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 30

No Nonsense Mutation (N = 3278)

50th Percentile

Mean 113 mg/dL

12

Frequency (%)

10 0 0

50

100

150

200

250

300

PCSK9142x or PCSK9679X (N=85) 30

Mean 100 mg/dL (-28%)

20 10

Coronary Heart Disease (%)

20

88% reduction in risk of CHD during 15-year follow-up

8

4

0 No

0 0

50 100 150 200 250 Plasma LDL Cholesterol in Black Subjects (mg/dL)

Adapted4 from Cohen JC. N Engl J Med 2006;354:1264-72

300

Yes

PCSK9142x or PCSK9679X

PCSK9-Directed Therapies in Development Company Sanofi/Regeneron

Drug Alirocumab (SAR 2236553/REGN727)

Agent

Indication

Phase

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

LGT-209

Monoclonal antibody

Hypercholesterolemia

2

LY3015014

Monoclonal antibody

Hypercholesterolemia

2

RG7652, MPSK3169A,

Monoclonal antibody

Hypercholesterolemia

2

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

SX-PCK9

Small peptide mimetic; LDLR antagonist

Hypercholesterolemia

Preclinical

TBD

Small molecule PCSK9 modulator

Metabolic disorders

Preclinical

Novartis Eli Lilly Roche/Genentech Alnylam Pharma

Serometrix Shifa Biomedical Corp.

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

Alirocumab: Dynamic Relationship Between mAb Levels, PCSK9 and LDL-C 200

0

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

180

-10

-20

140 120

-30

100 -40

80 60

-50

40 -60 20 0

-70 0

500

1000

1500

2000

Time (hours)

Total Alirocumab

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

free PCSK9

LDL-c

2500

LDL--C mean % change

Free/Total PCSK9 Conc. (ng/mL) Total Alirocumab (ng/mL) X 0.01

160

Alirocumab: First in Man LDL-C Dose Response Atorvastatin Combo-Rx, HeFH & Non-FH Combined and Diet Control Mean % Change from Baseline Mean Percent Change from Baseline in Calc LDLc (%)

30 20 10 0

-10 -20 -30 -40 -50 -60 -70 1

15

29

43

57

71

85

99

113

127

Study Days

Combined placebo

Combined 150mg

= Dose administered Swergold G et al. Circulation. 2011;124:A16265.

Diet placebo

Diet 150mg

141

155

Alirocumab Phase 2 Data:

*Alirocumab=SAR236553/REGN727 8 McKenney JM et al. J Am Coll Cardiol. 2012;59:2344-2353.

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

Evolocumab Q2W 70 mg N = 79

105 mg N = 79

Evolocumab Q4W 140 mg N = 78

280 mg N = 79

350 mg N = 79

420 mg N = 80

* p < 0.0001 for each dose vs placebo

73

53

44

69

60

58

(25)

(21)

(25)

(28)

(23)

(26)

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

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

Bococizumab (Phase 2 Data) • 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%

-35

-52

-54

-21

-38

-34%

-45%

-53%

-28%

-45%

1

0

4

0

2

LDL-C (mg/dL) at week 12

% change v. placebo AE -> D/C (n)

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

Monoclonal Antibodies to PCSK9 Markedly Lower LDL-C in a Variety of Patients Aliro Evolo

1. 2. 3. 4. 5. 6.

Background of low or high dose statin As monotherapy Statin intolerant patients Heterozygous FH Homozygous FH (most variants) Long-term (>1 year)

√ √ √ √ √ P √

√ √ √ √ √ √ √

Changes in Other Lipids with Top 2 Evolocumab Doses

-33%

-32%

-43%

-48%

-44%

-61%

-36% -56% P < 0.0001 versus placebo for all parameters Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error

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

-43%

-42%

-48%

-53%

Results: Mean % Change in Lp(a) at Week 12: Evolocumab v. Placebo

Mean % Change in Lp(a) at Week 12 Compared to Placebo

Evolocumab Q2W

Achieved Lp(a) at week 12, nmol/L, median (IQR)

Evolocumab Q4W

P hospitalization Stroke or TIA www.clinicaltrials.gov NCT 01764633, Accessed Dec 6, 2014

2 Phase 3 Outcomes Trials: Bococizumab No. Patients

Inclusion criteria

Exclusion criteria

Entry lipid values

SPIRE 1 (NCT-01975376)

SPIRE 2 (NCT-01975376)

17,000

9,000

Age ≥ 18 and high risk of CV event Must be on background lipid lowering therapy o Planned coronary revascularization o NYHA Class IV CHF or LVEF