Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in

Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized,

Placebo-controlled Study

Dirk Blom, Tomas Hala, Michael Bolognese, Michael J Lillestol,

Phillip D Toth, Lesley Burgess, Richard Ceska, Eli Roth,Michael J Koren, Maria Laura Monsalvo, Kate Tsirtsonis,

Jae B Kim, Scott M Wasserman, Rob Scott,Christie M Ballantyne, Evan A Stein, for the DESCARTES

Investigators

March 29, 2014, Featured Clinical Research Session 400American College of Cardiology, Washington DC

2

Background: PCSK9 Inhibition

PCSK9 is a well validated therapeutic target based on gain and loss of function human genetic abnormalities, Mendelian randomization studies, and its recently elucidated role in LDL receptor function and regulation of LDL cholesterol.

Evolocumab (AMG 145), a fully human monoclonal antibody against PCSK9, reduced LDL-C by up to 65% and was well tolerated in 4 randomized, placebo-controlled, phase 2 clinical trials of 12 weeks duration in over 1300 hypercholesterolemic patients.1-4

An open label extension study of patients from phase 2 trials with evolocumab (OSLER) recently reported 1 year safety and efficacy data.5

1. Lancet. 2012;380:1995-20062. Circulation. 2012;126:2408-2417

3. JAMA. 2012;308:2497-2506

4. Lancet. 2012;380:2007-20175. Circulation 2014;129:234-243

3

The DESCARTES Study

Durable Effect of PCSK9 antibody CompARed wiTh placEbo Study (NCT01516879)

A 52 week global, randomized, double-blind, placebo-controlled multicenter study to provide longer term data on the efficacy and safety of evolocumab

Included patients with a wide range of cardiovascular risk

Lipid-lowering therapy, ranging from diet alone to atorvastatin 80 mg plus ezetimibe, was optimized to reach NCEP ATP III LDL-C treatment goals

4

DESCARTES: Endpoints

Primary: % change from baseline in LDL-C measured by ultracentrifugation (UC) at week 52

Secondary

% change from baseline in UC LDL-C at week 12

Change from baseline in UC LDL-C at week 52

% of patients with UC LDL-C < 70 mg/dL at week 52

% changes from baseline for TC, HDL-C, ApoB, VLDL-C, triglycerides, and Lp(a) at week 52

% changes in total cholesterol/HDL cholesterol ratio and apolipoprotein B/apolipoprotein A1 ratio at week 52

5

DESCARTES: Patients

Adults aged 18 to 75 years

Screening

LDL-C ≥ 75 mg/dL and TG ≤ 400 mg/dL

Exclusion: LDL-C ≤ 99 mg/dL with CHD or risk equivalent and not receiving a statin

Following lipid stabilization period

At NCEP ATP III target or receiving maximal therapy (atorvastatin 80 mg plus ezetimibe 10 mg)

LDL-C ≥ 75 mg/dL

6

DESCARTES: Screening and Lipid Stabilization

Screening LDL-C ≥ 75 mg/dL

Background Therapy Assigned Based on CV Risk, LDL-C, and Current Therapy:

1) Diet alone2) Diet and atorvastatin 10 mg3) Diet and atorvastatin 80 mg4) Diet, atorvastatin 80 mg, and ezetimibe 10 mg

4 Week Dietary Run-in andLipid StabilizationS

cree

nin

g P

erio

d

4 W

eeks

to

16

Wee

ks

Yes

No

Initial LDL-C < 75 mg/dL= Screen Fail

LDL < 75 mg/dL= Screen Fail (except on

maximal background therapy – allowed one

downtitration

CHD/risk equivalent: LDL < 100 mg/dL OR No CHD/risk equivalent: LDL < 130 mg/dL OR

On Maximal background therapy

Up-titrate Background Therapy

Randomization 2:1 (~900 Subjects) Evolocumab 420 mg SC QM Placebo SC QM

7

DESCARTES: Study Overview

Day 1 Week 8

En

d o

f S

tud

y

Week 52*Week 4Visits:

Placebo SC QM n = 303

Evolocumab 420 mg SC QM n = 602

Ran

do

miz

atio

n2:

1

QM:

Study Drug (Evolocumab or Placebo)

Screening - Assign

background Rx based on

CV risk, LDL, and

+/- prior statin:

1. No drug2. Low dose: 10 mg

atorvastatin 3. High dose: 80 mg

atorvastatin 4. Maximal: 80 mg

atorvastatin + 10 mg ezetimibe

Subcutaneous injection of 6 mL Placebo

Period = Max. 16 weeks / Min: 4 weeks

Lipid Stabilization

Period

Fasting LDL-C 5–10 days

before randomization

* Last dose administered at week 48

8

DESCARTES: Patient Disposition

Screened: 2120

1485 entered lipid stabilization period

905 randomized to evolocumab or placebo

635 screen failures

580 lipid stabilization

period failures

9

DESCARTES: Patient Disposition II

112 Diet alone

(38 P: 74 Evo)

385 Atorvastatin 10

(129 P: 256 Evo)

219 Atorvastatin 80 (73 P: 146 Evo)

189 Atorvastatin 80 +

Ezetimibe 10(63 P: 126 Evo)

905 Randomized2:1 allocation to evolocumab or placebo

800 completed 52 weeks of Study Drug

E = Ezetimibe, Evo = Evolocumab, P = Placebo* Study Drug

4 never received SD*73 discontinued evolocumab28 discontinued placebo

10

DESCARTES: Baseline Characteristics

CharacteristicDiet

Alone A 10 mg/d A 80 mg/dA 80 mg/d +E10 mg/d All

n 111 383 218 189 901

Age, y, mean (SD)

51.7 (12.1)

57.1 (10.4)

58.0 (9.2)

54.8(10.7)

56.2 (10.6)

Male, % 45.0 43.9 50.0 54.5 47.7

BMI, kg/m2, mean (SD)

30.5 (7.6)

29.8 (6.2)

30.8 (5.7)

29.8 (4.8)

30.1 (6.0)

Race/White, % 67.6 85.9 86.2 69.8 80.4

A = AtorvastatinE = Ezetimibe

Full Analysis Set (FAS) data presented: Patients who received at least one dose of study drug

11

DESCARTES: Baseline Patient Characteristics II

CharacteristicDiet

Alone A 10 mg/d A 80 mg/dA 80 mg/d +E10 mg/d All

Coronary artery disease,%

1.8 2.6 15.6 47.6 15.1

Type 2 diabetes,% 2.7 7.0 15.1 21.7 11.5

Current smoker, % 17.1 11.7 14.2 21.2 15.0

Hypertension, % 42.3 41.8 57.3 56.1 48.6

Family history of premature CAD, %

13.5 14.6 22.0 47.1 23.1

2 or more CV risk factors, %

29.7 26.6 46.3 61.4 39.1

A = AtorvastatinE = Ezetimibe

12

DESCARTES: Baseline Lipids

  Placebo Evolocumab

n 302 599

*UC LDL-C, mg/dL, mean (SD) 104 (22) 104 (22)

ApoB, mg/dL, mean (SD) 88 (16) 87 (16)

Lipoprotein(a), nmol/L, median (Q1, Q3)

40 (12,145) 38 (14,137)

HDL-C mg/dL mean, (SD) 54 (16) 53 (16)

ApoA1, mg/dL mean, (SD) 155 (28) 152 (27)

Triglycerides, mg/dL, median,

(Q1, Q3)

110

(85,155)

105

(80,140)

*UC = ultracentrifugation

13

DESCARTES: Baseline LDL-C on Background Therapy Prior to First Dose of Study Drug

Treatment Diet Alone

A 10 mg/d A 80 mg/dA 80 mg/d

+ E 10 mg/d

All

 Group P EVO P EVO P EVO P EVO P EVO

n 37 74 129 254 73 145 63 126 302 599

UC LDL-C Baseline mg/dL

mean (SD)

112 (16)

112 (15)

98 (15)

101 (15)

96 (13)

95 (13)

120 (32)

117 (35)

104 (22)

104 (22)

A = AtorvastatinE = EzetimibeEVO = EvolocumabP = Placebo

14

DESCARTES: % Change in UC LDL-C From Baseline - FAS

UC

LD

L-C

Pe

rcen

t C

han

ge

fro

m B

asel

ine

, Mea

n (

± S

E)

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)

FAS = Full analysis set, UC = ultracentrifugation

-51.5%

6.0%

Treatment difference57%

15

-70

-60

-50

-40

-30

-20

-10

0

10

20

Me

an

Pe

rce

nt

Ch

an

ge

in

UC

LD

L-C

DESCARTES: % Change in UC LDL-C from Baseline at Week 52

Error bars represent standard error for treatment difference Treatment difference are least squares mean derived from a repeated measures model

EvolocumabPlacebo Treatment Difference

OverallDiet

AloneAtorvastatin

10 mgAtorvastatin

80 mg

Atorvastatin80 mg +

Ezetimibe 10 mg

16

0

10

20

30

40

50

60

70

80

90

100

3% 5% 6%11%

6%

84%90%

81%

67%

82%

Placebo Evolocumab

Pro

po

rtio

n o

f P

atie

nts

, %

Diet Alone Diet + Atorvastatin

10 mg

Diet + Atorvastatin

80 mg

Diet + Atorvastatin

80 mg +Ezetimibe 10 mg

DESCARTES: UC LDL-C Goal Achievement

LDL-C < 70 mg/dL at Week 52

Total

17

Changes in Mean Levels of Unbound PCSK9

0

100

200

300

400

500

600

700

Baseline Week 12 Week 13 Week 52

Mea

n ±

SE

PC

SK

9 L

evel

, ng

/mL

PlaceboDiet OnlyAtorvastatin 10 mg

Atorvastatin 80 mg

Atorvastatin 80 mg +Ezetimibe 10 mg

4 weekspost-dose

1 weekpost-dose

4 weekspost dose

Evolocumab

18

DESCARTES: Other Lipids at Week 52

0

6%

-2

0

2

4

6

3%(-17 to 25)

-9%(-26 to 13)

2%ApoB

Lp(a)

HDL-C

ApoA1

Triglycerides

-42%-50

-40

-30

-20

-10

0

10

-1%

2%

-2

-1

0

1

2

3

-6%(-21 to 1)

-28%(-49 to -6)

-30

-25

-20

-15

-10

-5

0

Placebo QM

Evolocumab 420 mg QM

Pe

rce

nt

Ch

an

ge

fro

mB

as

eli

ne

, M

ea

n (

%)

Pe

rce

nt

Ch

an

ge

fro

mB

as

eli

ne

, M

ed

ian

(%

)P

erc

en

t C

ha

ng

e f

rom

Ba

se

lin

e,

Me

dia

n (

%)

Pe

rce

nt

Ch

an

ge

fro

mB

as

eli

ne

, M

ea

n (

%)

Pe

rce

nt

Ch

an

ge

fro

mB

as

eli

ne

, M

ea

n (

%)

-6-4-20246

-10-8 Error bars represent standard error

Data in parentheses represent Q1 to Q3

DESCARTES: Safety and Tolerability

20

DESCARTES: Treatment Emergent Adverse Events

 n (%)PlaceboN=302

EvolocumabN=599

Any Treatment Emergent Adverse Event 224 (74.2) 448 (74.8)

Serious 13 (4.3) 33 (5.5)

Death 0 (0.0) 2 (0.3)

Adjudicated events 2 (0.7) 6 (1.0)

Leading to discontinuation of study drug 3 (1.0) 13 (2.2)

Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study

21

DESCARTES: Treatment Emergent Adverse Events II

 n (%)PlaceboN=302

EvolocumabN=599

Most Common Treatment Emergent AEs

Nasopharyngitis 29 (9.6) 63 (10.5)

Upper respiratory tract infection 19 (6.3) 56 (9.3)

Influenza 19 (6.3) 45 (7.5)

Back pain 17 (5.6) 37 (6.2)

Neurocognitive AEs 2 (0.7) 1 (0.2)

Amnesia - Short-term memory loss 0 (0.0) 1 (0.2)

Dementia With Lewy Bodies 1 (0.3) 0 (0.0)

Encephalopathy 1 (0.3) 0 (0.0)

Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study

22

DESCARTES: Hepatic and Muscle Safety

n (%)PlaceboN=302

EvolocumabN=599

Liver function tests

ALT or AST > 3 × ULN* 3 (1.0) 5 (0.8)

ALT or AST > 5 × ULN* 1 (0.3) 3 (0.5)

Muscle TEAEs and Laboratory Results

Myalgia 9 (3.0) 24 (4.0)

CK > 5 × ULN* 1 (0.3) 7 (1.2)

CK > 10 × ULN* 1 (0.3) 3 (0.5)

* At any visit post baseline, TEAE = treatment emergent adverse event

23

DESCARTES: Glycemic Parameters

Changes from baseline at week 52

   Placebo Evolocumab

 Diet

aloneA 10 mg/d

A 80 mg/d

A 80 mg/d +

E10 mg/d

n 273 63 225 131 114

Glucose, (mg/dL); mean (SE)

0.4 (0.9) -0.5 (1.5) 1.7 (1.2) 0.3 (1.0) 2.6 (1.9)

n 273 64 227 129 115

HbA1C, (%); mean (SE)

0.00(0.03)

-0.09 (0.04)

0.04 (0.02)

-0.02 (0.03)

0.09 (0.04)

A = AtorvastatinE = Ezetimibe

24

DESCARTES: Injection Sites and Antibodies

Potential injection site reactions

Evolocumab 34 (5.7%)

Placebo 15 (5.0%)

Antibodies to evolocumab

2 patients (allocated to evolocumab) had binding antibodies prior to evolocumab exposure

One patient on evolocumab developed transient binding antibodies during therapy

No neutralizing antibodies detected throughout study

25

DESCARTES: Conclusions

Largest and longest double-blind, randomized placebo controlled trial reported to date, of a monoclonal antibody to PCSK9

Evolocumab 420 mg QM reduced placebo adjusted UC LDL-C 57% from baseline in patients with a wide range of cardiovascular risk receiving background lipid lowering therapies ranging from diet alone to the combination of atorvastatin 80 mg/d and ezetimibe 10 mg/d

Durable effect with consistent LDL-C reductions at weeks 12 and 52

Similar AE profile in placebo and active treatment groups

No adverse laboratory signals observed

Cardiovascular outcome trial is ongoing