Transcript Define: Late Breaking Clinical Trials AHA 2010

Safety of Anacetrapib in Patients with or
at Risk for Coronary Heart Disease
Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes M. Dansky, MD,
Michael Davidson, MD, Eliot A. Brinton, MD, Antonio M. Gotto, Jr., MD,
DPhil, Michael Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons,
MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale Mitchel, MD, Philip
Barter, MD, PhD, for the DEFINE Investigators
Disclosures
C.P. Cannon has received research grants/support from the following
companies: Accumetrics, AstraZeneca, Glaxo Smith Kline, Intekrin,
Merck, and Takeda. He has served on advisory boards, (but donates
funds to charity) for Alnylam, Bristol-Myers Squibb/Sanofi Partnership,
and Novartis. He has received honoraria for educational symposia from
AstraZeneca and Pfizer. He also serves as a clinical advisor and holds
equity in Automedics Medical Systems.
P. Barter has served on advisory boards for AstraZeneca, Merck, Pfizer,
Roche and Sanofi-Aventis; has received honoraria from Abbott,
AstraZeneca, BMS, Merck, Pfizer, Roche and Sanofi-Aventis.
Other co-authors disclosures are listed in the published paper.
The trial was supported by Merck Research Laboratories, Rahway, NJ.
Background - HDL
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While statin therapy has reduced morbidity and mortality
from coronary heart disease by more than 25%, CV disease
remains the #1 cause of death worldwide
Epidemiologic studies: high HDL associated with ↓ risk
Current therapies raise HDL by 5-30%, but none has yet
been proven to reduce CV risk in current statin era
Cholesteryl ester transfer protein (CETP) inhibitors
substantially raise HDL
But, the first agent, torcetrapib, was found to have “off
target” effects in adrenal gland, and lead to increased BP,
mortality and CV events.
Background: CETP inhibition
Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the transfer
of CE from HDL to apoB-containing lipoproteins (VLDL and LDL-C) in exchange for Trig.
LDL-R
CE
LDL /
VLDL
SR-B1
Liver
FC
X inhibition
CETP
CE
LCAT
Bile
FC
HDL
Free Cholesterol (FC)
in Extrahepatic tissues
Anacetrapib
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Orally active, potent, selective CETP inhibitor
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Robust lipid efficacy in Phase I-II studies
No effects on blood pressure, electrolytes, and
aldosterone in preclinical and Phase I-II clinical studies
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In vitro HDL functional assays: HDL particles isolated
from anacetrapib-treated patients demonstrate preserved
(and possibly enhanced) cholesterol efflux properties
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Dose of 100 mg selected based on PK/PD modeling:
minimal dose to achieve maximal effects on HDL and LDL
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Study Objectives and Endpoints
Randomized, double-blind, placebo-controlled trial to
assess the efficacy and safety profile of anacetrapib in
patients with coronary heart disease (CHD) or CHD risk
equivalent disease
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The primary objective of this study was to evaluate safety
to allow decision making for large outcomes study
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Pre-specified safety parameters: BP, potassium, chloride,
sodium and bicarbonate, liver function tests, CPK, myalgia,
adjudicated major CV-events (CV death, non-fatal MI, nonfatal stroke, unstable angina) and death
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Efficacy endpoints:
Primary: LDL-C at Wk 24
Key Secondary: HDL-C, Apo B, Apo A-1, non-HDL-C, TG
at week 24 & 76, and LDL-C at week 76
Patient Population
Men and women, ≥18 and ≤80 years of age, with CHD or CHD riskequivalent disease (Framingham Risk score > 20%)
on background statin therapy +/- other lipid-modifying medications.
 LDL-C ≥50 and ≤100 mg/dL
 HDL-C <60mg/dL
 Triglycerides ≤400 mg/dL
Major Exclusion Criteria
 Chronic heart failure
 Uncontrolled hypertension
 Hepatic disease
 Severe renal impairment
 Treatment with warfarin, digoxin or potent inhibitors/inducers of
CYP3A4
Study Design
Randomization
Study drug stopped if
LDL-C<25mg/dL during
treatment
1:1 Ratio
• Age: 18-80 years
Anacetrapib 100 mg n=750
• LDL-C @ NCEP ATPIII
goal < 100 mg/dL
12 week
follow-up
R
• Statin ± other lipid
modifying therapy
Placebo n=750
Stable dose-regimen of lipid-modifying therapy
Week
Visit
1
-2
0
6 12 18 24 30 38 46 54
2
3
4
Screening
Placebo
Run-in
5
6
7
8
9
10 11
Treatment Phase
62
12
70
13
76
14
80
15
84
16
88
18
Reversibility
Phase
Safety Monitoring and Bayesian Analyses
Periodic review of unblinded safety throughout trial by
external, independent safety monitoring committee (SMC)

Statistical analyses performed by external, independent
statistical group
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All CV serious adverse events and deaths adjudicated by an
external, independent adjudication committee.
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A Bayesian approach was applied to determine the predictive
probability (confidence) to dismiss a torcetrapib-like 25%↑ in
CV events as observed in ILLUMINATE.
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Baseline Characteristics
Characteristic
Anacetrapib
(N=811)
Placebo
(N=812)
Age, mean years ± SD
62.5 ± 8.7
62.9 ± 9.0
Male gender, n (%)
77.6%
76.1%
CHD, n (%)
55.1%
54.3%
CHD risk equivalent, n (%)
44.9%
45.7%
Hypertension, n (%)
69.1%
66.6%
Diabetes, n (%)
53.1%
53.2%
Prior MI, n (%)
22.5%
22.8%
Statin therapy, n (%)
99.5%
99.1%
BMI, mean kg/m2 ± SD
30.4 ± 5.5
30.1 ± 5.2
LDL-C, mean mg/dL ± SD
81.4 ± 21.3
82.2 ± 20.7
HDL-C, mean mg/dL ± SD
40.5 ± 9.3
40.4 ± 9.1
Effects on LDL-C and HDL-C
LDL-C
100
120
100
HDL-C (mg/dL) (SE)
LDL-C (mg/dL) (SE)
80
-39.8% (p<0.001)
60
40
20
0
HDL-C
Anacetrapib
Placebo
80
60
40
20
BaselineWk 6 Wk 12Wk 18Wk 24Wk 30
Wk 46
Wk 62
Wk 76
Anacetrapib n = 804 771 716 687 646
604
568
540
Placebo n = 803 759 741 743 735
711
691
666
Study Week
+138.1% (p<0.001)
0
Anacetrapib
Placebo
BaselineWk 6 Wk 12Wk 18Wk 24Wk 30
Wk 46
Wk 62
Wk 76
Anacetrapib n = 776 757 718 687 647
607
572
543
Placebo n = 766 761 741 744 736
711
691
666
Study Week
Lipid Parameters
LS Mean Percent (95% CI) Placebo-Adjusted
Change from Baseline
Parameter
Week 24
Week 76
Non-HDL-C
-31.7*
(-33.6, -29.8)
-29.4*
(-31.6, -27.3)
Apo B
-21.0*
(-22.7, -19.3)
-18.3*
(-20.2, -16.4)
Apo A-1
44.7*
(42.8, 46.5)
42.3*
(40.5, 44.1)
TC
13.7*
(12.0, 15.3)
15.6*
(13.8, 17.3)
TG
-6.8
(-9.9, -3.9)
Lp(a)
-36.4
(-40.7, -32.3)
ApoE
29.2*
(24.7, 33.7)
*p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown
-5.3
-38.8
35.3*
(-8.9, -1.7)
(-44.5, -33.9)
(30.6, 40.1)
Systolic blood pressure (mmHg)
Anacetrapib had no effect on BP
220
200
18 0
16 0
SBP
14 0
12 0
10 0
80
60
40
A = A n a c et r a pi b L
B = Pla c e b o
20
0
Diastolic blood pressure (mmHg)
Baseline
6
12
18
24
14 0
30
Week
38
46
54
62
70
76
12 0
10 0
DBP
80
60
40
20
A = A n a c et r a pi b L
B= Pl ac eb o
0
Baseline
6
12
18
24
30
Week
38
46
54
62
70
76
Anacetrapib had no effect on key
safety parameters
Absolute
Difference
(%) 95% CI
Anacetrapib
n (%)
Placebo
n (%)
n/N (%)
n/N (%)
Sodium >ULN
86/800 (10.7)
84/797 (10.5)
0.2 (-2.8, 3.2)
0.89
Chloride>ULN
23/800 (2.9)
27/797 (3.4)
-0.5 (-2.3, 1.2)
0.56
Bicarbonate > ULN
11/800 (1.3)
17/797 (2.1)
-0.8 (-2.2, 0.6)
0.25
Potassium < LLN
38/800 (4.8)
38/797 (4.8)
-0.0 (-2.2, 2.1)
0.99
Consecutive elevations of ALT /or AST ≥ 3x ULN
1/800 (0.1)
8/797 (1.0)
-0.9 (-1.9, -0.2)
0.019
0/800
2/797(0.3)
-0.3 (-0.9, 0.2)
0.16
32 (4.0)
28 (3.5)
0.5(-1.4, 2.4)
0.61
15.0 ± 46.5
13.5 ± 48.4
2.0 (-3.0, 7.0)
0.27
Safety Parameters
CK ≥ 10*ULN
Any muscle symptom
Aldosterone
change from baseline (median +/-SD)
p-value
Adjudicated CV Events and Death
Anacetrapib
N=808
n (%)
Pre-specified adjudicated CV
Safety endpoint
Placebo
N=804
n (%)
16 (2.0)
21 (2.6)
Cardiovascular Death
4 (0.5)
1 (0.1)
Non-fatal MI
6 (0.7)
9 (1.1)
Hazard ratio
(95% CI)
0.76 (0.39, 1.45)
P value
0.40
1 (0.1)
6 (0.7)
Primary
Bayesian
Analysis:
Event
Distribution
indicates
a
Non-fatal Stroke
5 (0.6)
5 (0.6)
94%
probability
a 25% increase
Death from
anypredictive
Cause
11 (1.4) of dismissing
8 (1.0)
Revascularization
8 (1.0)
(3.5) Events
0.29 (0.13, 0.64)
0.001
(Torcetrapib-Type)
in28 CV
Unstable Angina
Death or major CV event
(Death/MI/UA/S/Revasc)**
**Post hoc analysis
27 (3.3)
43 (5.3)
0.62 (0.38, 1.01)
0.048
Conclusion
Anacetrapib treatment had robust effects on HDL-C, LDL-C,
non HDL-C and Lp(a) with sustained effects over 18 months.
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Anacetrapib had an acceptable side-effect profile with no
effects on blood pressure, electrolytes or aldosterone.
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Within the power of the study, anacetrapib did not exhibit
adverse cardiovascular effects seen with a prior CETP inhibitor
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The long term safety and efficacy of anacetrapib will now be
tested in a large clinical outcomes trial.
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Cannon CP et al. N Engl J Med 2010;363 (19) online 11/17/2010
• 30,000 patients with occlusive arterial disease in
North America, Europe and Asia
• Background LDL-lowering with atorvastatin
• Randomized to anacetrapib 100 mg vs. placebo
• Scheduled follow-up: 4 years
• Primary outcome: Coronary death, myocardial
infarction or coronary revascularization
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