEJM 2014:370:1809-19

15

Safety: Alirocumab (ODYSSEY LONG-TERM)

% (n) of patients All pts on background of maximally tolerated statin

± other lipid-lowering therapy

Alirocumab

(n=1550)

Alirocumab with

2 consecutive

LDL-C <25 mg/dL

(n=562)

Placebo

(n=788)

General allergic reaction events* 9.0% (140) 6.0% (34) 9.0% (71)

Treatment-emergent local injection site

reactions 5.8% (90) 3.7% (21) 4.3% (34)

Neurological events‡ 4.2% (65) 1.8% (10) 3.9% (31)

All cardiovascular events (adjudicated) 4.0% (62) 3.2% (18) 4.4% (35)

Ophthalmological events‡ 2.5% (38) 1.8% (10) 1.9% (15)

Neurocognitive disorders‡ 1.2% (18) 0.5% (3) 0.5% (4)

Haemolytic anaemia 0 0 0

* 1 alirocumab-treated patient diagnosed with Miller Fisher Syndrome at week 27 after typical prodromal

gastroenteritis, he had a complete recovery following treatment discontinuation; at week 24 the patient

had low LDL-C, reaching 1.5 mg/dL.

‡Company MedDRA Queries (CMQ).

Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients overall who completed W78 visit)

Robinson J, AHA 2014, Chicago (Preliminary Results)

Robinson J, AHA 2014, Chicago (Preliminary Results)

1174

2318

1160

2294

1098

2171

1057

2087

1026

2030

862

1713

349

698

127

252

84 72 60 48 36 24 12 0

0.06

0.05

0.03

0.02

0.01

0.00

0.04

16

Post-hoc Adjudicated Cardiovascular TEAEs†

Pooled from Phase 3 Placebo-controlled Trials C

um

ula

tive p

rob

ab

ilit

y o

f even

t Placebo + max-tolerated statin ± other LLT

Alirocumab + max-tolerated statin ± other LLT

Cox model analysis:

HR=0.65 (95% CI: 0.40 to 1.08)

Nominal p-value = 0.0985

Weeks No. at Risk

Placebo

Alirocumab

†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and

non-fatal ischemic stroke, Unstable angina requiring hospitalization. LLT, lipid-lowering therapy

Mean baseline LDL-C (mg/dL):

Alirocumab:126.0 to 129.1; placebo, 125.4 to 129.9

Mean percent change in LDL-C from baseline to W24:

Alirocumab, 48.6 to 60.4%; placebo, 4.3 to 0.5%

Mean on-treatment LDL-C difference: 70.5 to 72.6 mg/dL

Post-Hoc Analysis of CV Events with Alirocumab ODYSSEY LONG-TERM: 5 Phase 3 RCT (N=3549)

Robinson J, AHA 2014, Chicago (Preliminary Results)

ODYSSEY OUTCOMES Evaluation of Alirocumab After ACS

Population

• 18,000 pts 4–52 wks post-ACS

• Age > 40 years

LDL-C at Entry

• ≥70 mg/dL (1.81 mmol/L)

• On evidence-based medical Rx

Primary Endpoint

• Composite of

– CHD death

– Non-fatal MI

– Ischemic stroke

– High-risk UA hospitalization

Q2W=every other week; SC=subcutaneous; TLC=therapeutic lifestyle changes; UA=unstable angina.

*75 mg SC Q2W with titration (as necessary) to 150 mg SC Q2W, if LDL-C ≥50 mg/dL (1.29 mmol/L).

ClinicalTrials.gov. ODYSSEY OUTCOMES Study. http://clinicaltrials.gov/ct2/show/NCT01663402. Accessed December 2, 2014

Double-Blind Treatment Period (64 Weeks)

n=9000

n=9000

R

Placebo SC

Run-in

Screening

visit

Injection

training

visit

NCEP-ATPIII TLC diet or equivalent

Alirocumab SC*

Patients on maximum tolerated potent statins

atorvastatin 40–80 mg or rosuvastatin 20–40 mg

17 www.clinicaltrials.gov NCT 01663402, Accessed Dec 6, 2014

Evolocumab SC 140 mg Q2W or 420 mg QM

~11,250 Subjects

Placebo Q2W or QM

~11,250 Subjects

LDL-C

≥ 70 mg/dL

or

non-HDL-C

≥ 100 mg/dL

F/U

ave

rag

e 4

yrs

Screening, Placebo Run-in,

And Lipid Stabilization

Period

4 weeks stable on

Study-provided atorvastatin

(80 mg or max tolerated)

Ezetimibe can be added if

atorvastatin dose is maximal

FOURIER: CV Outcomes Trial of Evolocumab

27,500 stable patients with prior MI, ischemic stroke, or PAD

Age 40 to 85 years

At least 1 other high-risk feature

1º EP: CV death, MI, UA->hosp, stroke, coronary revasc

2º EP: All-cause mortality

Death or CHF -> hospitalization

Stroke or TIA

www.clinicaltrials.gov NCT 01764633, Accessed Dec 6, 2014

SPIRE 1 (NCT-01975376) SPIRE 2 (NCT-01975376)

No. Patients 17,000 9,000

Inclusion criteria Age ≥ 18 and high risk of CV event

Must be on background lipid lowering therapy

Exclusion criteria

o Planned coronary revascularization

o NYHA Class IV CHF or LVEF <25%

o Creatinine clearance < 30 ml/min/1.73m2

o Prior hemorrhagic stroke

Entry lipid values LDL-C ≥70 to <100 mg/dL LDL-C ≥ 100 mg/dL

Treatment Bococizumab 150 mg Q2W SQ vs. Placebo

Primary Endpoint 4-way composite endpoint of: CV death / Non-fatal MI / non-fatal stroke / hospitalization for

unstable angina needing urgent revascularization

Secondary Endpoints Composite endpoint of CV death, non-fatal MI, and non-fatal stroke

Composite endpoint of all-cause death, non fatal MI, and non-fatal stroke

Hospitalization for unstable angina needing urgent revascularization

Study start October 2013 October 2013

Study end June 2018 March 2018

2 Phase 3 Outcomes Trials: Bococizumab

www.clinicaltrials.gov NCT: 01975376 and 01975389, Accessed Dec 6,2014

Conclusions

• Monoclonal antibodies to PCSK lower LDL-C by 50-

70% compared to placebo in a variety of patient

populations

• PCSK9 inhibitors also lower non-HDL cholesterol,

triglycerides, apolipoprotein B, and Lp(a)

• PCSK9 inhibitors should permit the vast majority of

patients to achieve “low” LDL-C levels

• 4 large outcome trials will determine whether PCSK9

inhibition reduces CV events