safety of anacetrapib in patients with or at risk for coronary heart disease christopher p. cannon,...
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Safety of Anacetrapib in Patients Safety of Anacetrapib in Patients with or at Risk for Coronary Heart with or at Risk for Coronary Heart
DiseaseDiseaseChristopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes M. Dansky, MD, Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes M. Dansky, MD, Michael Davidson, MD, Eliot A. Brinton, MD, Antonio M. Gotto, Jr., MD, Michael Davidson, MD, Eliot A. Brinton, MD, Antonio M. Gotto, Jr., MD, DPhil, Michael Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons, DPhil, Michael Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons, MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale Mitchel, MD, Philip MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale Mitchel, MD, Philip Barter, MD, PhD, for the DEFINE Investigators Barter, MD, PhD, for the DEFINE Investigators
DisclosuresDisclosures
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 - HDLBackground - HDL
While statin therapy has reduced morbidity and mortality While statin therapy has reduced morbidity and mortality from coronary heart disease by more than 25%, CV disease from coronary heart disease by more than 25%, CV disease remains the #1 cause of death worldwide remains the #1 cause of death worldwide
Epidemiologic studies: high HDL associated with Epidemiologic studies: high HDL associated with ↓↓ risk risk Current therapies raise HDL by 5-30%, but none has yet Current therapies raise HDL by 5-30%, but none has yet
been proven to reduce CV risk in current statin erabeen 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 Background: CETP inhibitioninhibition
HDLHDL
LDL / LDL / VLDLVLDL
LiverLiver
BileBile
CECE
LDL-RLDL-R
FCFC
FCFC
LCATLCAT
CETPCETP
CECE
SR-B1SR-B1
X X inhibitioninhibition
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.
Free Cholesterol (FC) Free Cholesterol (FC) in Extrahepatic tissuesin Extrahepatic tissues
Anacetrapib Anacetrapib
Orally active, potent, selective CETP inhibitor Orally active, potent, selective CETP inhibitor
Robust lipid efficacy in Phase I-II studiesRobust lipid efficacy in Phase I-II studies
No effects on blood pressure, electrolytes, and No effects on blood pressure, electrolytes, and aldosterone in preclinical and Phase I-II clinical studies aldosterone in preclinical and Phase I-II clinical studies
In vitroIn vitro HDL functional assays: HDL particles isolated HDL functional assays: HDL particles isolated from anacetrapib-treated patients demonstrate preserved from anacetrapib-treated patients demonstrate preserved (and possibly enhanced) cholesterol efflux properties (and possibly enhanced) cholesterol efflux properties
Dose of 100 mg selected based on PK/PD modeling: Dose of 100 mg selected based on PK/PD modeling: minimal dose to achieve maximal effects on HDL and LDLminimal dose to achieve maximal effects on HDL and LDL
Study Objectives and EndpointsStudy Objectives and Endpoints
Randomized, double-blind, placebo-controlled trial to Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk patients with coronary heart disease (CHD) or CHD risk equivalent diseaseequivalent disease
The primary objective of this study was to evaluate safety The primary objective of this study was to evaluate safety to allow decision making for large outcomes studyto allow decision making for large outcomes study
Pre-specified safety parameters: BP, potassium, chloride, Pre-specified safety parameters: BP, potassium, chloride, sodium and bicarbonate, liver function tests, CPK, myalgia, sodium and bicarbonate, liver function tests, CPK, myalgia, adjudicated major CV-events (CV death, non-fatal MI, non-adjudicated major CV-events (CV death, non-fatal MI, non-fatal stroke, unstable angina) and deathfatal stroke, unstable angina) and death
Efficacy endpoints: Efficacy endpoints: Primary: LDL-C at Wk 24Primary: LDL-C at Wk 24Key Secondary: HDL-C, Apo B, Apo A-1, non-HDL-C, Key Secondary: HDL-C, Apo B, Apo A-1, non-HDL-C,
TG TG at week 24 & 76, and LDL-C at week 76 at week 24 & 76, and LDL-C at week 76
Patient PopulationPatient Population
Men and women, ≥18 and ≤80 years of age, with CHD or CHD risk-Men and women, ≥18 and ≤80 years of age, with CHD or CHD risk-equivalent disease (Framingham Risk score > 20%) equivalent disease (Framingham Risk score > 20%) on background statin therapy +/- other lipid-modifying medications. on background statin therapy +/- other lipid-modifying medications.
LDL-C ≥50 and ≤100 mg/dL LDL-C ≥50 and ≤100 mg/dL HDL-C <60mg/dL HDL-C <60mg/dL Triglycerides ≤400 mg/dLTriglycerides ≤400 mg/dL
Major Exclusion CriteriaMajor Exclusion Criteria Chronic heart failureChronic heart failure Uncontrolled hypertension Uncontrolled hypertension Hepatic diseaseHepatic disease Severe renal impairmentSevere renal impairment Treatment with warfarin, digoxin or potent inhibitors/inducers of Treatment with warfarin, digoxin or potent inhibitors/inducers of
CYP3A4CYP3A4
Study DesignStudy Design
• Age: 18-80 years
• LDL-C @ NCEP ATPIII goal < 100 mg/dL
• Statin ± other lipid modifying therapy
Week -2 0 6 12 18 24 30 38 46 54 62 70 76 80 84 88
Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18
ScreeningPlacebo
Run-inTreatment Phase
Stable dose-regimen of lipid-modifying therapy
R 12 week follow-up
Anacetrapib 100 mg n=750
Placebo n=750
Randomization
1:1 Ratio
Reversibility
Phase
Study drug stopped ifLDL-C<25mg/dL during
treatment
Safety Monitoring and Bayesian Safety Monitoring and Bayesian AnalysesAnalyses
Periodic review of unblinded safety throughout trial by Periodic review of unblinded safety throughout trial by external, independent safety monitoring committee (SMC) external, independent safety monitoring committee (SMC)
Statistical analyses performed by external, independent Statistical analyses performed by external, independent statistical groupstatistical group
All CV serious adverse events and deaths adjudicated by an All CV serious adverse events and deaths adjudicated by an external, independent adjudication committee. external, independent adjudication committee.
A Bayesian approach was applied to determine the predictive A Bayesian approach was applied to determine the predictive probability (confidence) to dismiss a torcetrapib-like 25%↑ in probability (confidence) to dismiss a torcetrapib-like 25%↑ in CV events as observed in ILLUMINATE.CV events as observed in ILLUMINATE.
Baseline CharacteristicsBaseline 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-CEffects on LDL-C and HDL-C
HDL-C
Study Week
BaselineWk 6 Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76
HD
L-C
(m
g/d
L) (
SE
)
0
20
40
60
80
100
120
AnacetrapibPlacebo
Anacetrapib n =Anacetrapib n = 776 757 718 687 647 607 572 543
Placebo n =Placebo n = 766 761 741 744 736 711 691 666
LDL-C
Study Week
BaselineWk 6 Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76
LDL-
C (
mg/
dL)
(SE
)
0
20
40
60
80
100
AnacetrapibPlacebo
Anacetrapib n = 804 771 716 687 646 604 568 540
Placebo n = 803 759 741 743 735 711 691 666
-39.8% (p<0.001) +138.1% (p<0.001)
Lipid ParametersLipid Parameters
ParameterLS Mean Percent (95% CI) Placebo-Adjusted
Change from Baseline
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) -5.3 (-8.9, -1.7)
Lp(a) -36.4 (-40.7, -32.3) -38.8 (-44.5, -33.9)
ApoE 29.2* (24.7, 33.7)35.3* (30.6, 40.1)
*p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown
Anacetrapib had no effect on Anacetrapib had no effect on BPBP
SBP
DBP
Sy
sto
lic
blo
od
pre
ss
ure
S
ys
toli
c b
loo
d p
res
su
re
(mm
Hg
)(m
mH
g)
Dia
sto
lic
blo
od
pre
ss
ure
D
ias
toli
c b
loo
d p
res
su
re
(mm
Hg
)(m
mH
g)
Baseline 6 1 2 1 8 24 3 0 3 8 4 6 5 4 6 2 70 7 6
0
2 0
4 0
6 0
8 0
10 0
12 0
14 0
16 0
18 0
2 0 0
2 2 0
A = A na c et ra pibB = Pl a c e b o
0
2 0
4 0
6 0
8 0
10 0
12 0
14 0
A = A n a c et ra pibB = Pl a c eb o
Week
Baseline 6 1 2 1 8 24 3 0 3 8 4 6 5 4 6 2 70 7 6
Week
L
L
Anacetrapib had no effect on key Anacetrapib had no effect on key
safety parameterssafety parameters
Safety ParametersAnacetrapib
n (%)Placebo
n (%)
Absolute Difference(%) 95% CI
n/N (%) n/N (%) p-value
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
CK ≥ 10*ULN 0/800 2/797(0.3) -0.3 (-0.9, 0.2) 0.16
Any muscle symptom 32 (4.0) 28 (3.5) 0.5(-1.4, 2.4) 0.61
Aldosteronechange from baseline (median +/-SD)
15.0 ± 46.5 13.5 ± 48.4 2.0 (-3.0, 7.0) 0.27
Adjudicated CV Events and Adjudicated CV Events and DeathDeath
Anacetrapib N=808n (%)
Placebo N=804n (%)
Hazard ratio (95% CI)
P value
Pre-specified adjudicated CVSafety endpoint
16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40
Cardiovascular Death 4 (0.5) 1 (0.1)
Non-fatal MI 6 (0.7) 9 (1.1)
Unstable Angina 1 (0.1) 6 (0.7)
Non-fatal Stroke 5 (0.6) 5 (0.6)
Death from any Cause 11 (1.4) 8 (1.0)
Revascularization 8 (1.0) 28 (3.5) 0.29 (0.13, 0.64) 0.001
Death or major CV event (Death/MI/UA/S/Revasc)**
27 (3.3) 43 (5.3) 0.62 (0.38, 1.01) 0.048
**Post hoc analysis
Primary Bayesian Analysis: Event Distribution indicates a 94% predictive probability of dismissing a 25% increase
(Torcetrapib-Type) in CV Events
Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C and Lp(a) with sustained effects over 18 months.and Lp(a) with sustained effects over 18 months.
Anacetrapib had an acceptable side-effect profile with no effects on blood Anacetrapib had an acceptable side-effect profile with no effects on blood pressure, electrolytes or aldosterone. pressure, electrolytes or aldosterone.
Within the power of the study, anacetrapib did not exhibit adverse Within the power of the study, anacetrapib did not exhibit adverse cardiovascular effects seen with a prior CETP inhibitorcardiovascular effects seen with a prior CETP inhibitor
The long term safety and efficacy of anacetrapib will now be tested in a The long term safety and efficacy of anacetrapib will now be tested in a large clinical outcomes trial. large clinical outcomes trial.
ConclusionConclusion
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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