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Mo-W1:1 Effects of cholesteryl ester transfer protein inhibition on lipoprotein metabolism in humans
11
Monday, June 19, 2006: Workshop Mo-W1
PHARMACOLOGY OF ARTERIAL DISEASE: HDL-TARGETED THERAPIES (lst PART)
IMo-W1:11 EP RF FOETCETI NS I
OF CHOLESTERYL ESTER TRANSFER INHIBITION ON LIPOPROTEIN M E T A B O L I S M IN H U M A N S
M.E. B r o u s s e a u ] , M.R. Diffenderfer ] , J.S. Millax 2, C. Naxtsupha ] , B.F. Asztalos 1, F.K. Welty 3 , M.L. Wolfe-, J.P. Mancuso 4 , A.G. Digenio 5 , D.J. Rader 2, E.J. Schaefer ] . 1Lipid Metabolism Laboratory,
JM-USDA-HNRCA at T~ts Universi~, Boston, MA: 2Department of Medicine and Center for Experimental Therapeutics, Universi~ of Pennsyh'ania School of Medicine, Philadelphia, PA: 3Division of Cardiology, Beth Israel Deaconess Medical Center; Boston, MA: 4Department of Clinical Biostatistics, Pfiz~er;Inc., Groton, CT: 5Department of Clinical Sciences, Pfiz~er; Inc., New London, CT, USA Objective: We have previously reported that torcetrapib, a potent inhibitor of cholesteryl ester transfer protein (CETP), markedly increased high density lipoprotein cholesterol (HDL-C) levels in subjects with low HDL-C ( < 4 0 mg/dL) [1]. The goal of the present study was to define the mechanism(s) responsible for the increased HDL levels. M e t h o d s : Nineteen subjects, 9 of whom were taking atorvastatin (atorva) 20 mg for hypercholesterolemia, received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for 4 weeks. In 6 subjects from the non-atorva cohort, the once daily regimen was followed by a 4-week period of torcetrapib 120 mg twice per day. At the end of each phase, subjects underwent a primedconstant infusion of (5,5,5--H3)-L-leucme to determine the kinetics of HDL apolipoprotein (apo) A-I. HDL subspecies were assessed using 2-dimensional lipoprotein electrophoresis. Results: Torcetrapib was well-tolerated, without clinically important drugrelated adverse events or withdrawals. Mean inhibition of CETP activity (%), determined immediately before administration of the last dose, was 38-4-22 (P=0.001) for the atorva cohort and 28-4-16 (P=0.003) and 65-4-16 (P=0.01) for the non-atorva 120 mg once and twice daily cohorts. Torcetrapib 120 mg daily increased plasma concentrations of HDL-C by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorva and non-atorva cohorts, respectively, while the 120 mg twice daily dose increased HDL-C by 106 percent (P<0.001). Torcetrapib had striking effects on concentrations of alpha-1-migrating HDL, which we have consistently shown to be inversely associated with atherosclerotic risk [2,3]. Relative to placebo, torcetrapib 120 mg daily increased the amount of apoA-I in alpha-l-migrating HDL in both the atorva (136%, P<0.001) and non-atorva (153%, P<0.01) cohorts, while an increase of 382% (P<0.01) was observed in the 120 mg twice daily group. Torcetrapib increased HDL apoA-I pool size by 8-4-15% in the atorva cohort (P=0.16) and by 16-4-7% (P<0.0001) and 34-4-8% (P<0.0001) in the non-atorva 120 mg once and twice daily cohorts. These changes were primarily due to reductions in HDL apoA-I fractional catabolic rates (FCR, pools~d), with torcetrapib reducing HDL apoA-I FCR by 6.8%, from 0.237-4-0.042 to 0.218-4-0.030 (P=0.10), in the atorva cohort, by 8.2%, from 0.252-4-0.071 to 0.237-4-0.074 (P<0.001), in the non-atorva 120 mg daily cohort, and by 20.9%, from 0.228-4-0.033 to 0.179-4-0.020 (P<0.01), in the non-atorva 120 mg twice daily cohort. Torcetrapib did not affect HDL apoA-I production rate in any of the cohorts. Conclusions: These data indicate that partial inhibition of CETP with torcetrapib: 1) normalizes apoA-I levels within alpha-l-migrating HDL and 2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism. References [1] M.E. Brousseau, et al. NEngl JMed. 2004;350:1505-15. [2] B.F. Asztalos, et al. Arterioscler Thromb Vasc Biol. 2000;20:2670-6. [3] B.F. Asztalos, et al. Arterioscler Thromb Vasc Biol. 2005;25:2185-91. Funding: This work was supported by the Department of Clinical Research, Medicinal Products Research and Development, Pfizer, Inc., Grotom CT.
~
HDL THERAPY FOR THE SUB-ACUTE TREATMENT OF PATIENTS WITH ACUTE CORONARY SYNDROMES
R.S. Newton. Esperion Therapeutics, A Division of Pfizer Global Researeh and Development, Ann Arbor; Michigan, USA Pharmacologic interventions to treat patients with atherosclerosis originally focused on lowering elevated LDL-cholesterol levels as a therapeutic target. A smaller number of intervention trials have also demonstrated the effect of elevating low HDL-cholesterol levels to reduce cardiovascular morbidity and mortality. Although the mechanism(s) by which HDL beneficially alters the atherosclerotic disease process is (axe) still unknown, it is presumed that high levels of HDL can facilitate the efflux of cholesterol from the arterial wall, thereby enhancing the transport of cholesterol and other lipids from the arterial wall back to the liver for biliary excretion as fecal sterols and bile acids. It has been hypothesized that through a rapid facilitation of HDL-mediated cholesterol efflux from the arterial wall by infusion of synthetic apolipoprotein A-I (apoA-I)/phospholipid complexes, HDL therapy could have a sub-acute therapeutic application to treat cardiovascular disease at the site of action, namely the vulnerable, unstable, lipid-rich atherosclerotic plaque. Individuals recently hospitalized with acute coronary syndromes have been identified as an initial target patient group who might possibly benefit from this type of therapy. Single high dose infusions and repeated injections of lower doses of apoA-I variants or mimetics complexed to phospholipids have produced remarkable and rapid effects on the progression and regression of the atherosclerotic disease process in multiple animal models. The positive results of these preclinical experiments have compelled researchers to perform exploratory studies in human subjects in which reconstituted HDL and synthetic apoAI/phospholipid complexes are infused through a peripheral vein. These clinical studies are testing the hypothesis and the potential use of HDL therapy as a new treatment modality for patients with acute coronary syndromes as an adjunct to the standard of care. A small pilot study of recombinant ApoA-I Milano/phospholipid complex (ETC-216) was conducted in patients with acute coronary syndromes. Intravascular ultrasound (IVUS) was used to measure changes in coronary plaque volume. Five doses of ETC-216 were administered at weekly intervals, with an IVUS measurement done before initiation of treatment and within one to two weeks after completion of treatment, with each patient enrolled in the study acting as his or her own control. This initial study with ETC-216 demonstrated, for the first time, statistically significant regression of coronary atherosclerosis in patients with acute coronary syndromes. The regression of atherosclerosis observed in this study was not associated with any change in the dimensions of the arterial lumen. These promising results will need to be confirmed in larger clinical trials. It is recognized that the ultimate benefit of HDL therapy to patients should be in its ability to reduce cardiovascular events, providing incremental benefit to the current standard of care. This presentation will include a historical review, update and discussion of the preclinical and clinical studies that support the development of HDL therapy for reducing cardiovascular morbidity and mortality in the sub-acute treatment of patients with acute coronary syndromes. References [1] Newton RS, Krause BR. HDL therapy for the acute treatment of atherosclerosis. Atherosclerosis Suppl. 2002;3:31-38. [2] Nicholls S J, Tuzcu EM, SipaJai IS, et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J A m Coll Cardiol. 2006;47:992-997. [3] Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant apoAI Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003; 290:2292-2300. Funding: Clinical study funded by Esperion Therapeutics (now a Division of Pfizer Global R&D), Ann Arbor, Michigan, USA
XIV bzterTtational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006
Monday, June 19, 2006: Workshop Mo-W1
PHARMACOLOGY OF ARTERIAL DISEASE: HDL-TARGETED THERAPIES (lst PART)
IMo-W1:11 EP RF FOETCETI NS I
OF CHOLESTERYL ESTER TRANSFER INHIBITION ON LIPOPROTEIN M E T A B O L I S M IN H U M A N S
M.E. B r o u s s e a u ] , M.R. Diffenderfer ] , J.S. Millax 2, C. Naxtsupha ] , B.F. Asztalos 1, F.K. Welty 3 , M.L. Wolfe-, J.P. Mancuso 4 , A.G. Digenio 5 , D.J. Rader 2, E.J. Schaefer ] . 1Lipid Metabolism Laboratory,
JM-USDA-HNRCA at T~ts Universi~, Boston, MA: 2Department of Medicine and Center for Experimental Therapeutics, Universi~ of Pennsyh'ania School of Medicine, Philadelphia, PA: 3Division of Cardiology, Beth Israel Deaconess Medical Center; Boston, MA: 4Department of Clinical Biostatistics, Pfiz~er;Inc., Groton, CT: 5Department of Clinical Sciences, Pfiz~er; Inc., New London, CT, USA Objective: We have previously reported that torcetrapib, a potent inhibitor of cholesteryl ester transfer protein (CETP), markedly increased high density lipoprotein cholesterol (HDL-C) levels in subjects with low HDL-C ( < 4 0 mg/dL) [1]. The goal of the present study was to define the mechanism(s) responsible for the increased HDL levels. M e t h o d s : Nineteen subjects, 9 of whom were taking atorvastatin (atorva) 20 mg for hypercholesterolemia, received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for 4 weeks. In 6 subjects from the non-atorva cohort, the once daily regimen was followed by a 4-week period of torcetrapib 120 mg twice per day. At the end of each phase, subjects underwent a primedconstant infusion of (5,5,5--H3)-L-leucme to determine the kinetics of HDL apolipoprotein (apo) A-I. HDL subspecies were assessed using 2-dimensional lipoprotein electrophoresis. Results: Torcetrapib was well-tolerated, without clinically important drugrelated adverse events or withdrawals. Mean inhibition of CETP activity (%), determined immediately before administration of the last dose, was 38-4-22 (P=0.001) for the atorva cohort and 28-4-16 (P=0.003) and 65-4-16 (P=0.01) for the non-atorva 120 mg once and twice daily cohorts. Torcetrapib 120 mg daily increased plasma concentrations of HDL-C by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorva and non-atorva cohorts, respectively, while the 120 mg twice daily dose increased HDL-C by 106 percent (P<0.001). Torcetrapib had striking effects on concentrations of alpha-1-migrating HDL, which we have consistently shown to be inversely associated with atherosclerotic risk [2,3]. Relative to placebo, torcetrapib 120 mg daily increased the amount of apoA-I in alpha-l-migrating HDL in both the atorva (136%, P<0.001) and non-atorva (153%, P<0.01) cohorts, while an increase of 382% (P<0.01) was observed in the 120 mg twice daily group. Torcetrapib increased HDL apoA-I pool size by 8-4-15% in the atorva cohort (P=0.16) and by 16-4-7% (P<0.0001) and 34-4-8% (P<0.0001) in the non-atorva 120 mg once and twice daily cohorts. These changes were primarily due to reductions in HDL apoA-I fractional catabolic rates (FCR, pools~d), with torcetrapib reducing HDL apoA-I FCR by 6.8%, from 0.237-4-0.042 to 0.218-4-0.030 (P=0.10), in the atorva cohort, by 8.2%, from 0.252-4-0.071 to 0.237-4-0.074 (P<0.001), in the non-atorva 120 mg daily cohort, and by 20.9%, from 0.228-4-0.033 to 0.179-4-0.020 (P<0.01), in the non-atorva 120 mg twice daily cohort. Torcetrapib did not affect HDL apoA-I production rate in any of the cohorts. Conclusions: These data indicate that partial inhibition of CETP with torcetrapib: 1) normalizes apoA-I levels within alpha-l-migrating HDL and 2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism. References [1] M.E. Brousseau, et al. NEngl JMed. 2004;350:1505-15. [2] B.F. Asztalos, et al. Arterioscler Thromb Vasc Biol. 2000;20:2670-6. [3] B.F. Asztalos, et al. Arterioscler Thromb Vasc Biol. 2005;25:2185-91. Funding: This work was supported by the Department of Clinical Research, Medicinal Products Research and Development, Pfizer, Inc., Grotom CT.
~
HDL THERAPY FOR THE SUB-ACUTE TREATMENT OF PATIENTS WITH ACUTE CORONARY SYNDROMES
R.S. Newton. Esperion Therapeutics, A Division of Pfizer Global Researeh and Development, Ann Arbor; Michigan, USA Pharmacologic interventions to treat patients with atherosclerosis originally focused on lowering elevated LDL-cholesterol levels as a therapeutic target. A smaller number of intervention trials have also demonstrated the effect of elevating low HDL-cholesterol levels to reduce cardiovascular morbidity and mortality. Although the mechanism(s) by which HDL beneficially alters the atherosclerotic disease process is (axe) still unknown, it is presumed that high levels of HDL can facilitate the efflux of cholesterol from the arterial wall, thereby enhancing the transport of cholesterol and other lipids from the arterial wall back to the liver for biliary excretion as fecal sterols and bile acids. It has been hypothesized that through a rapid facilitation of HDL-mediated cholesterol efflux from the arterial wall by infusion of synthetic apolipoprotein A-I (apoA-I)/phospholipid complexes, HDL therapy could have a sub-acute therapeutic application to treat cardiovascular disease at the site of action, namely the vulnerable, unstable, lipid-rich atherosclerotic plaque. Individuals recently hospitalized with acute coronary syndromes have been identified as an initial target patient group who might possibly benefit from this type of therapy. Single high dose infusions and repeated injections of lower doses of apoA-I variants or mimetics complexed to phospholipids have produced remarkable and rapid effects on the progression and regression of the atherosclerotic disease process in multiple animal models. The positive results of these preclinical experiments have compelled researchers to perform exploratory studies in human subjects in which reconstituted HDL and synthetic apoAI/phospholipid complexes are infused through a peripheral vein. These clinical studies are testing the hypothesis and the potential use of HDL therapy as a new treatment modality for patients with acute coronary syndromes as an adjunct to the standard of care. A small pilot study of recombinant ApoA-I Milano/phospholipid complex (ETC-216) was conducted in patients with acute coronary syndromes. Intravascular ultrasound (IVUS) was used to measure changes in coronary plaque volume. Five doses of ETC-216 were administered at weekly intervals, with an IVUS measurement done before initiation of treatment and within one to two weeks after completion of treatment, with each patient enrolled in the study acting as his or her own control. This initial study with ETC-216 demonstrated, for the first time, statistically significant regression of coronary atherosclerosis in patients with acute coronary syndromes. The regression of atherosclerosis observed in this study was not associated with any change in the dimensions of the arterial lumen. These promising results will need to be confirmed in larger clinical trials. It is recognized that the ultimate benefit of HDL therapy to patients should be in its ability to reduce cardiovascular events, providing incremental benefit to the current standard of care. This presentation will include a historical review, update and discussion of the preclinical and clinical studies that support the development of HDL therapy for reducing cardiovascular morbidity and mortality in the sub-acute treatment of patients with acute coronary syndromes. References [1] Newton RS, Krause BR. HDL therapy for the acute treatment of atherosclerosis. Atherosclerosis Suppl. 2002;3:31-38. [2] Nicholls S J, Tuzcu EM, SipaJai IS, et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J A m Coll Cardiol. 2006;47:992-997. [3] Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant apoAI Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003; 290:2292-2300. Funding: Clinical study funded by Esperion Therapeutics (now a Division of Pfizer Global R&D), Ann Arbor, Michigan, USA
XIV bzterTtational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006