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.

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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