new developments in lipid management cgr 0800 h 11 may 2015 rob hegele md frcpc facp distinguished...
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New developments in lipid managementCGR 0800 h 11 May 2015
Rob Hegele MD FRCPC FACPDistinguished Professor of Medicine and Biochemistry
Western UniversityLondon, Canada
Financial disclosure: speaker and ad board member for Aegerion, Amgen, Merck, Pfizer, Sanofi, Valeant
Overview
existing drugsnew drugs
Overview
existing drugsnew drugs:
PCSK9 inhibitors
LDL-C and CHD risk
≥4.52 3.88-<4.52 3.23-<3.88 2.58-<3.23 1.94-<2.58 1.29-<1.94 <1.290
5
10
15
20
25
30
35
Major cardiovascular eventsMajor coronary eventsMajor cerebrovascular events
Achieved LDL-C concentration in mmol/L
% in
cide
nce
of e
vent
s
Boekholdt SM et al. JACC 2014; 64:5485-94
Lower on-Rx LDL-C and reduced risk
Reduced all-cause mortality with statins
4S Investigators Lancet 2004; 364:771-7.
Second line drugs
1. Bile acid sequestrants
2. Ezetimibe
3. Fibrates
4. Niacin
Bile acid sequestrantsLipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT)
Lipid Research Clinics. JAMA 1984;251:351-364.
Life-table cumulative incidence of primary end point (definite CHD death and/or definite nonfatal MI) in treatment groups, computed by Kaplan-Meier method.
1 2 3 4 5 6 7 8 90
2
4
6
8
10
12
Years of Follow up
Life
-Tab
le C
umul
ative
Inci
denc
e (%
)
Placebo
Cholestyramine resin
8
LDL-C and Lipid ChangesM
ean
LD
L-C
(m
mo
l/L
)
1.0
1.25
1.5
1.75
2.0
2.25
2.5
QE R 1 4 8 12 16 24 36 48 60 72 84 96Time since randomization (months)Number at risk:
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 1.81 3.75 1.55 1.24 3.8 mg/dl
EZ/Simva 1.38 3.25 1.36 1.26 3.3 mg/dl
Δ in mmol/L
-0.43 -0.50 -0.19 +0.2 -0.5mg/dl
median time avg1.8 vs. 1.4 mmol/L
AHA Scientific Sessions, 17 Nov 2014
Primary Endpoint — ITT
Simva — 34.7% 2742 events
EZ/Simva — 32.7% 2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke
7-year event rates
NNT= 50
AHA Scientific Sessions, 17 Nov 2014
Simva* EZ/Simva* p-value
Primary 34.7 32.7 0.016 CVD/MI/UA/Cor Revasc/CVA Secondary #1 40.3 38.7 0.034 All D/MI/UA/Cor Revasc/CVA Secondary #2 18.9 17.5 0.016 CHD/MI/Urgent Cor Revasc Secondary #3 36.2 34.5 0.035 CVD/MI/UA/All Revasc/CVA
0.936
Ezetimibe/Simva Better
Simva Better
UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization (≥30 days after randomization); All D, all-cause death; CHD, coronary heart disease death; All Revasc, coronary and non-coronary revascularization (≥30 days)
*7-year event rates (%)
Primary and 3 Prespecified Secondary Endpoints — ITT
0.8 1.0 1.1
0.948
0.912
0.945
AHA Scientific Sessions, 19 Nov 2014
Safety — ITT
No statistically significant differences in cancer or muscle- or gallbladder-related events
Simva n=9077
%
EZ/Simvan=9067
% p
ALT and/or AST≥3x ULN 2.3 2.5 0.43
Cholecystectomy 1.5 1.5 0.96
Gallbladder-related AEs 3.5 3.1 0.10
Rhabdomyolysis* 0.2 0.1 0.37
Myopathy* 0.1 0.2 0.32
Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64
Cancer* (7-yr KM %) 10.2 10.2 0.57
* Adjudicated by Clinical Events Committee % = n/N for the trial duration
IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit
CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.
IMPROVE-IT
Fibrates: Gemfibrozil Reduced MCVEin Patients with CAD by 22%
Rubins HB et al. NEJM 1999; 341: 410-8
ACCORD-Lipid: MACE
16
Possible role for fibrates
Sacks F et al. N Engl J Med 2010; 363:692-695
High TG, low HDL-C subgroups Normolipidemic subgroups
Coronary Drug Project:Effect of Niacin in Post-MI Patients
The Coronary Drug Project Research Group. JAMA. 1975;231:360-381.
Cumulative Rate of Nonfatal MI in Post-MI Patients Treated With Niacin or PlaceboCu
mul
ative
Eve
nt R
ate
(%)
(P < 0.004)
27%
Recurrent nonfatal MI
0 12 34 36 48 60
15
10
5
PlaceboNiacin
Patients receiving niacin (n=1119) vs patients receiving placebo (n=2789). Total mortalitywas similar between the 2 groups at 5 years.
Months of Follow-up
HPS2-THRIVE: Major Vascular Events on Niacin/Laropiprant (ERN/LRPT)
0 1 2 3 4 Years of follow-up
0
5
10
15
20
Pat
ient
s s
uffe
ring
even
ts (
%)
15.0% 14.5%
Placebo ERN/LRPT
Risk ratio 0.96 (95% CI 0.90–1.03) Logrank P=0.29
Armitage J, et al "HPS2-THRIVE: Randomized placebo-controlled trial of ER Niacin and laropriprant in 25,673 patients with pre-existing cardiovascular disease" ACC 2013.
CVD end point reduction
Drug class No background statin
With background statin
Bile acid sequestrants
Yes (LRC-CPPT) Not done
Ezetimibe Not done Yes (SHARP; IMPROVE-IT)
Fibrates Yes (HHS, VA-HIT) No (ACCORD, FIELD)
Niacin Yes (CDP) No (AIM-HIGH, HPS2)
20
Combination treatment: safety
Very safe: statin + bile acid sequestrantstatin + ezetimibe
Quite safe: statin + niacinstatin + fenofibratestatin + bezafibrate
Riskier statins: lova, simva
Reduce dose: fenofibrate if creatinine > 150
Avoid: statin + gemfibrozil
Compound Dose % LDL lowering Evidence level
Isoflavones (soy protein powder) 50-100 mg 3-11% A-I
Soluble fibre 5-15 g 5-20% A-I
Oatmeal 60 g 2-6% A-I
Plant sterols 1.3 g 4-13% A-I
AHA Step 2 diet 5-10% A-I
Mediterranean diet 5-10% A-I
Portfolio diet 10-20% A-I
Almonds 50-80 g 5% B-I
Green tea extract 1.2 g 10% B-I
High carb diet 60% of calories 5-10% B-I
High protein diet 25% of calories 5-10% B-I
Red yeast rice 1-2 g 7-20% A-IIa
Guggulipid 100 mg 12% A-IIb
Huang et al. Can J Cardiol 2011: 488-505
Non-pharmacological LDL-lowering
• keep LDL-C targets
• combination Rx
• non-statin LDL-C lowering
• non-HDL-C as alternate
• non-fasting lipids
• ongoing RCTs – PCSK9i lower LDL-C < 1.0 mmol/L
• ongoing RCTs – CETP inhibitors
Looking forward to the 2015 guidelines
Emerging lipid therapies
effect- lomitapide lowers LDL-C by 40% - mipomersen lowers LDL-C by 40%- anti-PCSK9 lowers LDL-C by 60%- CETP inh (ana, eva) lowers LDL-C by 30%
- alipogene tiparvovec lowers TG by 30%- anti-APOC3 lowers TG by 50%- anti-ANGPTL lowers TG by 50%
Four Mechanisms for Reducing LDL-C
Lilly SM, Rader DJ. Curr Opin Lipid. 2007;18:650–655.; Shinkai H. Vasc Health Risk Manag. 2012;8:323-331.
Emerging lipid therapies
Emerging lipid therapies
Proprotein
Emerging lipid therapies
ProproteinConvertase
Emerging lipid therapies
ProproteinConvertaseSubtilisin
Emerging lipid therapies
ProproteinConvertaseSubtilisinKexin
Emerging lipid therapies
ProproteinConvertaseSubtilisinKexin9
PCSK9 inhibitors
- very potent LDL-C reduction: up to 70%- non-statin mechanism- mAbs: sc q2 or q4 wk- competitive environment- signal for 50% reduced MCVE
Loss-of-Function Mutations in PCSK9 are Associated with Lower Serum LDL-C and Lower Incidence of CHD
Cohen JC et al. N Engl J Med. 2006;354:1264-72.
PCSK9 mutations were associated with a 28% reduction in mean LDL-C and an 88% reduction in the lifetime risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95% CI, 0.02 to 0.81; P = 0.03)
30
20
10
0
Fre
quen
cy (
%)
1.3 2.6 5.2 6.5 7.8
Plasma LDL-C in Black Subjects (mmol/L)
0
No Mutation(N=3 278) 50th Percentile
30
20
10
01.3 2.6 3.9 5.2 6.5 7.80
PCSK9142X or PCSK9679X
(N=85)
12
8
4
0No Yes
PCSK9142X or PCSK9679X
Cor
onar
y H
eart
Dis
ease
(%
)
3.9
Loss-of-Function Mutations in PCSK9 are Associated with Lower Serum LDL-C and Lower Incidence of CHD
PCSK9 mutations were associated with a 28% reduction in mean LDL-C and an 88% reduction in the lifetime risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95% CI, 0.02 to 0.81; P = 0.03)
30
20
10
0
Fre
quen
cy (
%)
1.3 2.6 5.2 6.5 7.8
Plasma LDL-C in Black Subjects (mmol/L)
0
No Mutation(N=3 278) 50th Percentile
30
20
10
01.3 2.6 3.9 5.2 6.5 7.80
PCSK9142X or PCSK9679X
(N=85)
12
8
4
0No Yes
PCSK9142X or PCSK9679X
Cor
onar
y H
eart
Dis
ease
(%
)
3.9
• PCSK9 LOF mutations found in 1% to 4% of population• Associated with
- Lower serum LDL-C- Lower incidence of coronary heart disease
Cohen JC et al. N Engl J Med. 2006;354:1264-72.
In the Presence of PCSK9, the LDL-R Is Degraded and Does Not Cycle Back to Cell Surface
Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.
Serum LDL-Cholesterol Binds to LDL-Receptors. Following Internalization, LDL is Degraded and the Receptor Recycled
Monoclonal Antibody binds to PCSK9 and inhibits Binding to the LDL-Receptor
Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.
Blocking PCSK9 Activity Inhibits Intracellular Degradation of LDL-R
PCSK9-Directed Therapies in DevelopmentCompany Drug Agent Indication Phase
Inhibition of PCSK9 binding to LDLR
Amgen Evolocumab Fully Human mAb Hypercholesterolemia 3
Sanofi/Regeneron Alirocumab Fully Human mAb Hypercholesterolemia 3
Pfizer/Rinat Neuroscience
Bococizumab mAb Hypercholesterolemia 3
Novartis LGT209 mAb Hypercholesterolemia 2
Roche/ Genentech RG7652 mAb Hypercholesterolemia 2
Eli-Lilly LY3015014 mAb Hypercholesterolemia 2
PCSK9 protein binding fragment
BMS/ Adnexus BMS-962476 Adnexins Hypercholesterolemia 1
Inhibition of PCSK9 synthesis (gene silencing)
Alnylam ALN-PCS02 siRNA oligonucleotides Hypercholesterolemia 2
Idera TBDAntisense
oligonucleotideHypercholesterolemia Preclinical
Inhibition of PCSK9 autocatalytic processing
Seometrix SX-PCK9 Small peptide mimetic Hypercholesterolemia Preclinical
Shifa Biomedical TBD Small molecule Metabolic Disorders Preclinical
Cadila Healthcare TBD Small molecule Preclinical
Adapted from Rhainds D, et al. Clin Lipidol. 2012;7:621-640.;Lambert G, et al. J Lipid Res. 2012;53:2515-24;clinicaltrials.gov; Stein EA. Swergold GR. Curr Atheroscler Rep. 2013:15:310.
mAb: monoclonal antibody; CVD: cardiovascular disease
Terminology of Monoclonal Antibodies
1. Weiner LM. J Immunother. 2006;29:1-9.; 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.; 3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125.; 4. Gerber DE. Am Fam Physician. 2008;77:311-319.
Mouse(0% human)
Human(100% human)
Humanized (> 90% human)
Chimeric (65% human)
-umab-zumab-ximab-omabGeneric suffix:
Source (% human protein)
High LowPotential for immunogenicity
Alirocumab: Phase II/III LDL-C Lowering Summary
*P<0.0001 vs. Placebo 1. Stein EA, et al. Presented at ACC 2014. Abstract 1183-126.2. McKenney JM, et al. J Am Coll Cardiol. 2012;59(25):2344-53.3. Roth EM, et al. Poster presentation at ACC 2014. Abstract 1183-125..
Placebo Alirocumab
0
-10
-20
-30
-40
-50
-60
-70LS
Me
an
% C
ha
ng
e in
LD
L-C
Le
vel
at
We
ek
8/1
2 L
OC
F
HeFH12 wk RCT+ 52 wk open-label extension
add-on therapy, Mean LDL-C 3.9 mmol/L
Open-label extension1
Placebon=15
Q2Wn=45
150 mg
-67.9%
Hypercholesterolemia12 weeks
N=88, add-on therapy, inclusion LDL-C ≥2.6 mmol/L
Dose Ranging
Q2W†
n=30Placebo
n=31
*
150 mg
Alirocumab was well tolerated with no evidence of any liver or creatine kinase elevations. Injection site bruising the most frequently reported adverse event.
Hypercholesterolemia24 weeks
N=103, monotherapyInclusion LDL-C 2.6-4.9 mmol/L
ODYSSEY MONO3
150 mg
Q2Wn=52
EZEn=51
Ezetimibe
10 mg
-47%
-16%
150 mg 100 mg 50 mg
Q2Wn=29
Q4Wn=30
Q4Wn=28
Q2Wn=31
-5.0%
200 mg 300 mg
-40.0%
-64%
-72%
-48%
-43%
*
*
*
* † LDL-C reductions with SAR236553 weresimilar among atorvastatin doses (10, 20, 40 mg)
-10.7%
Q2Wn=54
-59.5%
150 mg
Bococizumab: Efficacy as add-on therapy in hypercholesterolemia 24 week study
Phase 2 StudyHypercholesterolemiaN=354, add-on therapy,
inclusion LDL-C ≥2.1 mmol/L
LS Mean % Change in LDL-C Levelat Week 8/12 LOCF
0
-10
-20
-30
-40
-50
-60
-70
150 mg
Q2WQ2W
150 mg 150 mg
50 mg 100 mg 150 mg
Q2W Q4W
-34%
-45%
-53%
-28%
200 mg
-45%
300 mg
Q4W
Ballantyne CM, et al. Poster presentation at ACC 2014. Abstract 1183-129
• Incidence and profile of adverse events similar across groups.
Sabatine M et al. NEJM Mar 2015 online
Evolocumab: effect on LDL-C
LDL-C 3.1 mmol/L
LDL-C 1.24 mmol/L
Evolocumab: CVD reduction
Sabatine M et al. NEJM Mar 2015 online
Evolocumab: adverse events
Sabatine M et al. NEJM Mar 2015 online
Alirocumab: effect on LDL-C
Robinson J et al. NEJM Mar 2015 online
Alirocumab: CVD reduction
Robinson J et al. NEJM Mar 2015 online
Alirocumab: adverse events
Robinson J et al. NEJM Mar 2015 online
Four Mechanisms for Reducing LDL-C
Lilly SM, Rader DJ. Curr Opin Lipid. 2007;18:650–655.; Shinkai H. Vasc Health Risk Manag. 2012;8:323-331.
Proprietary. ©2014 Aegerion Pharmaceuticals, Inc. All Rights Reserved. Juxtapid is a trademark of Aegerion Pharmaceuticals, Inc. Licensed User Aegerion Pharmaceuticals (Canada) Ltd.
10
0
–10
–20
–30
–40
–50
–60
–70
Me
an
% c
ha
ng
e in
LD
L-C
(±9
5%
CI)
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
Lomitapide: LDL-C change from baseline
48
(Week 126 Completers Population)
APOB antisense: mipomersen in HoFH
Raal D et al. Lancet 2010; 375:998-1006.
CETP inhibition: effect on LDL-C
Kastelein J et al. Lancet 2015 75:998-1006.
CETP inhibition: effect on HDL-C
Kastelein J et al. Lancet 2015 75:998-1006.
Summary
- statins are good- LDL-C targets will remain in guidelines- second line drugs work – depends on context- novel Rx for LDL-C:
- PCSK9 inhibitors- lomitapide- APOB antisense- CETP inhibitors