are pcsk 9 inhibitors poised for breakthrough?
TRANSCRIPT
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