1. Current Status of Anacetrapib: A Second Generation CETP Inhibitor to Raise HDL and Lower LDL
Yale Mitchel, MD
Cardiovascular Disease Department
Merck Research Laboratories

2. DISCLOSURES
Yale B. Mitchel, MD
Salary
Merck & Co., Inc.

3. Role of CETP in Lipoprotein Metabolism
Macrophage CE FC
HDL
Bile
ABCA1
ABCG1
ApoA1 BA CE CE TG
LCAT
Nascent-Preb HDL
FC, PL
ApoA1 FC CE
SR-B1
Lipases TG
LDLR CE TG
CETP inhibition
CETP CE TG CE
ApoB
VLDL/LDL

4. Torcetrapib: “Beneficial” Effects on Lipoproteins, but Increased Cardiovascular and Non- Cardiovascular Morbidity and Mortality
8 week study
Data from 12/18/02 analysts meeting
N Engl J Med 2007;357:
Is the toxicity of torcetrapib related to the mechanism or the molecule?

5. Scientific Case for Developing the CETP inhibitor Anacetrapib
CHD remains a significant unmet medical need; substantial residual CV risk on statins
Strong biologic plausibility of CETP inhibition mechanism
Strong epidemiology supporting CV protective role of HDL
Large LDL-C lowering and HDL-C raising with anacetrapib
No evidence that HDL from anacetrapib-treated patients is dysfunctional
Anacetrapib clearly distinguished from torcetrapib
Data suggests off-target vascular effects of torcetrapib
Anacetrapib is well tolerated: No increase in BP, no change in electrolytes or aldosterone
Merck believes that CETP inhibition target is at equipoise and that anacetrapib is an appropriate molecule to test the mechanism

6. Protocol 03: Anacetrapib Monotherapy Dose Ranging Study: Effects of Monotherapy LDL-C and HDL-C
Weeks on Treatment
-20 20 40 60 80
100
120
140
160 2 4 8
Percent Change from Baseline
in HDL-C
HDL-C
Weeks on Treatment 2 4 8
-80
-60
-40
-20 20
Percent Change from Baseline
in LDL-C
Placebo
Anacetrapib 10 mg
Anacetrapib 40 mg
Anacetrapib 150 mg
Anacetrapib 300 mg
Bloomfield et al. Am Heart J 2009;157:352-60

7. HDL cholesterol concentration (g/mL) concentration (g/mL)
Effect of HDL from Anacetrapib-treated Patients (300 mg) on Cholesterol Efflux from Human THP-1 Macrophages
MǾ incubated with 50μg/mL acLDL for 24h,then incubated with increasing PEG-isolated HDL-C concs (12, 36, 72μg/mL) from pre- and post-anacetrapib rx’ed pts for 6h
TC, FC, CE measured in media in triplicate experiments. Values are means±SEM. 5 10 15 20 12 36 72
HDL cholesterol concentration (g/mL)
(g/mg cell protein)
∆TC in media
Before treatment
After treatment *
HDL cholesterol
concentration (g/mL)
∆FC in media
∆CE in media
*P<0,05, significant difference vs control PEG-HDL
Tall A, 2009 XV International Symposium on Atherosclerosis; June 2009

8. Effect of HDL from Anacetrapib-treated Patients (300 mg) on Suppression of Inflammation in Macrophages
MǾ rxed with 50μg/mL acLDL for 16h, then incubated with increased volumes of control and anacetrapib-HDL-2 for 3h, then washed and incubated with LipidA for 3h.
Inflammatory transcript levels (TNFα, IL-6, MIP1α and MIP2) measured in triplicate experiments; means ±SEM expressed as arbitrary units (a.u).
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
Basal
LPS
5l
10l
25l
IL-6 mRNA (a.u)
Volume of HDL (l) 50
100
150
200
250
MIP1 mRNA (a.u)
MIP1 mRNA
IL-6 mRNA
control-HDL
Anacetrapib-HDL
Tall, A 2009 XV International Symposium on Atherosclerosis; June 2009

9. MK-0859 Anacetrapib (50 mg/kg)
Effect of Torcetrapib and Anacetrapib on Blood Pressure in Conscious Rhesus Monkeys
Torcetrapib
(500 mg/kg)
MK-0859
Anacetrapib (50 mg/kg)
14.0 µM
at 3 hrs
23.7 µM
at 6 hrs
13.3 µM
at 24 hrs
Forrest et al. British Journal of Pharmacology (2008) 154, 1465–1473

10. The Effect of Torcetrapib and Anacetrapib on Aldosterone Secretion from Primary Rat Adrenocortical Cells
Anacetrapib
Anacetrapib has no effect on aldosterone release up to 10 uM
Torcetrapib
Dose-dependent increase in aldosterone release with torcetrapib
Forrest et al., British Journal Pharmacology 2008;154:

11. Phase I Study: Effect of Anacetrapib on 24-H Ambulatory Systolic Blood Pressure
Krishna et al., Lancet 2007; 370: 1907–14

12. LS Mean % Change from Baseline (±SE)
Protocol 03: Anacetrapib Dose Ranging Study Change in Blood Pressure
-10 -5 5 10
Systolic
Diastolic
LS Mean % Change from Baseline (±SE)
Placebo
Placebo
Treatment
Anacetrapib 10 mg
Anacetrapib 40 mg
Anacetrapib 150 mg
Anacetrapib 300 mg
Anacetrapib 10 mg
Anacetrapib 40 mg
Anacetrapib 150 mg
Anacetrapib 300 mg
Bloomfield et al. Am Heart J 2009;157:352-60

13. Development Strategy for MK-859
Large outcome study necessary to demonstrate benefit of mechanism
Merck embarked on a step-wise approach to the outcome study
Atherosclerosis imaging tools/biomarkers not sufficiently robust for decision making
Conduct phase II/III study (protocol 019: DEFINE); N=1600 high risk individuals treated for 18 months
Gain additional clinical experience in a high risk patient population
Careful evaluation on key safety parameters (BP, electrolytes, aldosterone, CV events)
Safety monitoring by external DSMB
Continuing investigations into mechanism of action
Outcome trial triggered after “sufficient” experience gained in PN019

14. Program Timelines
1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q
Phase II/III Study (PN019)
(Data trigger)
Carco
Outcomes Planning Activities
Clinical Outcomes (PN031)
6 m *
12 m *
18 m *
* All pts complete

15. Stable dose-regimen of statin ± other lipid-modifying therapy
Phase II/III: PN019 Study Design
Endpoints
Co-Primary: change in LDL-C 24 wks
Co-primary: Tolerability:
Tier 1 AE: CK, AST/ALT, electrolytes, blood pressure, adjudicated CV events
Stopping rules based on distribution of CV events using Bayesian approach
Inclusion Criteria
Age: years
CHD, CHD risk equiv
LDL-C: > 50 mg/dL <100 mg/dL
HDL-C<60
Statin ± other lipid modifying therapy
Randomization
1:1 Ratio
Anacetrapib 100 mg n=800 R
Placebo n=800
Stable dose-regimen of statin ± other lipid-modifying therapy
Treatment Phase
Week
Cannon et al, Am Heart J 2009;158: e3.

16. DEFINE (P019) Status Enrollment
2423 patients screened & 1623 randomized
Exposure (as of 8-Feb-10)
Safety
Thus far drug well tolerated
No evidence of an effect on blood pressure or electrolytes
Small number of liver function and muscle abnormalities
No unexpected adverse experiences
Weeks 6 12 18 24 30 38 46 54 62 70 76
# patient exp
1569
1509
1461
1409
1365
1317
1295
1261
958
555
232
Cannon et al, Am Heart J 2009;158: e3.

17. CETP Inhibition and Anacetrapib
CETP inhibition mechanism is at equipoise
Anacetrapib is an appropriate molecule to assess CETP inhibition mechanism
Proceeding in a step-wise fashion
Interim data from ongoing phase II/III study will trigger outcome study
Outcome study will assess effect of anacetrapib on top of statin therapy in patients at high risk of CV events