Non-statin Therapies for the Management of LDL …Non-statin Therapies for the Management of...
Transcript of Non-statin Therapies for the Management of LDL …Non-statin Therapies for the Management of...
Non-statin Therapies for the Management of LDL-associated ASCVD
RiskPamela B. Morris, MD, FACC, FACP, FACPM, FAHA, FNLA
Chair, American College of Cardiology Prevention of Cardiovascular Disease
Section
Associate Professor of Medicine
Director, Seinsheimer Cardiovascular Health Program
Co-Director, Women's Heart Care
Medical University of South Carolina
Disclosures
• Advisory board—Amgen, AstraZeneca, Sanofi-Regeneron
Discussion Objectives
1. Describe mechanism of action of new and emerging
agents for LDL-C lowering based on targets in
lipoprotein synthesis, transport, and regulation
2. Outline clinical trial data on the efficacy and safety of
novel agents for lowering LDL-C
High, Moderate, and Low-intensity
Statin Therapy Used in Clinical Trials
High-Intensity
Statin Therapy
Moderate-Intensity
Statin Therapy
Low-Intensity
Statin Therapy
Daily dose lowers LDL-C
on average, by
approximately ≥50%
Daily dose lowers LDL-C
on average, by
approximately 30 to <50%
Daily dose lowers LDL-C
on average, by
approximately <30%
Atorvastatin 40*-80* mg
Rosuvastatin 20*-40** mg
Atorvastatin 10* (20**) mg
Rosuvastatin (5**) 10* mg
Simvastatin 20*-40* mg
Pravastatin 40* (80**) mg
Lovastatin 40* mg
Fluvastatin XL 80** mg
Fluvastatin 40 mg BID*
Pitavastatin 2-4** mg
Simvastatin 10** mg
Pravastatin 10*-20* mg
Lovastatin 20* mg
Fluvastatin 20**-40** mg
Pitavastatin 1** mg
*Statins demonstrated reduction in major CVD events.**FDA approved doses not tested in clinical trials.
FDA = Food and Drug Administration.Goff DC, et al. Circulation. 2014;129(25 Suppl 2):S49-73.Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.
Are there unmet clinical needs?
• High absolute ASCVD risk and inadequate
response/elevated LDL-C despite maximally
tolerated statin therapy
• Familial hypercholesterolemia
• Statin intolerance and high ASCVD risk or
known ASCVD
Lowering LDL-C: Treatment options
• Reduce absorption
– Ezetimibe
– Bile acid sequestrants
• Reduce production
– Mipomersen
– Lomitapide
• Increase clearance
– Statins
– PCSK9 inhibition
Approaches to additional LDL-C lowering
Ray KK, et al. Lancet. 2015:386:412-15
Ezetimibe
8
IMProved Reduction of Outcomes: Vytorin Efficacy
International Trial (IMPROVE IT): Design
Cannon CP, et al. Am Heart J. 2008;156:826-32.
Patients stabilized post-ACS ≤ 10 days
LDL-C ≤ 125 mg/dL (or ≤ 100 mg/dL if prior statin)
Double-blind
N ~ 18,000
ASA + Standard Medical Therapy
Simvastatin 40 mg*Ezetimibe/Simvastatin
10/40 mg*
Follow-up visit day 30, every 4 months
Duration: Minimum 2.5 year follow-up (5250 events)
Primary Endpoint: CV death, MI, Hospitalization for UA, Revascularization
(> 30 days after randomization), or Stroke
*uptitrated to
80 mg if LDL-C
> 79 mg/dL
IMProved Reduction of Outcomes: Vytorin Efficacy
International Trial (IMPROVE IT)
Cannon CP et al. N Engl J Med 2015;372:2387-2397.
100
90
80
70
60
50
40
QE R 1 4 8 12 16 24 36 48 60 72 84 96
Time since randomization (months)
Number at risk
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Simva 9009 8921 8306 7843 7289 6939 6607 6192 5684 5267 4395 3387 2569 1068
Mean
LD
L-C
(m
g/d
L)
Median Time avg
69.5 vs. 53.7 mg/dL
Simva 69.9 145.1 137.1 48.1 3.8
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
1 yr mean LDL-C TC TG HDL-C hs-CRP
Ez/Simva 8990 8899 8230 7701 7264 6864 6583 6256 5734 5354 4508 3484 2608 1078
Cannon CP et al. N Engl J Med 2015;372:2387-2397.
IMPROVE-IT: Kaplan–Meier Curves for the Primary
Efficacy End Point
34.7%
2742 events
32.7%
2572 events
Cannon CP et al. N Engl J Med 2015;372:2387-2397.
Plot of the IMPROVE-IT Trial Data and Statin Trials for Change in
Low-Density Lipoprotein (LDL) Cholesterol versus Clinical Benefit.
The size of the box is proportional to the number of end points in the study.
Post-hoc analysis: Is it safe to achieve very low
levels of LDL-C?
Giugliano RP, et al., ESC 2015
Post-hoc analysis: Is it safe to achieve very low
levels of LDL-C?
Giugliano RP, et al., ESC 2015
Myalgia w/CK AE->D/c ALT/AST > 3x
ULN
Gallbladder
AENeurocognitive
Post-hoc analysis: Primary efficacy endpoint (CV death, MI, hospitalization for UA, coronary revascularization, stroke)
Giugliano RP, et al., ESC 2015
Myalgia w/CK AE->D/c ALT/AST > 3x
ULN
Gallbladder
AENeurocognitive
Mipomersen
16
Mipomersen: Mechanism of Action
1. Kastelein JJ, et al Circulation. 2006;114(16):1729-35;
2. Crooke ST, ed. Antisense Drug Technology: Principles, Strategies and Applications. 2nd ed. 2008:601-39;
3. Yu R, et al. Drug Metab Dispos. 2007;35(3):460-8.
Mipomersen (apoB)
antisense strand G C C T C A G T C T G C T T C G C A C C
Phosphorothioate
backbone
2′ MOE2′ MOE
2′ deoxy
(supports RNase H activity)
Mipomersen crosses the
hepatocyte and nuclear
membranes to target
apoB mRNA
Nucleus
apoB mRNA
DNA
mRNA–antisense duplex
RNase H recognizes
duplex
RNA is cleaved
Hepatocyte cell
membrane
Cytoplasm
Summary of mipomersen efficacy in combination
with maximally-tolerated lipid-lowering therapy
Raal FJ, et al. Lancet. 2010;375(9719):998-1006; McGowan MP, et al. PLoS One. 2012;7(11):e49006; Stein EA, et al. Circulation. 2012;126(19):2283-92;
Cromwell W, et al. J Am Coll Cardiol. 2011;57:Poster 1011-304.
% change from baseline
Patient
population
Baseline
LDL-C
(mmol/L)
LDL-CMean
ApoBMean
Lp(a)Median
TG Median
HDL-CMean
HoFH 11.4 –25% –27% –32% –18% 19%
Severe HC 7.2 –36% –36% –39% –15% 6%
HeFH with
CAD4.0 –28% –26% –21% –14% 3%
HC at high
risk for CAD3.2 –37% –38% –26% –26% 2%
Percentage change from baseline in LDL-C, apoB, Lp(a), TG and HDL-C
in patients treated with mipomersen
Phase 3: SafetyOn-Treatment Adverse Events and Clinical Findings
• Adverse Events
– Most common AEs were mild to moderate injection site reactions & flu-like
symptoms
• Clinical Findings
– Transaminase increases
– No effect on liver synthetic function, i.e. total bilirubin, albumin, PT
– Modest median increase in hepatic fat, which was reversible after cessation
of dosing
• No clinically significant drug-drug interactions
• No interactions with warfarin
• No QTc changes in dedicated ECG study
Santos RD, et al. Eur Heart J. 2013 [Epub Ahead of Print].
Microsomal Triglyceride
Transfer Protein Inhibition
↑TG results in ↑ hepatic fat
↑TG contributes to
GI tolerability issues
Predicted Effects of MTP Inhibition
Liver Cell
Intestinal
Epithelial
Cell
TG
ER
Lumen
Cytoplasm
Apo B100Degraded
MTP
TG
Apo B48Degraded
MTP
Blood Vessel
Lower
VLDL, LDL,
chylomicrons,
and
chylomicron
remnants
ER
Lumen
Cytoplasm
Hussain et al. J Lipid Res. 2003:44;22-32.
10
0
–10
–20
–30
–40
–50
–60
–70
Mea
n %
ch
ange
in
LDL-
C (±
95
%C
I)
0 10 18 26 36 46 56 66 78 90 102 114 126Week
17 17 16 17 17 17 17 17 17 17 17 17 17
Phase 3 Long-Term Extension
n:
–80
Phase 3 Long-Term Extension Trial:
Mean percent change from baseline in LDL-C by study
visit (week 126 completers population)
Cuchel et al. Circulation. 2013; 128: A16516.
Hepatic Safety: Hepatic Fat (N=19 safety population)*
WeekN
Median, %Mean, %Range, %
Baseline170.70.8
0, 2.4
126137.710.2
1.6–24.7
78176.57.9
0.6–19.0
26175.96.5
1.1–16.3
Week
Med
ian
hep
atic
fat
, % (±
IQR
)
1747
7.67.3
0.6–15.6
150127.6
11.1 0.7–35.2
Cuchel et al. Circulation. 2013; 128: A16516
Lomitapide
• Dose titration schedule can limit GI side effects
• Due to its mechanism of action it may reduce absorption of fat-soluble
vitamins
– Supplements of vit E 400 IU, linoleic acid 200 mg, ALA 210 mg, EPA
110 mg, DHA 80 mg provided
• Low-fat (<20%) diet to minimize GI side effects
• Limit alcohol to one serving daily
• Inhibitors of CYP3A4 may increase exposure to lomitapide
– Do not exceed 30 mg in patients on weak CYP3A4 inhibitors
• Use only low-dose simvastatin and lovastatin
• Lomitapide increases plasma concentrations of warfarin
Mipomersen and Lomitapide
• Orphan Drugs: available for patients with rare genetic
diseases
– Both associated with increase in intrahepatic fat
– Long-term consequences unknown
• Available through a REMS (Risk Evaluation and
Mitigation Strategy) program
• Prescriber training and certification
• Controlled distribution through certified pharmacies
• Prescription authorization forms
PCSK9 Inhibition
PCSK9-mediated degradation of the LDLR:
Schematic of the major domains of PCSK9
Jay D. Horton et al. J. Lipid Res. 2009;50:S172-S177
• Member of the family of proteases
involved in degradation of LDL
receptor
• Secreted by a variety of cells but
primarily in the liver
• Cleavage of the prodomain is
necessary for maturation and
secretion
• PCSK9 binds the EGF-A domain of
the LDL-R and promotes
degradation of the LDL-R within the
lysosome
• Prevents dissociation of the LDL-R
and lipoproteins before and during
the endosomal pathway toward the
lysosome
PCSK9 Regulates the Surface Expression of
LDLRs by Targeting for Lysosomal Degradation
Qian YW, et al. J Lipid Res. 2007;48(7):1488-1498Horton JD, et al. J Lipid Res. 2009;50:S172-S177
Zhang DW, et al. J Biol Chem. 2007;282(55):18602-18612
Genetic variants of PCSK9 demonstrate
its importance in regulating LDL levels
Swiss Med Wkly. 2015;145:w14094
n=301n=9223
11.8
6.3
Peterson AS, Fong LG, Young SG. J Lipid Res. 2008;49(7):1595-1599 Cohen J, et al. Nature Genetics. 2005;37(2):161-165
Cohen JC, et al. N Engl J Med. 2006;354(12):1264-1272
PCSK9 Loss-of-Function Mutations Resulted in
Low LDL-C Levels and Reduced CHD Rates
• Wild-type PCSK9 degrades
LDL receptors.
• Loss-of-function mutations
increase hepatic LDL-R
expression, reducing LDL-C
levels by 15%-40%.
• CHD was reduced 47% to
88% in PCSK9 loss-of-
function mutation carriers
compared with normal
individuals.
Black Subjects
0
12
CH
D (
%)
2
8
10
6
White Subjects
Normal Subject
Mutation Carrier
n=85n=3278
9.7
1.2
4
P=.008 P=.008
Mode of Action Drug Company Phase
PCSK9 binding:
Monoclonal antibodies Alirocumab (REGN727/SAR236553)
Evolocumab (AMG 145)
Bococizumab (RN316)
LY3015014
RG7652
LGT209
Sanofi/Regeneron
Amgen
Pfizer
Eli Lilly
Roche/Genentech
Novartis
3
3
3
2
2 (terminated)
2 (terminated)
Modified binding protein
(adnectin)
(small molecule)
BMS-962476 Bristol-Myers
Squibb/Adnexus
1
PCSK9 synthesis:
RNA interference ALN-PCS02 Alnylam 1
LNA antisense
oligonucleotide SPC-5001 Santaris 1 (terminated)
RNA antisense BMS-844421 Isis/Bristol-Myers Squibb
1 (terminated)
Approaches to PCSK9 Inhibition
Adapted from Stein, Swergold. Curr Atheroscler Rep. 2013;15:310.
J Am Coll Cardiol 2015;65:2638–51
[2914 patients]
J Am Coll Cardiol 2015;65:2638–51[11,598 patients]
Total of 14,512 patients in Phase
2 and Phase 3 Studies
PCSK9 inhibitors: Cardiovascular Outcomes Trials
Alirocumab Evolocumab Bococizumab
Sponsor Sanofi/Regeneron Amgen Pfizer
Trial ODYSSEY Outcomes FOURIER SPIRE I SPIRE II
Sample Size 18,000 22,500 12,000 6300
Patients 4-16 weeks post-ACS MI, stroke, or PAD High risk of CV event
Statin Evidence-based RxAtorvastatin ≥20 mg or
equivalentLipid-lowering Rx
LDL-C ≥70 mg/dL ≥70 mg/dL 70-99 mg/dL ≥100 mg/dL
PCSK9i
DosingEvery 2 weeks Every 2 or Every 4 weeks Every 2 weeks
Endpoint
CHD death, MI,
ischemic stroke, or UA
hospitalization
Primary: CV death, MI,
stroke, UA hospitalization or
coronary revascularization
Key Secondary: CV death,
MI, or stroke
CV death, MI, stroke, or urgent
revascularization
Completion March 2018 December 2017 August 2017
58,800 patients in long-term
cardiovascular outcomes trials
Change in Calculated LDL-C at 2 Weekly
Intervals from Baseline to Week 12
JACC. 2012;59:2344-2353
Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12
in the modified intent-to-treat (mITT) population, by treatment group.
Week 12 estimation using LOCF method.
∆ -5.1% Placebo
-80
-20
-30
0
-10
-40
-50
-60
-70
LD
L-C
Mean
(±S
E)
% C
han
ge f
rom
Baselin
e
Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12
∆ -39.6% SAR236553
50 mg Q2W
∆ -43.2% SAR236553
200 mg Q4W∆ -47.7% SAR236553
300 mg Q4W
∆ -64.2% SAR236553
100 mg Q2W
∆ -72.4% SAR236553
150 mg Q2W
(A) Percentage Changes from Baseline in Levels of LDL-C (calculated) for Patients Treated Every 2 Weeks
(Q2W), (B) Treated Every 4 Weeks
Stein et al. Eur Heart J 2014;35:2249-59.
Evolocumab (AMG-145)
Mean percentage change from baseline in LDL-C. Change over time is shown for the (A) Q14 days and (B)Q28 days
placebo and bococizumab dose groups.
American Journal of Cardiology. 2015;115:1212-21
Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase
Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study
in Statin-Treated Subjects With Hypercholesterolemia
OSLER Trial: Effect of Evolocumab on
Cardiovascular Outcomes
Evolocumab plus standard of care(n=2976)
1
2
HR 0.47
95% CI 0.28-0.78
P=0.003
Composite Endpoint: Death, MI, UA hosp,
coronary revasc, stroke, TIA, or CHF hosp
Standard of care alone
(n=1489)
0.95%
2.18%
3
Days Since Randomization
Cu
mu
lati
ve
Inc
ide
nc
e(%
)
.
Sabatine MS, et al. N Engl J Med. 2015;372:1500-1509
0 30 60 90 120 150 180 210 240 270 300 330 365
Post hoc Analysis of Adjudicated
Major Adverse Cardiovascular Events*
Placebo + maximally
tolerated statin ± other LLT
Alirocumab + maximally
tolerated statin ± other LLT
Cu
mu
lati
ve
pro
ba
bil
ity o
f e
ve
nt
Time (weeks)
Cox model analysis
HR = 0.52 (95% CI 0.31 to 0.90)
Nominal p-value = 0.02
No. at risk:Placebo
Alirocumab
788 776 731 700 670 653 644 597
1550 1533 1445 1392 1342 1306 12661170
1.0
0.8
0.6
0.4
0.2
0.0
0 12 24 36 52 64 78 86
0.06
0.04
0.02
0.00
0 12 24 36 52 64 7886
*Based on primary endpoint for the ODYSSEY OUTCOMES trial, including CHD death,
non-fatal MI, fatal and non-fatal ischemic stroke, and unstable angina requiring
hospitalization. Unstable angina requiring hospitalization was considered based on strict
criteria/clear progression of ischemia.
Robinson JG, et al. N Eng J Med. 2015;372:1489-99.
Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With
Hypercholesterolemia: A Systematic Review and Meta-analysis of effects of PCSK9
Antibodies in Adults With Hypercholesterolemia
Ann Intern Med. 2015;163(1):40-51. doi:10.7326/M14-2957
All-cause mortality
Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults
With Hypercholesterolemia: A Systematic Review and Meta-analysis of effects
of PCSK9 Antibodies in Adults With Hypercholesterolemia
Ann Intern Med. 2015;163(1):40-51. doi:10.7326/M14-2957
Analysis of cardiovascular mortality, adjusted for follow-up.
Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults
With Hypercholesterolemia: A Systematic Review and Meta-analysis of effects
of PCSK9 Antibodies in Adults With Hypercholesterolemia
Ann Intern Med. 2015;163(1):40-51. doi:10.7326/M14-2957
Analysis of myocardial infarction, adjusted for follow-up.
Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults
With Hypercholesterolemia: A Systematic Review and Meta-analysisEffects of
PCSK9 Antibodies in Adults With Hypercholesterolemia
Ann Intern Med. 2015;163(1):40-51. doi:10.7326/M14-2957
Analysis of serious adverse events, adjusted for follow-up.
CETP Inhibition
Barter PJ, et al. N Engl J Med. 2007;357(21):2109-2122Qiu X, et al. Nat Struct Mol Biol. 2007;14(2):106-112
CETP Inhibitors and Modulators
CETP
EvacetrapibTorcetrapib Anacetrapib Dalcetrapib
Is the toxicity of torcetrapib related to the mechanism or the molecule?
Torcetrapib: “beneficial” effects on lipoproteins, but increased
cardiovascular and non-cardiovascular morbidity and mortality
Barter PJ, et al. N Engl J Med. 2007;357(21):2109-2122.
0
92
100
96
Pati
ents
wit
ho
ut
Ev
ent
(%)
360 540 8100
Days after Randomization
90
98
94
180 450 72090 270 630
Atorvastatin only
Torcetrapib
plus Atorvastatin
Schwartz GG, et al. N Engl J Med. 2012;367(22):2089-99.
dal-OUTCOMES Results: No ↓CVD
0
30
100
70
Cu
mu
lati
ve I
ncid
en
ce o
f
Pri
mary
Ou
tco
me (
% o
f P
ati
en
ts)
2 30
10
90
50
1
YearNo. at Risk:
Placebo 1743655173867933Dalcetrapib 1736649573727938
Dalcetrapib
Placebo
20
60
80
400
12
2 30
10
1
2
6
8
4
P=.52 by log-rank test
Lipid Effects of CETP Inhibitors/Modulators% Change from Baseline
CETP AgentDose
(Mg/day)HDL-C (%) LDL-C (%) TG (%)
Torcetrapib 60 61 -24 -9
Dalcetrapib 600 31 -2 -3
Anacetrapib 100 138 -40 -7
Evacetrapib 500 129 -36 -11
Adapted from Cannon C et al. JAMA. 2011;306:2153-2155
Nicholls SJ et al. JAMA. 2011;306:2099-2109
Anacetrapib Evacetrapib
Name (ID) REVEAL (NCT01252953 ACCELERATE (NCT01687998
Company Merck (Oxford Trial Sponsor) Eli Lilly
Sample size 30,000 12,092
Inclusion 1) Age >50 years
2) History of MI
3) Stroke or cerebrovascular
revascularization
4) PAD repair/revascularization
5) DM with symptomatic CAD
1) Age >18 years
2) History of ACS (30-365 days)
3) Cerebrovascular disease
4) PAD
5) DM with CAD
Primary end point CHD death, MI, coronary
revascularization
CV death, MI, CVA, coronary
revascularization, hospitalization for
UA
Study duration Median 4 years Median 2 years
Clinical Trials.gov NCT01252953 NCT01687998
Trial Completion January 2017 July 2016
CETP Inhibitors: Ongoing Phase 3 Trials
Conclusions• Current guidelines permit discretion to discern if LDL-C
reduction is adequate. If not, or if patient is statin intolerant or
only tolerates a low dose of a statin, then non-statin therapy may
be used.
• Mipomersen is an anti-sense molecule that increases
degradation of the mRNA for apoB100.
• Lomitapide is a MTP inhibitor that reduces lipidation and
maturation of apoB100 in the endoplasmic reticulum.
• Mipomersen and lomitapide are only indicated for the treatment
of HoFH.
Conclusions
• Monoclonal antibodies directed against PCSK9 are promising class of
LDL-C lowering agent.
– Being tested in large-scale outcomes trials vs statin background in
patients with stable ischemic heart disease and s/p ACS.
– Alirocumab and evolocumab now FDA approved
• In addition to increasing HDL-C, CETP inhibitors reduce LDL-C, non-
HDL-C, apo B, and Lp(a).
– Anacetrapib and evacetrapib have a favorable safety profiles and
are being tested for clinical efficacy vs statin background in
REVEAL and ACCELERATE trials.
• Adjuvant therapies will ultimately have to demonstrate incremental
benefit against a statin background.