Efficacy and Safety of Evolocumab (AMG 145) Monotherapy Compared With Ezetimibe and Placebo in Hypercholesterolemic Subjects: A Phase 3 Randomized Clinical Trial

1
Efficacy and Safety of Evolocumab (AMG 145)
Monotherapy Compared With Ezetimibe and Placebo
in Hypercholesterolemic Subjects A Phase 3
Randomized Clinical Trial

• Michael J Koren,1 Pernille Lundqvist,2 Michael
  Bolognese,3 Joel M Neutel,4 Maria Laura
  Monsalvo,5 Jingyuan Yang,5 Jae B Kim,5 Rob
  Scott,5 Scott M Wasserman,5 Harold Bays6 for the
  MENDEL-2 Investigators
• 1Jacksonville Center for Clinical Research,
  Jacksonville, FL, USA 2Center for Clinical and
  Basic Research, Ballerup, Denmark 3Bethesda
  Health Research Center, Bethesda, MD, USA
  4Orange County Research Center, Tustin, CA, USA
  5Amgen Inc., Thousand Oaks, CA, USA 6L-MARC
  Research Center, Louisville, KY, USA
• March 29, 2014, Featured Clinical Research
  Session 400
• American College of Cardiology, Washington DC

2
Background

• Evolocumab, a fully human monoclonal antibody
  against PCSK9, has emerged as a novel therapeutic
  option for lowering LDL-C in patients with
  hypercholesterolemia.
• In Phase 2 studies, treatment with evolocumab was
  well tolerated and significantly reduced LDL-C in
  diverse groups of subjects, with LDL-C reductions
  maintained over 52 weeks.1-5
• Because statins up-regulate PCSK9 production,
  evaluation of evolocumab as monotherapy is
  required to fully understand its pharmacodynamics
  and safety profile in populations not confounded
  by statin use or a history of statin intolerance,
  particularly at doses anticipated for use in
  clinical practice.

1. Lancet. 20123801995-2006.
2. Lancet. 20123802007-2017.
3. JAMA. 20123082497-2506.
4. Circulation. 20121262408-2417.
5. Circulation. 2014129234-243.

3
The MENDEL-2 Study

• Monoclonal Antibody Against PCSK9 to Reduce
  Elevated LDL-C in Patients Currently Not
  Receiving Drug Therapy For Easing Lipid Levels-2
  (NCT01763827)
• DesignA 12 week randomized, double-blind,
  placebo- and ezetimibe-controlled multicenter
  phase III study
• Objective To evaluate efficacy and safety of
  evolocumab in primary hypercholesterolemic
  patients not taking statins

4
MENDEL and MENDEL-2 Compared
Characteristics MENDEL MENDEL-2
Phase 2 3
N 406 614
Population Framingham Risk lt 10 Framingham Risk lt 10
Fasting LDL-C Range 100 and lt 190 mg/dL 100 and lt 190 mg/dL
Background Lipid Therapy None None
Evolocumab Dose 70, 105, or 140 mg biweekly 280, 350, or 420 mg monthly 140 mg biweekly 420 mg monthly
Comparators Placebo biweekly or monthly Open ezetimibe 10 mg/day Placebo biweekly or monthly Blinded ezetimibe 10 mg/day
Treatment Duration 12 wks 12 wks
Evolocumab Delivery 70 mg/ml vial and syringe in clinics 140 mg/ml prefilled auto-injector in clinic and home
5
MENDEL-2 Study Design
140 mg Evolocumab Q2W / Placebo PO QD
N 153
420 mg Evolocumab QM / Placebo PO QD
N 153
Placebo SC Q2W / 10 mg Ezetimibe PO QD

• Screening
• Period
• with
• Placebo
• Injection

N 77
221111
End of Study
Randomization
Placebo SC QM / 10 mg Ezetimibe PO QD
N 77
Placebo SC Q2W / Placebo PO QD
N 77
Placebo SC QM / Placebo PO QD
N 78
Day 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Week 14
Q2W
Biweekly SC administration
QM
EOS
Monthly SC administration
EOS
1 patient was randomized but not dosed. Phone
call for AEs, SAEs. AEs, adverse events.EOS, end
of study QD, daily Q2W, biweekly QM, monthly.
6
MENDEL-2 Primary Endpoints

• Co-primary endpoints Percent change from
  baseline in LDL-C at week 12 and mean of weeks 10
  and 12
• Secondary endpoints
• At mean of weeks 10 and 12 and at week 12
• Percent change from baseline in ApoB, ApoA-I,
  lipoprotein(a), TG, and HDL-C
• Percent of patients with LDL-C lt70 mg/dL
• Key safety endpoints
• Treatment-emergent and serious adverse events
• Muscle and hepatic enzyme elevations
• Anti-evolocumab antibodies

7
MENDEL-2 Baseline Demographics
Biweekly Biweekly Biweekly Monthly Monthly Monthly
PBO Q2W PBO QD (N 76) PBO Q2W EZE QD (N 77) Evolocumab 140 mg Q2W PBO QD(N 153) PBO QM PBO QD (N 78) PBO QM EZE QD (N 77) Evolocumab 420 mg QM PBO QD(N 153)
Age (years), mean (SD) 54 (10) 54 (11) 53 (14) 53 (11) 53 (13) 53 (12)
Female, 63 69 68 60 68 66
Race, white, 83 82 86 81 78 84
NCEP risk categories, High Moderately high Moderate Low 0 8 33 59 0 4 47 49 1 3 41 55 3 5 26 67 1 5 40 53 1 5 34 60
Risk category definitions high, diagnosed CHD
or risk equivalent moderately high, 2 or more
risk factors and Framingham risk score 10-20
moderate, 2 or more risk factors and Framingham
risk score lt10 lower, 0 or 1 risk factor. CV,
cardiovascular EZE, ezetimibe PBO, placebo
Q2W, biweekly QM, monthly QD, daily.
8
MENDEL-2 Baseline Lipids
Biweekly Biweekly Biweekly Monthly Monthly Monthly
PBO Q2W PBO QD (N 76) PBO Q2W EZE QD (N 77) Evolocumab 140 mg Q2W PBO QD(N 153) PBO QM PBO QD (N 78) PBO QM EZE QD (N 77) Evolocumab 420 mg QM PBO QD(N 153)
LDL-C, mg/dL, mean (SD) 140 (21) 143 (24) 142 (22) 144 (24) 144 (23) 144 (23)
ApoB, md/dL, mean (SD) 104 (17) 107 (20) 105 (17) 107 (20) 106 (18) 108 (18)
Lp(a), nmol/L, median (Q1,Q3) 21 (9, 49) 28 (11, 120) 20 (7, 58) 22 (7, 62) 28 (12, 64) 28 (9, 104)
TG, mg/dL, median (Q1,Q3) 114 (83, 178) 113 (84, 158) 112 (82, 148) 118 (86, 179) 117 (90, 159) 119 (83, 169)
PCSK9, ng/mL, mean (SD) 281 (89) 270 (94) 272 (81) 270 (82) 265 (94) 274 (84)
Determined by the Friedewald formula with
reflexive testing via preparative
ultracentrifugation when calculated LDL-C was lt40
mg/dL (1.0 mmol/L) or triglyceride levels were
gt400 mg/dL (3.9 mmol/L). CV, cardiovascular EZE,
ezetimibe PBO, placebo Q2W, biweekly QM,
monthly QD, daily.
9
MENDEL-2 EvolocumabPrimary Endpoint Biweekly
Dose
Treatment Difference vs Placebo Average at weeks 10 and 12 -57 Plt0.001
Treatment Difference vs Placebo At week 12 -57 Plt0.001
Treatment Difference vs Ezetimibe Average at weeks 10 and 12 -39 Plt0.001
Treatment Difference vs Ezetimibe At week 12 -39 Plt0.001
10
0
0.1
10
18
20
Mean Percent Change in LDL-C from Baseline
30
40
50
57
60
BL
Week 2
Week 8
Week 10
Week 12
Day 1
Week 4
Week 6
Biweekly SCadministration
Study Week
Placebo (N 76)
Ezetimibe (N 77)
Evolocumab biweekly (N 153)
BL, baseline. Vertical lines represent the
standard error around the mean. Plot is based on
observed data with no imputation for missing
values. P values are multiplicity adjusted.
10
MENDEL-2 EvolocumabPrimary Endpoint Monthly Dose
Treatment Difference vs Placebo Average at weeks 10 and 12 -57 Plt0.001
Treatment Difference vs Placebo At week 12 -55 Plt0.001
Treatment Difference vs Ezetimibe Average at weeks 10 and 12 -40 Plt0.001
Treatment Difference vs Ezetimibe At week 12 -38 Plt0.001
10
1
0
10
19
20
Mean Percent Change in LDL-C from Baseline
30
40
50
56
60
BL
Week 2
Week 8
Week 10
Week 12
Day 1
Week 4
Week 6
Monthly SCadministration
Study Week
Placebo (N 78)
Ezetimibe (N 77)
Evolocumab monthly (N 153)
BL, baseline. Vertical lines represent the
standard error around the mean. Plot is based on
observed data with no imputation for missing
values. P values are multiplicity adjusted.
11
MENDEL-2 Change in LDL-C from Baseline at Week
12 for Individual Patients
Placebo (N 76)
Ezetimibe (N 77)
Evolocumab (N 153)
60
40
20
0
Percent Change in LDL-C (mg/dL)
Biweekly
20
40
60
80
100
Placebo (N 78)
Ezetimibe (N 77)
Evolocumab (N 153)
60
40
20
0
Monthly
Percent Change in LDL-C (mg/dL)
20
40
60
80
100
? Subjects with early termination of subcutaneous
or oral study drug No notable difference in
results for average at weeks 10 and 12
12
MENDEL-2 Other Lipids at Week 12
ApoB
Biweekly
Monthly
Treatment difference (biweekly and monthly) vs
placebo P lt 0.001 vs ezetimibe P lt 0.001
Lp(a)
Biweekly
Monthly
Treatment difference (biweekly and monthly) vs
placebo P lt 0.001 vs ezetimibe P lt 0.001
Placebo
Ezetimibe
Error bars represent standard error for mean
treatment difference and 95 CI for median
treatment difference. No notable difference in
results for average at weeks 10 and 12. P values
are multiplicity adjusted.
13
MENDEL-2 Other Lipids at Week 12 - II
Triglycerides
Biweekly
Monthly
Treatment difference (monthly) vs placebo P lt
0.001 (biweekly and monthly) vs ezetimibe P lt 0.05
Non-HDL-C
Biweekly
Monthly
Treatment difference (biweekly and monthly) vs
placebo P lt 0.001 vs ezetimibe P lt 0.001
Placebo
Ezetimibe
Error bars represent standard error for mean
treatment difference and 95 CI for median
treatment difference. No notable difference in
results for average at weeks 10 and 12. P values
are multiplicity adjusted.
14
MENDEL-2 Other Lipids at Week 12 - III
HDL-C
Biweekly
Monthly
Treatment difference (biweekly and monthly) vs
placebo P lt 0.05 vs ezetimibe P lt 0.05
ApoA-I
Biweekly
Monthly
Treatment difference (monthly only) vs placebo P
lt 0.01 vs ezetimibe P lt 0.05
Placebo
Ezetimibe
Error bars represent standard error for mean
treatment difference and 95 CI for median
treatment difference. No notable difference in
results for average at weeks 10 and 12. P values
are multiplicity adjusted.
15
MENDEL-2 Treatment Difference According to
Subgroups at Week 12
Evolocumab Q2W vs Ezetimibe
Evolocumab Q2W vs Placebo
Evolocumab QM vs Ezetimibe
Evolocumab QM Vs Placebo
Sex
Female
Male
Age
lt65 years
65 years
Race
White
Black
Other
History of Met Syn
Yes
No
Screening LDL-C
lt130mg/dL
130mg/dL
Triglycerides
lt200 mg/dL
200 mg/dL
Overall
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
Percent Change from Baseline at Week 12
Met Syn metabolic syndrome
16
MENDEL-2 Treatment Difference According to
Subgroups at Week 12
Evolocumab Q2W vs Ezetimibe
Evolocumab Q2W vs Placebo
Evolocumab QM vs Ezetimibe
Evolocumab QM vs Placebo
Hypertension
Yes
No
Smoker
Yes
No
Baseline CHD risk factors
lt2
2
Region
North America
Europe
Other
PCSK9
ltbaseline median (261.0 ng/mL)
baseline median (261.0 ng/mL)
Overall
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
-100
-80
-60
-40
-20
0
Percent Change from Baseline at Week 12
17
MENDEL-2 Safety and Tolerability
Adverse Events (AEs), n () Placebo (N 154) Ezetimibe (N 154) Evolocumab (N 306)
Treatment-emergent AEs 68 (44) 70 (46) 134 (44)
Common treatment-emergent AEs Headache Diarrhea Nausea Urinary Tract Infection Constipation Nasopharyngitis Upper Respiratory Infection 4 (3) 6 (4) 1 (1) 2 (1) 4 (3) 3 (2) 4 (3) 5 (3) 3 (2) 3 (2) 3 (2) 1 (1) 6 (4) 5 (3) 10 (3) 9 (3) 8 (3) 7 (2) 6 (2) 6 (2) 5 (2)
Serious AEs 1 (1) 1 (1) 4 (1)
AEs leading to study drug discontinuation 6 (4) 5 (3) 7 (2)
Deaths 0 (0) 0 (0) 0 (0)
Potential injection site reactions 8 (5) 7 (5) 16 (5)
Muscle-related SMQ Myalgia Musculoskeletal pain 6 (4)3 (2) 2 (1) 5 (3)3 (2)1 (1) 8 (3)3 (1)3 (1)
Neurocognitive AEs 0 (0) 0 (0) 0 (0)
CK gt 5 x ULN 2 (1) 0 (0) 2 (1)
ALT or AST gt 5 x ULN 2 (1) 0 (0) 1 (0.3)
Anti-evolocumab antibodies NA NA 0
Reported in 3 of patients in one or more
treatment arms. Reported using high-level term
grouping, which includes injection site (IS)
rash, IS inflammation, IS pruritus, IS reaction,
and IS urticaria. Standard MedDRA Queries.
Binding or neutralizing.
18
MENDEL-2 Conclusions

• In the largest monotherapy trial with a PCSK9
  inhibitor to date, evolocumab biweekly (140 mg)
  or monthly (420 mg) rapidly and markedly lowered
  LDL-C over 12 weeks compared with placebo or
  ezetimibe in patients with hypercholesterolemia
  not taking statins.
• Evolocumab 140 mg biweekly and 420 mg monthly
  dosing regimens are clinically equivalent.
• Evolocumab treatment resulted in favorable
  changes in other lipoproteins.
• Evolocumab was well tolerated over the 12-week
  study
• The overall incidence of treatment-emergent AEs,
  CK, and AST/ALT elevations was comparable across
  treatment groups.

19
MENDEL-2 Conclusions

• Though we anticipate that evolocumab treatment
  will find use primarily as a treatment for high
  risk patients in conjunction with statins,
  MENDEL-2 demonstrated that evolocumab produces
  large LDL-C lowering effects as monotherapy.
• These lipid effects occur consistently across
  several pre-specified sub-groups.
• The MENDEL-2 findings support future
  investigation of evolocumab in higher-risk
  patient population who might benefit from
  anti-PCSK9 monotherapy.

20
Disclosures
This study was funded by Amgen Inc. MJ Koren
Employee of Jacksonville Center for Clinical
Research, which has received research grants from
Amgen Inc. and other PCSK9-related research
funding from Regeneron, Sanofi, Roche, and
Pfizer. P Lundqvist None. MA Bolognese
Research grant from Amgen Inc. JM Neutel None ML
Monsalvo, J Yang, JB Kim, R Scott, SM Wasserman
Employees of Amgen Inc. and own Amgen stock/stock
options. H Bays Research grant and
consultant/advisory board from Amgen Inc., and
consultant/advisory board/speaker's bureau for
many other pharmaceutical companies. Amgen Inc.
provided editorial support for the development of
this presentation.