Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: Rationale and design of the ODYSSEY COMBO I and II trials

BMC Cardiovascular Disorders

Volumn 14, Issue 1, 2014, Pages

  Colhoun, Helen M ^a   Robinson, Jennifer G ^b   Farnier, Michel ^c   Cariou, Bertrand ^d   Blom, Dirk ^e   Kereiakes, Dean J ^f   Lorenzato, Christelle ^g   Pordy, Robert ^h   Chaudhari, Umesh ^g  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

^b UNIVERSITY OF IOWA   (United States)

^c Point Medical   (France)

^d NANTES UNIVERSITY HOSPITAL   (France)

^e UNIVERSITY OF CAPE TOWN   (South Africa)

^f The Carl & Edyth Lindner Center for Research & Education   (United States)

^g SANOFI   (France)

^h REGENERON PHARMACEUTICALS INC   (United States)

Author keywords

Alirocumab; Ezetimibe; Low density lipoprotein cholesterol; Monoclonal antibody; Proprotein convertase subtilisin kexin type 9

Indexed keywords

ALIROCUMAB; ATORVASTATIN; EZETIMIBE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; ROSUVASTATIN; SIMVASTATIN; BIOLOGICAL MARKER; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MONOCLONAL ANTIBODY; PCSK9 PROTEIN, HUMAN; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR;

ADULT; ARTICLE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CLINICAL EFFECTIVENESS; CONTROLLED STUDY; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG SAFETY; HUMAN; HYPERCHOLESTEROLEMIA; MAJOR CLINICAL STUDY; MULTICENTER STUDY; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RISK ASSESSMENT; TREATMENT DURATION; TREATMENT OUTCOME; TREATMENT PLANNING; ANTAGONISTS AND INHIBITORS; BLOOD; CARDIOVASCULAR DISEASES; CLINICAL PROTOCOL; CLINICAL TRIAL; COMPLICATION; DRUG COMBINATION; ENZYMOLOGY; IMMUNOLOGY; MAXIMUM TOLERATED DOSE; METABOLISM; METHODOLOGY; RISK FACTOR; TIME; UNITED STATES;

ANTIBODIES, MONOCLONAL; BIOLOGICAL MARKERS; CARDIOVASCULAR DISEASES; CHOLESTEROL, LDL; CLINICAL PROTOCOLS; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERCHOLESTEROLEMIA; MAXIMUM TOLERATED DOSE; PROPROTEIN CONVERTASES; RESEARCH DESIGN; RISK ASSESSMENT; RISK FACTORS; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS; TIME FACTORS; TREATMENT OUTCOME; UNITED STATES;

EID: 84921323646     PISSN: None     EISSN: 14712261     Source Type: Journal    
DOI: 10.1186/1471-2261-14-121     Document Type: Article

References (40)

1. Mihaylova B, Eüberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C: The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012, 380:581-590.
2. Baigent C, Blackwell L, Eüberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010, 376:1670-1681.
3. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvänne M, op Scholte op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F: European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth 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 2012, 2012(33):1635-1701.
4. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D: ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011, 32:1769-1818.
5. Anderson TJ, Gregoire J, Hegele RA, Couture P, Mancini GB, McPherson R, Francis GA, Poirier P, Lau DC, Grover S, Genest J Jr, Carpentier AC, Dufour R, Gupta M, Ward R, Leiter LA, Lonn E, Ng DS, Pearson GJ, Yates GM, Stone JA, Ur E: 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013, 29:151-167.
6. Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, Golüberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Aübert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, et al: ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014, 129:S1-S45.
7. Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Peto R, Collins R: Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010, 376:1658-1669.
8. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, et al: Executive summary: heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation 2013, 127:143-152.
9. Jones PH, Nair R, Thakker KM: Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc 2012, 1:e001800.
10. Banegas JR, Lopez-Garcia E, Dallongeville J, Guallar E, Halcox JP, Borghi C, Masso-Gonzalez EL, Jimenez FJ, Perk J, Steg PG, De Backer G, Rodríguez-Artalejo F: Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study. Eur Heart J 2011, 32:2143-2152.
11. Gitt AK, Junger C, Smolka W, Bestehorn K: Prevalence and overlap of different lipid abnormalities in statin-treated patients at high cardiovascular risk in clinical practice in Germany. Clin Res Cardiol 2010, 99:723-733.
12. Hermans MP, Castro CM, Stranüberg T, Ferrieres J, Feely J, Elisaf M, Michel G, Sansoy V: Centralized Pan-European survey on the under-treatment of hypercholesterolaemia (CEPHEUS): overall findings from eight countries. Curr Med Res Opin 2010, 26:445-454.
13. Kotseva K, Wood D, De Backer G, De Backer D, Pyorala K, Keil U: Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009, 373:929-940.
14. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011, 365:2255-2267.
15. Ginüberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP: Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010, 362:1563-1574.
16. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M: The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003, 100:928-933.
17. Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, Tang J, Liu Q, Higbee J, Xia Z, Di Y, Shetterly S, Arimura Z, Salomonis H, Romanow WG, Thibault ST, Zhang R, Cao P, Yang XP, Yu T, Lu M, Retter MW, Kwon G, Henne K, Pan O, Tsai MM, Fuchslocher B, Yang E, Zhou L, Lee KJ, et al: A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A 2009, 106:9820-9825.
18. Welder G, Zineh I, Pacanowski MA, Troutt JS, Cao G, Konrad RJ: High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res 2010, 51:2714-2721.
19. Farnier M: PCSK9 inhibitors. Curr Opin Lipidol 2013, 24:251-258.
20. Cariou B, Le May C, Costet P: Clinical aspects of PCSK9. Atherosclerosis 2011, 216:258-265.
21. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, Wu R, Pordy R: Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012, 380:29-36.
22. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA: Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012, 59:2344-2353.
23. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA: Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012, 367:1891-1900.
24. Siddiqui O, Hung HM, O'Neill R: MMRM vs. LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. J Biopharm Stat 2009, 19:227-246.
25. National Research Council: The Prevention and Treatment of Missing Data in Clinical Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences and Education. In Washington, DC: The National Academies Press; 2010.
26. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JA, Mahaffey KW, Moryusef A, Pordy R, Roe MT, Rorick T, Sasiela WJ, Shirodaria C, Szarek M, Tamby JF, Tricoci P, White H, Zeiher A, Steg PG: Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial. Am Heart J in press.
27. Wang KF, Chang CC, Wang KL, Wu CH, Chen LC, Lu TM, Lin SJ, Chiang CE: Determinants of low-density lipoprotein cholesterol goal attainment: Insights from the CEPHEUS Pan-Asian Survey. J Chin Med Assoc 2014, 77:61-67.
28. Keating AJ, Campbell KB, Guyton JR: Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy. Ann Pharmacother 2013, 47:398-404.
29. Xanthopoulou I, Davlouros P, Siahos S, Perperis A, Zaharioglou E, Alexopoulos D: First-line treatment patterns and lipid target levels attainment in very high cardiovascular risk outpatients. Lipids Health Dis 2013, 12:170.
30. Karalis DG, Victor B, Ahedor L, Liu L: Use of Lipid-Lowering Medications and the Likelihood of Achieving Optimal LDL-Cholesterol Goals in Coronary Artery Disease Patients. Cholesterol 2012, 2012:861924.
31. Arca M, Pigna G: Treating statin-intolerant patients. Diabetes Metab Syndr Obes 2011, 4:155-166.
32. Jackevicius CA, Mamdani M, Tu JV: Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002, 288:462-467.
33. Toth PP, Foody JM, Tomassini JE, Sajjan SG, Ramey DR, Neff DR, Tershakovec AM, Hu XH, Tunceli K: Therapeutic practice patterns related to statin potency and ezetimibe/simvastatin combination therapies in lowering LDL-C in patients with high-risk cardiovascular disease. J Clin Lipidol 2014, 8:107-116.
34. Morrone D, Weintraub WS, Toth PP, Hanson ME, Lowe RS, Lin J, Shah AK, Tershakovec AM: Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 2012, 223:251-261.
35. Pordy R, Lecorps G, Bessac L, Sasiela WJ, Ginüberg HN: Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9: therapeutic dosing in phase 3 studies. J Clin Lipidol 2013, 7:279.
36. Lewington S, Whitlock G, Clarke R, Sherliker P, Eüberson J, Halsey J, Qizilbash N, Peto R, Collins R: Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007, 370:1829-1839.
37. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD: Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989, 320:904-910.
38. Goldstein LB: Low LDL cholesterol, statins, and brain hemorrhage: should we worry? Neurology 2007, 68:719-720.
39. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004, 110:227-239.
40. Anderson TJ, Gregoire J, Hegele RA, Couture P, Mancini GB, McPherson R, Francis GA, Poirier P, Lau DC, Grover S, Genest J Jr, Carpentier AC, Dufour R, Gupta M, Ward R, Leiter LA, Lonn E, Ng DS, Pearson GJ, Yates GM, Stone JA, Ur E: Are the ACC/AHA guidelines on the treatment of blood cholesterol a game changer? A perspective from the Canadian Cardiovascular Society Dyslipidemia Panel. Can J Cardiol 2014, 30:377-380.