A highly durable RNAi therapeutic inhibitor of PCSK9

New England Journal of Medicine

Volumn 376, Issue 1, 2017, Pages 41-51

  Fitzgerald, Kevin ^a   White, Suellen ^a   Borodovsky, Anna ^a   Bettencourt, Brian R ^a   Strahs, Andrew ^a   Clausen, Valerie ^a   Wijngaard, Peter ^b   Horton, Jay D ^c   Taubel, Jorg ^d   Brooks, Ashley ^e   Fernando, Chamikara ^e   Kauffman, Robert S ^a   Kallend, David ^b   Vaishnaw, Akshay ^a   Simon, Amy ^a  

^a ALNYLAM PHARMACEUTICALS   (United States)

^b MEDICINES COMPANY   (United States)

^c UNIVERSITY OF TEXAS AT DALLAS   (United States)

^d ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

^e 206 Carnegie Center   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ATORVASTATIN; GAMMA GLUTAMYLTRANSFERASE; INCLISIRAN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; PROPROTEIN CONVERTASE 9; ALN-PCS; HYPOCHOLESTEROLEMIC AGENT; N ACETYLGALACTOSAMINE; PCSK9 PROTEIN, HUMAN; RNA INDUCED SILENCING COMPLEX; SMALL INTERFERING RNA;

ADULT; AGED; ARTICLE; BACKACHE; CHOLESTEROL BLOOD LEVEL; COHORT ANALYSIS; CONTROLLED STUDY; COUGHING; DIARRHEA; DISEASE SEVERITY; DRUG SAFETY; ENZYME BLOOD LEVEL; FEMALE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; HEADACHE; HUMAN; HYPERPIGMENTATION; INJECTION SITE RASH; MALE; MUSCULOSKELETAL PAIN; NORMAL HUMAN; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; RNAI THERAPEUTICS; SIDE EFFECT; SINGLE BLIND PROCEDURE; SINGLE DRUG DOSE; ADOLESCENT; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; BLOOD; CLINICAL TRIAL; METABOLISM; MIDDLE AGED; SUBCUTANEOUS DRUG ADMINISTRATION; YOUNG ADULT;

ACETYLGALACTOSAMINE; ADOLESCENT; ADULT; AGED; ANTICHOLESTEREMIC AGENTS; CHOLESTEROL, LDL; FEMALE; HEALTHY VOLUNTEERS; HUMANS; INJECTIONS, SUBCUTANEOUS; MALE; MIDDLE AGED; PROPROTEIN CONVERTASE 9; RNA, SMALL INTERFERING; RNA-INDUCED SILENCING COMPLEX; RNAI THERAPEUTICS; SINGLE-BLIND METHOD; YOUNG ADULT;

EID: 85008485863     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMoa1609243     Document Type: Article

References (27)

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 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. J Am Coll Cardiol 2014;63:2889-934.
2. Barkas F, Liberopoulos EN, Kostapanos MS, Liamis G, Tziallas D, Elisaf M. Lipid target achievement among patients with very high and high cardiovascular risk in a lipid clinic. Angiology 2015;66:346-53.
3. Jameson K, Zhang Q, Zhao C, et al. Total and low-density lipoprotein cholesterol in high-risk patients treated with atorvastatin monotherapy in the United Kingdom: analysis of a primary-care database. Curr Med Res Opin 2014;30:655-65.
4. 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(6):e001800.
5. Hooper AJ, Burnett JR. Anti-PCSK9 therapies for the treatment of hypercholesterolemia. Expert Opin Biol Ther 2013;13:429-35.
6. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009;94:2537-43.
7. Mousavi SA, Berge KE, Leren TP. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med 2009;266:507-19.
8. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of lossof-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006;79:514-23.
9. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009;50: Suppl: S172-S177.
10. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007;193:445-8.
11. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163:40-51.
12. Zhang XL, Zhu QQ, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 2015;13:123.
13. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
14. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
15. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014;383:60-8.
16. Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 2014;136:16958-61.
17. Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A 2008;105:11915-20.
18. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013;369:819-29.
19. Tabernero J, Shapiro GI, LoRusso PM, et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 2013;3:406-17.
20. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebocontrolled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol 2012;60:1888-98.
21. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012;380:1995-2006.
22. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108-18.
23. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial. Int J Cardiol 2014;176:55-61.
24. Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol 2015;115:1212-21.
25. Rouleau J. Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Am J Med 2005;118: Suppl 12A:28-35.
26. Henne KR, Ason B, Howard M, et al. Anti-PCSK9 antibody pharmacokinetics and low-density lipoprotein-cholesterol pharmacodynamics in nonhuman primates are antigen affinity-dependent and exhibit limited sensitivity to neonatal Fc receptor-binding enhancement. J Pharmacol Exp Ther 2015;353:119-31.
27. Egom EE, Hafeez H. Biochemistry of statins. Adv Clin Chem 2016;73:127-68.