Colesterol HDL como target terapeútico en cardiología

Nuevos fármacos para elevar el HDL-C

Colesterol HDL como objetivo terapé utico Desarrollo de nuevos fármacos para elevar el HDL: ¿Qué sabemos y cuál es su estatus?

José Ló pez-Sendó n Hospital U. La Paz. Madrid

Nuevos fármacos para elevar el HDL-C Estrategia Estatina M ayor dosis estatina Selecció n estatina Sec. Ac biliar Ac Nicotinico Fibratos Estrogenos Ejercicio Dieta Vino Intestinal resection

HDL

LDL

+ 0-10% + 0-5%

+ +

Beneficio Clínico + +

+ 0-5% + 5-10% + 15-35% + 5-15% + 5-10% + 10-25% + 5% + 5-25% + 4%

+ + + + + + + + +

+ +/+/+/+ + + +

Nuevos fármacos para elevar el HDL-C

STELLAR STUDY: Change in HDL-C Rosuvastatin Atorvastatin Simvastatin Pravastati n

12 ‡ † 9.6 9.5

10 8

* 7.7

6.8 6.0

5.7

6

4.8

5.3

4.4

4.4

4

3.2 2.1

D H ni e gna h C ) %( e nil e s a b

2 0

5.6

5.2

10 20 40

10 20 40 80

10 20 40 80

Dose (mg)

*p<0.002 vs pravastatin 10 mg †p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mg Observed data in ITT population Adapted from Jones P et al. Am J Cardiol 2003;92:152–160

10 20 40

Nuevos fármacos para elevar el HDL-C

Coronary Drug Project Placebo

Niacin

Canner et al J Am Coll Cardiol, 1986; 8:1245

• • • •

1966-1975 8341 patients with previous MI < 66 years 11% mortality reduction in 15 years

Nuevos fármacos para elevar el HDL-C Helsinki Heart Study. Gemfibrocil in Primay Prevention Cardiac death or M yocadial infarction • 4.081 men 40-55 years • No CAD symptoms • Screening 1981 • HDL increase 11% • LDL decrease 7% • Triglycerides decrease: 40%

Placebo 84 endpoints

Gemfibrocil 57 endpoints

Frick H et al. N Engl J Med 1987;317:1237

Nuevos fármacos para elevar el HDL-C VA-HIT trial. Gemfibrocil in secondary prevention HDL Coronary death or Myocardial 2531 men with CHD Infarction

6%

HDL <40 year 1991-1995

Placebo

P<0.006

LDL

Gemfibrocil

NNT 115/y Triglycerides

Rubins et al. N Engl J Med 1999;341:410–418.

Nuevos fármacos para elevar el HDL-C FIELD trial Fenofibrate treatment and CVD events in type 2 diabetes

FIELD study ● 9.795 type 2 diabetic patients ● 5 year F-up ● 1º Endpoint CHD death or 1st M I: 11% reduction (NS)

Cumulative Risk (%)

Total CVD events Placebo

15

HR 0.89 (95% CI 0.80–0.99) P=0.035

10 Fenofibrate 5

0 0

Numbers at risk

Keech et al. Lancet 2005;366:1849–1861

placebo fenofibrate

1

2

3

4

5

6

Time since randomization (years)

4900 4762 4895 4771

4586 4604

4419 4669

4257 4305

2340 2370

750 775

Nuevos fรกrmacos para elevar el HDL-C

ACCORD NEJM March 2010 Diabetes Type 2 Simvastatin plus Fenofibrate or Placebo

Nuevos fรกrmacos para elevar el HDL-C

ACCORD NEJM March 2010 Diabetes Type 2 Simvastatin plus Fenofibrate or Placebo

Nuevos fรกrmacos para elevar el HDL-C

Nuevos fรกrmacos para elevar el HDL-C

LD L

HD L

Nuevos fรกrmacos para elevar el HDL-C

CETP inhibitors

Cholesteril Ester Transfer Protein

HDLc

LDLc

Nuevos fármacos para elevar el HDL-C

Role of CETP inhibition in atherosclerosis LDL-R

LDL

VLDL CE CETP

Foam cells

TG ABC-A1 RCT Bile LIVER

HDL PLASMA

Atherosclerosis

LDL

ABC-G1

Free cholesterol PERIPHERAL TISSUE

Human CETP deficiency is associated with marked increases in HDL-C1 CETP activity is inversely correlated with plasma HDL-C1 Reduction in CETP activity is associated with a marked reduction in the cholesterol burden in TG-rich particles in both fasting and postprandial phases2,3 Decreasing CETP activity has consistently inhibited atherosclerosis in animal models1 1Barter et al. Arterioscler Thromb Vasc Biol. 2003;23:160–167; 2Contacos et al. Atherosclerosis. 1998;141:87–98; 3Guerin et al. Arterioscler Thromb Vasc Biol. 2008;28:148–154.

Nuevos fรกrmacos para elevar el HDL-C CETP inhibitors Differences in chemical structure and physicochemical properties Anacetrapib3 Dalcetrapib1 Torcetrapib2 F F F

F F F

o F F

o

N

o

F

F

Molecular weight Lipophilicity

389.60

600.40

cLogP ~7

cLogP ~9

NOTE: The clinical relevance of these differences is not known; Clinical development of torcetrapib was halted due to off-target adverse effects 1http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc; 2http://www.ama-assn.org/ama1/pub/upload/mm/365/torcetrapib.doc; 3http:// www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.

637.51 cLogP ~9

Nuevos fĂĄrmacos para elevar el HDL-C

Comparison of CETP inhibitors Dalcetrapib

Torcetrapib Anacetrapib

CETP inhibition

37.2%4

â&#x2030;Ľ 80%5

90%3

HDL-C increase

33.9%4

91%5

129%6

3Masson D. Curr Opin Invest Drugs. 2009;10:980 4de Grooth et al. Circulation. 2002;105:2159 5Clark et al. Arterioscler Thromb Vasc Biol. 2004;24:490

Nuevos fármacos para elevar el HDL-C

ILLUMINATE Torcetrapib/ Atorvastatin Group (Post Run-In)

Lipids (mg/dL)

140

127 115

120

112

112

112

TG -9% (-27,+13)*

100

79.7

80 60

48.6

40

71.8

77.5

80.9

82.9

HDL-C +72.1% (34.7) †

59.7

59.3

1

3

58.2

58.3

LDL-C -24.9% (28.5) †

20 0

Baseline

N Engl J Med 2007;357:2109

6

Study Month

12

*median % change (IQR) for TG at month 12; p<0.001 vs atorvastatin † mean % change (SD) for LDL-C, HDL-C at month 12; p<0.001 vs atorvastatin

Nuevos fármacos para elevar el HDL-C

ILLUMINATE Deaths and major cardiovascular events Death from Any Cause

Patients without Event (%)

100

Major Cardiovascular Events Atorvastatin only

100

99

99

98

98 Torcetrapib plus atorvastatin

97

97

HR 1.58 (95% CI 1.14– 1.29) P=0.006

96

96

95

95

0

0 0

Atorvastatin only

90 180 270 360 450 540 630 720 810 Days after Randomization

Torcetrapib plus atorvastatin HR 1.25 (95% CI 1.09– 1.44) P=0.001

0

90 180 270 360 450 540 630 720 810 Days after Randomization

No. at Risk Atorvastatin only Torcetrapib plus atorvastatin

7534

7530

7521 7509 7487 5833 4043 2078

956

109

7533

7526

7511 7494 7464 5827 4049 2069

943

114

7534 7479 7406 7340 7255 5627 3872 1965 7533 7434 7345 7267 7177 5567 3838 1953

NOTE: Clinical development of torcetrapib was halted due to off-target adverse effects1 Barter et al. N Engl J Med 2007;357:2109–2122.

989 888

103 107

Nuevos fรกrmacos para elevar el HDL-C

On-Trial Blood Pressure By Study Month Torcetrapib Atorvastatin Group

Blood Pressure (mmHg)

Atorvastatin Group 140

123.0

123.9

122.9

128.2*

73.9

73.7

73.7

75.7*

120 100 80 60 40

0

1

3

6

9

12

0

1

3

6

9

12

Study Month Barter et al. N Engl J Med 2007;357:2109

* p<0.001 vs atorvastatin at month 12

Nuevos fรกrmacos para elevar el HDL-C

Serum Aldosterone Percentage of patients with aldosterone > 8 ng/dl

Torcetrapib P value* Atorvastatin + Atorva Baseline

17.1%

16.3%

0.2

Month 3

17.8%

21.6%

< 0.001

Performed after study termination on the 87% of patients with stored baseline and month 3 samples 55% of the analyzed samples had aldosterone levels below the lower limit of quantification by the technique It was, however, possible to determine unambiguously whether or not an analyzed sample had an aldosterone level of 8 ng/dL or more.

*

Barter et al. N Engl J Med 2007;357:2109Wilcoxon comparisons after truncating the data below 8 ng/dl

Nuevos fármacos para elevar el HDL-C

Comparison of CETP inhibitors Dalcetrapib CETP binding site IC50 CETP inhibition HDL-C increase Blood pressure increase Increases aldosterone production (in vitro)

Torcetrapib

Anacetrapi b

9 µM1 37.2%4 33.9%4

Helices at the end of the C and N barrels2 50 nM2 ≥80%5 91%5

No7

Yes8

No3

No7

Yes7

No9

Cys 13 residue1

? (Similar to torcetrapib)3 57 nM3 90%3 129%6

1Okamoto et al. Nature. 2000;406:203–207; 2Clark et al. J Lipid Res. 2006;47:537–552; 3Masson D. Curr Opin Invest Drugs. 2009;10:980-987; 4de Grooth et al. Circulation. 2002;105:2159–2165; 5Clark et al. Arterioscler Thromb Vasc Biol. 2004;24:490–497; 6Krishna et al. Lancet.

2007;370:1907–1914; 7Stein et al. Am J Cardiol. 2009;104:82–91; 8Barter et al. N Engl J Med. 2007;357:2109–2122; 9Forrest et al. Br J Pharmacol 2008;154:1465–1473

Nuevos fĂĄrmacos para elevar el HDL-C

Aldosterone (fmol/g protein)

Torcetrapib, but not dalcetrapib, stimulated aldosterone production in human adrenal H295R cells over 24 hours in vitro1

700 600 500

Therapeutic range

* Dalcetrapib Torcetrapib Angiotensin II Control

400

* *

*

*

*

*

300 200 100 0 0

0.001 0.005

0.01 0.025

0.1

1

2.5

Concentration (ÂľM)

5

7.5

10

AngII 0.1 Âľ M

1Stein et al. Am J Cardiol. 2009;104:82; 2Barter et al. N Engl J Med.

Nuevos fĂĄrmacos para elevar el HDL-C Phase IIb trial: HDL-C increase at week 12 Change from Baseline (%)

40 35

*P<0.0001 vs placebo

* *

30 25 20

*

15 10 5 0

Placebo n=73

dalcetrapib 300 mg n=75

NOTE: Dalcetrapib 600 mg is the dose used in phase III

Stein et al. Am J Cardiol. 2009;104:82â&#x20AC;&#x201C;91.

dalcetrapib 600 mg n=67

dalcetrapib 900 mg n=72

Nuevos fĂĄrmacos para elevar el HDL-C Phase IIb trial: Increase in ApoA-I at week 12 Change from Baseline (%)

16 14

*P<0.001 vs placebo **P<0.0001 vs placebo

** **

12 10 8

*

6 4 2 0

Placebo n=73

dalcetrapib 300 mg n=75

NOTE: Dalcetrapib 600 mg is the dose used in phase III

Stein et al. Am J Cardiol. 2009;104:82â&#x20AC;&#x201C;91.

dalcetrapib 600 mg n=67

dalcetrapib 900 mg n=72

Nuevos fรกrmacos para elevar el HDL-C

Niesor EJ et al. AHA Scientific Sessions, 2009.

Nuevos fรกrmacos para elevar el HDL-C Dalcetrapib, torcetrapib and anacetrapib increased [3H]-cholesterol in plasma HDL 0.5

Radioactivity (kBq/mL) plasma

#

**

#

**

**

0.4 #

*

0.3 0.2 0.1 0.0 Day 3

Day 7

*p<0.05; **p<0.01 vs. control (Dunnett test) #p<0.05 vs. control (Steel test) Dalcetrapib 100 mg/kg bid; torcetrapib 30 mg/kg qd; anacetrapib 30 mg/kg qd Niesor EJ et al. AHA Scientific Sessions, 2009.

Day 10

control dalcetrapib torcetrapib anacetrapib

Nuevos fĂĄrmacos para elevar el HDL-C Dalcetrapib increased fecal [3H]-bile acid and [3H]-neutral sterol radioactivity: Hamster macrophage model of reverse cholesterol transport [3H]-neutral sterols

12

[3H]-total neutral sterol in feces (% of injected)

[3H]-bile acids in feces (% of injected)

[3H]-bile acids (+28%) (+19% )

**

10

*

8 6 4 2 0 C

t on

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ol Da

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p ib To

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a e tr

pib

a An

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a e tr

5

**

4 3 2 1 0

p ib

Data shown are mean ÂąSD *p<0.05; **p<0.01 vs. control (Dunnett test) Dalcetrapib 100 mg/kg bid; torcetrapib 30 mg/kg qd; anacetrapib 30 mg/kg qd Niesor EJ et al. AHA Scientific Sessions, 2009.

(+21%)

C

tr on

ol Da

lc

a e tr

pib To

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a e tr

pib

An

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a e tr

p ib

Nuevos fรกrmacos para elevar el HDL-C The dal-HEART Program dalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport Enhancing HDL efficacy through CETP modulation Double blind, randomized, placebo-controlled studies

dalOUTCOMES1 15,600 pts recently hospitalized for ACS To evaluate the effect of dalcetrapib on CV outcomes RECRUITING

dal-VESSEL2

dal-PLAQUE3

450 pts with CHD or CHD risk equivalent

130 patients with CHD

Effect of dalcetrapib on endothelial function and blood pressure, measured by FMD and ABPM RECRUITMENT COMPLETE

Effect of dalcetrapib on inflammation, plaque size and burden, measured by PET/CT and MRI RECRUITMENT COMPLETE

dal-PLAQUE 24 900 patients with CAD Effect of dalcetrapib on atherosclerotic disease progression, assessed by IVUS and carotid B-mode ultrasound RECRUITING

1Schwartz et al. Am Heart J. 2009;158:896-901; 2http://clinicaltrials.gov/ct2/show/NCT00655538 Accessed April 1st 2010; 3http://clinicaltrials.gov/ct2/show/NCT00655473 Accessed 1st April 2010; 4http://clinicaltrials.gov/ct2/show/NCT01059682 Accessed April 1st 2010 .

Nuevos fármacos para elevar el HDL-C dal-OUTCOMES

• 15.600 stable patients early after ACS (1 – 12 weeks) • Morbidity / Mortality / Safety CHD death, major nonfatal coronary event (MI, hospitalization for ACS, resuscitated cardiac arrest), or stroke of presumed atherothrombotic etiology Pre-randomization phase

Double-blind dalcetrapib 600 mg

Single-blind placebo run-in 4–12 Weeks

placebo

Until 1600 events occur but at least a minimum of 2 years

background of standard medication for ACS (including aspirin, antihypertensives and statins)

Visit 1

Visit 2

Visit 3 Randomization

At least 2 years; Follow up 1st year: every 3 months Following years: every 4 months at least 80% of patients followed for 2.5 years

Schwartz et al. Am Heart J. 2009;158:896

Nuevos fármacos para elevar el HDL-C

The dal-HEART Program Data and Safety M onitoring Board (DSMB) ● DSMB reviewing data of the whole dal-HEART Program ● Charter with clear stopping rules for both safety and efficacy ● Endpoint data as adjudicated by the Clinical Events Committee and as assessed by investigators ● Other safety data: AEs, vital signs, ECGs, and lab tests ● DSMB reviews unblinded data ● Review schedule: every 8 weeks Schwartz et al. Am Heart J. 2009;158:896

Nuevos fรกrmacos para elevar el HDL-C

Anacetrapib

n= 1500 DEFINE n=48 Pharmacoquinetic s n=72 Pharmacoquinetic s n=400 Dose finding n=40 Lipid metablism

Nuevos fármacos para elevar el HDL-C

Anacetrapib.

CP et al.

DEFINE trial Cannon Am Heart J 2009;158:513-9.

● 1500 patients with stable CAD or equivalent

● Safety: Blood pressure, multiple Lab tests, SAEs ● Efficacy: Morbi/mortality, Lipid: HDL, LDL, Apo A1, Apo B

Nuevos fรกrmacos para elevar el HDL-C

Late-Breaking Clinical Trials IV Primary Results of the DEFINE trial: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib Wednesday, Nov 17, 2010, 11:07 AM -11:17 AM Room S100c Presenter: Christopher P Cannon, TIMI Study Group, Boston, MA; Sukrut Shah, Hayes M Dansky, Merck, Rahway, NJ; Michael Davidson, Univ of Chicago Medical Cente, Chicago, IL; Eliot A Brinton, Univ of Utah Sch of Med, Salt Lake City, UT; Antonio M Gotto, Jr., Cornell Medical Sch, New York, NY; Michael Stepanavage, Sherry Xueyu Liu, Patrice Gibbons, Tanya B Ashraf, Jennifer Zafarino, Yale B Mitchel, Merck, Rahway, NJ; Philip Barter, Heart Res Inst, Sydney, Australia

Nuevos fármacos para elevar el HDL-C

Conclusions • HDL increase: an old target with new players • CETP inhibitors: Dalcetrapib and Anacetrapid best near future options • New theraphy strategies: new antithrombotics, new antiatherogenic drugs