Dalcetrapib: A review of Phase II data

Expert Opinion on Investigational Drugs

Volumn 19, Issue 6, 2010, Pages 795-805

  Robinson, Jennifer G ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

CETP inhibitor; Cholesteryl ester transfer protein; Dalcetrapib; HDL C

Indexed keywords

2 METHYLPROPANETHIOIC ACID S [2 [1 (2 ETHYLBUTYL)CYCLOHEXYLCARBOXAMIDO]PHENYL] ESTER; ATORVASTATIN; C REACTIVE PROTEIN; CHOLESTEROL ESTER TRANSFER PROTEIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; KETOCONAZOLE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; PRAVASTATIN; R 04607381; ROSIGLITAZONE; ROSUVASTATIN; SIMVASTATIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; AREA UNDER THE CURVE; ATHEROSCLEROSIS; BLOOD PRESSURE; CARDIOVASCULAR RISK; CHOLESTEROL TRANSPORT; CLINICAL TRIAL; CONFORMATIONAL TRANSITION; CREATINE KINASE BLOOD LEVEL; DIARRHEA; DRUG ANTAGONISM; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; HEART DISEASE; HEART RATE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; ISCHEMIC HEART DISEASE; MAXIMUM PLASMA CONCENTRATION; MYALGIA; NONHUMAN; PHARMACODYNAMICS; PHASE 2 CLINICAL TRIAL; POTASSIUM BLOOD LEVEL; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SIDE EFFECT; SODIUM BLOOD LEVEL; TIME TO MAXIMUM PLASMA CONCENTRATION; TOXIC HEPATITIS; VASCULAR DISEASE;

ANIMALS; ANTICHOLESTEREMIC AGENTS; CARDIOVASCULAR DISEASES; CHOLESTEROL ESTER TRANSFER PROTEINS; CHOLESTEROL, HDL; CLINICAL TRIALS, PHASE II AS TOPIC; HUMANS; SULFHYDRYL COMPOUNDS;

EID: 77952410983     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.2010.488219     Document Type: Review

References (61)

1. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med 2007;356:2388-2398
2. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics-2010 update. A report from the American Heart Association. Circulation 2009 December 17, 2009: CIRCULATIONAHA.109.192667
3. World Health Organization. The top 10 causes of death. Fact sheet No 310. 2008. Available from: http://www.who. int/mediacentre/factsheets/fs310/en/ index. html [Cited 21 January 2010]
4. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278
5. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48:438-445
6. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207
7. National Cholesterol Education Panel. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106:3143-3421
8. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310
9. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: fourth joint task force of the European Society of Cardiology and other Societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2007;28(19):2375-2414 (Pubitemid 47542237)
10. Gordon D, Probstfield J, Garrison R, et al. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 1989;79:8-15
11. AIM-HIGH: Niacin plus statin to prevent vascular events (NCT00120289). 2006. Available from: http://www. clinicaltrials.gov/show/NCT00120289 [Accessed 21 November 2006]
12. Oxford University by the Clinical Trial Service Unit. Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE). 2006 press release
13. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: Efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009;158:896-901.e3
14. Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009;338(1):b92
15. Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J 2010;31:149-164
16. Lewis G, Rader D. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005;96:1221-1232 (Pubitemid 40962099)
17. Barter PJ, Nicholls S, Rye K-A, et al. Antiinflammatory properties of HDL. Circ Res 2004;95:764-772
18. Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res 2006;98:1352-1364
19. Robinson JG, Davidson MH. Investigational drugs targeting HDL-C metabolism and reverse cholesterol transport. Fut Lipidol 2007;2:285-301
20. Coronary Drug Project. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-380
21. Buse JB, ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(12 Suppl 1):S21-33
22. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol 2007;99(6 Suppl 1):S3-18
23. Barter PJ, Kastelein JJP. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol 2006;47:492-499
24. Boekholdt SM, Sacks FM, Jukema JW, et al. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-znalysis of 13,677 subjects. Circulation 2005;111:278-287
25. Barzilai N, Atzmon G, Schechter C, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 2003;290:2030-2040
26. Hirano K, Yamashita S, Kuga Y, et al. Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscler Thromb Vasc Biol 1995;15:1849-1856
27. Zhong S, Sharp DS, Grove JS, et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest 1996;97:2917-2923
28. Curb JD, Abbott RD, Rodriguez BL, et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res 2004;45:948-953
29. Vasan RS, Pencina MJ, Robins SJ, et al. Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community. Circulation 2009;120(24):2414-2420
30. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-2122
31. Kastelein JJP, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;352:1425-1435
32. Nissen SE, Tardif J-C, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-1316
33. Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: Was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol 2007;27:257-260
34. Nicholls SJ, Tuzcu EM, Brennan DM, et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis. Insights from ILLUSTRATE (investigation of lipid level management using coronary ultrasound to assess reduction of atherosclerosis by CETP inhibition and HDL elevation). Circulation 2008;118:2506-2514
35. Okamoto H, Yonemori F, Wakitani K, et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000;406:203-207
36. Okamoto H, Miyai A, Sasase T, et al. Cholesteryl ester transfer protein promotes the formation of cholesterol-rich remnant like lipoprotein particles in human plasma. Clinica Chim Acta 2007;375:92-98
37. Shimoji E, Zhang B, Fan P, Saku K. Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits. Atherosclerosis 2004;172:247-257
38. Zhang B, Fan P, Shimoji E, et al. Inhibition of cholesteryl ester transfer protein activity by JTT-705 increases apolipoprotein E-containing high-density lipoprotein and favorably affects the function and enzyme composition of high-density lipoprotein in rabbits. Arterioscler Thromb Vasc Biol 2004;24:1910-1915
39. Yvan-Charvet L, Matsuura F, Wang N, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 2007;27:1132-1138
40. Niesor E, Okamoto H, Maugeais C, et al. The effects of dalcetrapib on macrophage reverse cholesterol transport in a rodent model [abstract]. Circulation 2009;120:S468
41. Kobayashi J, Okamoto H, Otabe M, et al. Effect of HDL, from Japanese white rabbit administered a new cholesteryl ester transfer protein inhibitor JTT-705, on cholesteryl ester accumulation induced by acetylated low density lipoprotein in J774 macrophage. Atherosclerosis 2002;162:131-135
42. Huang Z, Inazu A, Nohara A, et al. Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia. Clin Sci 2002;103:587-594
43. Morehouse LA, Sugarman ED, Bourassa P-A, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res 2007;48:1263-1272
44. Hermann F, Enseleit F, Spieke LE, et al. Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia. Thromb Res 2009;123:460-465
45. Maugeais C, Magg C, Dernick G, et al. Dalcetrapib binds to and changes the conformation of CETP in a unique manner (differing to that observed with torcetrapib) [abstract]. Circulation 2009;120:S445
46. Niesor EJ, von der Marck E, Brousse M, Maugeais C. Inhibition of cholesteryl ester transfer protein (CETP): Different in vitro characteristics of RO4607381/JTT-705 and torcetrapib (TOR). Atherosclerosis 2008;199(1):231
47. Okamoto H, Iwamoto Y, Maki M, et al. Effect of JTT-705 on cholesteryl ester transfer protein and plasma lipid levels in normolipidemic animals. Eur J Pharmacol 2003;466:147-154
48. Stein EA, Stroes ESG, Steiner G, et al. Safety and tolerability of dalcetrapib. Am J Cardiol 2009;104:82-91
49. Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J 2010;31:480-488
50. Derks M, Fowler S, Kuhlmann O. In vitro and in vivo assessment of the effect of dalcetrapib on a panel of CYP substrates. Curr Med Res Opin 2009;25:891-902
51. Derks M, Fowler S, Kuhlmann O. A single-center, open-label, one-sequence study of dalcetrapib coadministered with ketoconazole, and an in vitro study of the S-methyl metabolite of dalcetrapib. Clin Ther 2009;31:586-599
52. Derks M, Abt M, Phelan M, et al. Coadministration of dalcetrapib with pravastatin, rosuvastatin, or simvastatin: No clinically relevant drug-drug interactions. J Clin Pharmacol 2010; In press
53. Roche. Roche announces start of new atherosclerosis study (dal-PLAQUE 2) for dalcetrapib. 2009. Available from: http://www.roche.com/investors/ir-update/ inv-update-2009-11-18b.htm [Cited 27 January 2010]
54. Duriez P. CETP inhibition. Lancet 2007;370:1882-1883
55. Niesor E, Capponi A, Stauffer A, et al. Effects of CETP inhibitors and mechanism leading to increase in aldosterone production: in vitro structure-activity relationships [abstract]. Arterioscler Tromb Vasc Biol 2009;29:e69
56. Capponi A, Clerc R, Campos L, et al. No increase in the in vitro production of aldosterone or the expression of CYP11B2 with the CETP modulator dalcetrapib (RO4607381/JTT-705), in contrast with torcetrapib [abstract]. Circulation 2008;118:S452
57. Stroes E, Kastelein JJP, Bénardeau A, et al. Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats. Br J Pharmacol 2009;158:1763-1770
58. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 2009;157:352-60.e2
59. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007;370:1907-1914
60. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib. Am Heart J 2009;158:513-9.e3
61. Shinkai H. Cholesteryl ester transfer protein inhibitors as high-density lipoprotein raising agents. Expert Opin Ther Pat 2009;19:1229-1237