DEVELOPMENT OF PCSK9 INHIBITOR TO LOWER LDL-CHOLESTEROL
DOI:
https://doi.org/10.69598/tbps.13.1.105-123Keywords:
พีซีเอสเค9, ตัวรับแอลดีแอล, ยาลดคอเลสเตอรอลในเลือด, PCSK9, LDL-receptor, antihypercholesterolemiaAbstract
พีซีเอสเค9 (PCSK9) คือโปรตีนในร่างกายชนิดหนึ่งที่มีบทบาทต่อเมแทบอลิซึมของไขมันผ่านการควบคุมจำนวนตัวรับแอลดีแอลที่เซลล์ตับ และส่งผลต่อการนำแอลดีแอล-คอเลสเตอรอลจากกระแสเลือดเข้าสู่เซลล์ตับ PCSK9 เป็นเป้าหมายที่น่าสนใจในการรักษาภาวะไขมันในเลือดสูงเนื่องจากพบว่าผู้ที่มีการกลายพันธุ์บนยีน PCSK9 ชนิดที่มีผล
ทำให้การทำงานของ PCSK9 ลดลงจะมีระดับคอเลสเตอรอลต่ำกว่าคนทั่วไป ปัจจุบันมีการศึกษาพัฒนายาเพื่อยับยั้ง PCSK9 ผ่านกลไกต่างๆ ได้แก่ การสังเคราะห์ การหลั่ง PCSK9 ออกจากเซลล์ หรือการจับกับตัวรับแอลดีแอลด้วยสารในกลุ่มต่างๆ เช่น antisense oligonucleotides small interfering RNA mimetic peptides หรือ monoclonal antibodies เป็นต้น สารยับยั้ง PCSK9 ที่ประสบความสำเร็จมากที่สุดในปัจจุบันคือ monoclonal antibodies ที่จำเพาะต่อ PCSK9 โดยมียาที่ได้รับการขึ้นทะเบียนเพื่อใช้รักษาภาวะคอเลสเตอรอลในเลือดสูงแล้ว 2 ชนิด คือ evolocumab และ alirocumab จากการวิจัยทางคลินิกพบว่ายาทั้งสองชนิดมีความปลอดภัยและประสิทธิภาพในการลดระดับไขมันชนิดแอลดีแอลได้ดี ดังนั้นยากลุ่มนี้จึงเป็นทางเลือกใหม่สำหรับผู้ป่วยที่ไม่สามารถรับประทานยากลุ่ม statin หรือผู้ป่วยที่ใช้ยากลุ่ม statin ในขนาดสูงสุดแล้วไม่สามารถลดระดับแอลดีแอล-คอเลสเตอรอลได้ถึงเป้าหมาย โดยขณะนี้ข้อมูลการศึกษาทางคลินิกในแง่การป้องกันความเสี่ยงต่อการเกิดโรคหัวใจและหลอดเลือดของยาทั้งสองชนิดยังอยู่ในระหว่างการศึกษาในโครงการวิจัยขนาดใหญ่ สำหรับบทความนี้จะกล่าวถึงข้อมูลการศึกษาพัฒนาสารยับยั้ง PCSK9 รวมถึงผลการศึกษาทางคลินิกของยากลุ่มนี้ในผู้ป่วยกลุ่มต่าง ๆ ที่มีข้อมูลในปัจจุบัน
The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in lipid metabolism by regulating LDL receptor degradation and the uptake of circulating LDL-cholesterol into the hepatic cells. PCSK9 has become an attractive agent for the treatment of hypercholesterolemia because individuals with loss-of-function mutations in gene encoding PCSK9 have lower LDL cholesterol levels than normal individuals. At present, drugs targeting PCSK9 have been designed to inhibit this enzyme through various mechanisms including PCSK9 synthesis, PCSK9 secretion or LDL-receptor binding by using inhibitors such as antisense oligonucleotides, small interfering RNA, mimetic peptides or monoclonal antibodies. PCSK9 monoclonal antibodies (mAb) are now the most successful PCSK9 inhibitors. Two PCSK9 mAb, evolocumab and alirocumab, have been approved for the treatment of hypercholesterolemia. Clinical trials have shown that these drugs effectively reduce LDL-cholesterol levels with good safety profiles. Consequently, PCSK9 mAb have become an alternative treatment for statin-intolerant patients or for those who use statiin at the maximum level, but cannot reduce the target level of cholesterol. The effect of PCSK9 mAb on cardiovascular morbidity and mortality is currently under investigation in major clinical trials. This review provides an overview of drug development against PCSK9 and the clinical efficacy of PCSK9 inhibitor antibodies in specific target populations.
References
1. Rashid H, Meredith IT, Nasis A. PCSK9 monoclonal antibodies in 2016: Current status and future challenges. Heart Lung Circ. 2017;26(8):786-98.
2. Page MM, Watts GF. PCSK9 inhibitors – mechanisms of action. Aust Prescr. 2016;39(5):164-7.
3. Zhang PY. PCSK9 as a therapeutic target for cardiovascular disease. Exp Ther Med. 2017;13(3):810-4.
4. Melendez QM, Krishnaji ST, Wooten CJ, Lopez D. Hypercholesterolemia: The role of PCSK9. Arch Biochem Biophys. 2017;625:39-53.
5. Ito MK, Santos RD. PCSK9 inhibition with monoclonal antibodies: Modern management of hypercholesterolemia. J Clin pharmacol. 2017;57(1):7-32.
6. Costet P, Krempf M and Cariou B. PCSK9 and LDL cholesterol: unravelling the target to design the bullet. Trends Biochem Sci. 2008;33(9):426-34.
7. Glerup S, Schulz R, Laufs U, Schlüter K-D. Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic Res Cardiol. 2017;112:32.
8. He N-y, Li Q, Wu C-y, Ren Z, Gao Y, Pan L-h, et al. Lowering serum lipids via PCSK9-targeting drugs: Current advances and future perspectives. Acta Pharmacol Sin. 2017;38(3):301-11.
9. Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol. 2017;9(2):76-91.
10. Visser ME, Witztum JL, Stroes ESG, Kastelein JJP. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J. 2012;33(12):1451-8.
11. Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007;48(4):763-7.
12. Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, et al. PCSK9 RNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther. 2012;20(2):376-81.
13. van Poelgeest EP, Hodges MR, Moerland M, Tessier Y, Levin AA, Persson R, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): A first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol. 2015;80(6):1350-61.
14. Svoboda P. Renaissance of mammalian endogenous RNAi. FEBS Lett. 2014;588(15):2550-6.
15. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642-55.
16. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. P Natl Acad Sci. 2008;105(33):11915-20.
17. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE. 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;383:60-68.
18. Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376(1):41-51.
19. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. New Eng J Med. 2017;376(15):1430-40.
20. Singh V, Braddick D, Dhar PK. Exploring the potential of genome editing CRISPR-Cas9 technology. Gene. 2017;599:1-18.
21. Ding Q, Strong A, Patel KM, Ng SL, Gosis BS, Regan SN, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res. 2014;115(5):488-92.
22. Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, et al. CRISPR-Cas9 targeting of PCSK9 in human hepatocytes in vivo-brief report. Arterioscler Thromb Vasc Biol. 2016;36(5):783-6.
23. Cameron J, Ranheim T, Kulseth MA, Leren TP, Berge KE. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 2008;201(2):266-73.
24. Dong B, Li H, Singh AB, Cao A, Liu J. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway. J Biol Chem. 2015;290(7):4047-58.
25. Wang X, Liu R, Zhang W, Zhang X, Liao N, Wang Z, et al. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol Cell Endocrinol. 2013;376(1-2):70-80.
26. Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, et al. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem. 2014;289(2):942-55.
27. Mitchell T, Chao G, Sitkoff D, Lo F, Monshizadegan H, Meyers D, et al. Pharmacologic profile of the Adnectin BMS-962476, A small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J Pharmacol Exp Ther. 2014;350(2):412-24.
28. Stein EA, Kasichayanula S, Turner T, Kranz T, Arumugam U, Biernat L, et al. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: Results of a single ascending dose study. J Am Coll Cardiol. 2014;63(12):A1372.
29. PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION PRALUENT (alirocumab) 2016 [cited 2017 May 22]. Available from: http://products. sanofi.ca/en/praluent.pdf.
30. PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION REPATHA(evolocumab) 2016 [cited 2017 May 22]. Available from: https:// www amgenca/products~media/ae162719487 c459391bd1b1584a25ead.pdf.
31. Ferri N, Corsini A, Sirtori CR, Ruscica M. Bococizumab for the treatment of hypercholesterolaemia. Expert Opin Biol Ther. 2017;17(2):237-43.
32. Levisetti M, Joh T, Wan H, Liang H, Forgues P, Gumbiner B, et al. A Phase I randomized study of a specifically engineered, pH-sensitive PCSK9 Inhibitor RN317 (PF-05335810) in hypercholesterolemic subjects on statin therapy. Clin Transl Sci. 2017;10(1):3-11.
33. Markham A. Alirocumab: First Global Approval. Drugs. 2015;75(14):1699-705.
34. Manniello M, Pisano M. Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. Pharm Ther. 2016;41(1):28-53.
35. Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, et al. Efficacy and safety of alirocumab in patients with heterozygous FH not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drug Ther. 2014;28(3):281-9.
36. Kastelein JJP, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003.
37. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [cited 2017 JUNE 2]. Available from: https://clinicaltrials.gov/ct2/show/ NCT01663402.
38. Cariou B, LeiterLA , Mu¨ller-Wieland D, Bigot G, Colhoun HM, Prato SD, el al. Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial. Diabetes Metab 2017;43:453–9.
39. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.
40. Ridker PM, Amarenco P, Brunell R, Glynn RJ, Jukema JW, Kastelein JJ, et al. Evaluating bococizumab, a monoclonal antibodies to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and Design of the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) lipid lowering and SPIRE cardiovascular outcomes trials. Am Heart J. 2016;178:135-44.
41. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, et al. Results of bococizumab, a monoclonal antibodies 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(9):1212-21.
42. Pfizer discontinues global development of bococizumab, its investigational PCSK9 inhibitor. Press release from Pfizer, New York, November 1, 2016 [cited 2017 JUNE 2]. Available from: https://www.pfizer. com/news/press-releasepress-release-detailpfizer_discontinues_global_ development_of_bococizumab_its_ investigational_pcsk9_inhibitor.
43. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376 (16):1527-39.
44. Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. J Clin Lipidol. 2014;8(1):18-28.
45. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB. Effect of a monoclonal antibodies to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108-18.
46. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R. Effect of a monoclonal antibodies 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.
47. Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc Drug Ther. 2016;30(5):473-83.
48. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: The Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408-17.
49. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965): 331-40.
50. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906-15.e13.
51. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186-94.
52. Roth EM, Moriarty PM, Bergeron J, Langslet G, Manvelian G, Zhao J, et al. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis. 2016;254:254-62.
53. Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A Phase 3 Study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol. 2016;117(1):40-7.
54. Fitchett DH, Hegele RA, Verma S. Statin intolerance. Circulation. 2015;131(13):e389-91.
55. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-69.
56. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V. Effect of a monoclonal antibodies to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308(23):2497-506.
57. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF. Anti-PCSK9 antibodies effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-8.
58. Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-90.
59. Ito MK, Watts GF. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Drugs. 2015;75(15):1715-24.
60. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965): 341-50.
61. Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet. 2015;385(9965):307-10.
2. Page MM, Watts GF. PCSK9 inhibitors – mechanisms of action. Aust Prescr. 2016;39(5):164-7.
3. Zhang PY. PCSK9 as a therapeutic target for cardiovascular disease. Exp Ther Med. 2017;13(3):810-4.
4. Melendez QM, Krishnaji ST, Wooten CJ, Lopez D. Hypercholesterolemia: The role of PCSK9. Arch Biochem Biophys. 2017;625:39-53.
5. Ito MK, Santos RD. PCSK9 inhibition with monoclonal antibodies: Modern management of hypercholesterolemia. J Clin pharmacol. 2017;57(1):7-32.
6. Costet P, Krempf M and Cariou B. PCSK9 and LDL cholesterol: unravelling the target to design the bullet. Trends Biochem Sci. 2008;33(9):426-34.
7. Glerup S, Schulz R, Laufs U, Schlüter K-D. Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic Res Cardiol. 2017;112:32.
8. He N-y, Li Q, Wu C-y, Ren Z, Gao Y, Pan L-h, et al. Lowering serum lipids via PCSK9-targeting drugs: Current advances and future perspectives. Acta Pharmacol Sin. 2017;38(3):301-11.
9. Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol. 2017;9(2):76-91.
10. Visser ME, Witztum JL, Stroes ESG, Kastelein JJP. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J. 2012;33(12):1451-8.
11. Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007;48(4):763-7.
12. Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, et al. PCSK9 RNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther. 2012;20(2):376-81.
13. van Poelgeest EP, Hodges MR, Moerland M, Tessier Y, Levin AA, Persson R, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): A first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol. 2015;80(6):1350-61.
14. Svoboda P. Renaissance of mammalian endogenous RNAi. FEBS Lett. 2014;588(15):2550-6.
15. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642-55.
16. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. P Natl Acad Sci. 2008;105(33):11915-20.
17. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE. 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;383:60-68.
18. Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376(1):41-51.
19. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. New Eng J Med. 2017;376(15):1430-40.
20. Singh V, Braddick D, Dhar PK. Exploring the potential of genome editing CRISPR-Cas9 technology. Gene. 2017;599:1-18.
21. Ding Q, Strong A, Patel KM, Ng SL, Gosis BS, Regan SN, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res. 2014;115(5):488-92.
22. Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, et al. CRISPR-Cas9 targeting of PCSK9 in human hepatocytes in vivo-brief report. Arterioscler Thromb Vasc Biol. 2016;36(5):783-6.
23. Cameron J, Ranheim T, Kulseth MA, Leren TP, Berge KE. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 2008;201(2):266-73.
24. Dong B, Li H, Singh AB, Cao A, Liu J. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway. J Biol Chem. 2015;290(7):4047-58.
25. Wang X, Liu R, Zhang W, Zhang X, Liao N, Wang Z, et al. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol Cell Endocrinol. 2013;376(1-2):70-80.
26. Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, et al. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem. 2014;289(2):942-55.
27. Mitchell T, Chao G, Sitkoff D, Lo F, Monshizadegan H, Meyers D, et al. Pharmacologic profile of the Adnectin BMS-962476, A small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J Pharmacol Exp Ther. 2014;350(2):412-24.
28. Stein EA, Kasichayanula S, Turner T, Kranz T, Arumugam U, Biernat L, et al. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: Results of a single ascending dose study. J Am Coll Cardiol. 2014;63(12):A1372.
29. PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION PRALUENT (alirocumab) 2016 [cited 2017 May 22]. Available from: http://products. sanofi.ca/en/praluent.pdf.
30. PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION REPATHA(evolocumab) 2016 [cited 2017 May 22]. Available from: https:// www amgenca/products~media/ae162719487 c459391bd1b1584a25ead.pdf.
31. Ferri N, Corsini A, Sirtori CR, Ruscica M. Bococizumab for the treatment of hypercholesterolaemia. Expert Opin Biol Ther. 2017;17(2):237-43.
32. Levisetti M, Joh T, Wan H, Liang H, Forgues P, Gumbiner B, et al. A Phase I randomized study of a specifically engineered, pH-sensitive PCSK9 Inhibitor RN317 (PF-05335810) in hypercholesterolemic subjects on statin therapy. Clin Transl Sci. 2017;10(1):3-11.
33. Markham A. Alirocumab: First Global Approval. Drugs. 2015;75(14):1699-705.
34. Manniello M, Pisano M. Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. Pharm Ther. 2016;41(1):28-53.
35. Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, et al. Efficacy and safety of alirocumab in patients with heterozygous FH not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drug Ther. 2014;28(3):281-9.
36. Kastelein JJP, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003.
37. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [cited 2017 JUNE 2]. Available from: https://clinicaltrials.gov/ct2/show/ NCT01663402.
38. Cariou B, LeiterLA , Mu¨ller-Wieland D, Bigot G, Colhoun HM, Prato SD, el al. Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial. Diabetes Metab 2017;43:453–9.
39. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.
40. Ridker PM, Amarenco P, Brunell R, Glynn RJ, Jukema JW, Kastelein JJ, et al. Evaluating bococizumab, a monoclonal antibodies to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and Design of the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) lipid lowering and SPIRE cardiovascular outcomes trials. Am Heart J. 2016;178:135-44.
41. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, et al. Results of bococizumab, a monoclonal antibodies 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(9):1212-21.
42. Pfizer discontinues global development of bococizumab, its investigational PCSK9 inhibitor. Press release from Pfizer, New York, November 1, 2016 [cited 2017 JUNE 2]. Available from: https://www.pfizer. com/news/press-releasepress-release-detailpfizer_discontinues_global_ development_of_bococizumab_its_ investigational_pcsk9_inhibitor.
43. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376 (16):1527-39.
44. Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. J Clin Lipidol. 2014;8(1):18-28.
45. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB. Effect of a monoclonal antibodies to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108-18.
46. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R. Effect of a monoclonal antibodies 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.
47. Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc Drug Ther. 2016;30(5):473-83.
48. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: The Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408-17.
49. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965): 331-40.
50. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906-15.e13.
51. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186-94.
52. Roth EM, Moriarty PM, Bergeron J, Langslet G, Manvelian G, Zhao J, et al. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis. 2016;254:254-62.
53. Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A Phase 3 Study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol. 2016;117(1):40-7.
54. Fitchett DH, Hegele RA, Verma S. Statin intolerance. Circulation. 2015;131(13):e389-91.
55. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-69.
56. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V. Effect of a monoclonal antibodies to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308(23):2497-506.
57. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF. Anti-PCSK9 antibodies effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-8.
58. Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-90.
59. Ito MK, Watts GF. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Drugs. 2015;75(15):1715-24.
60. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965): 341-50.
61. Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet. 2015;385(9965):307-10.
Downloads
Published
2018-03-15
How to Cite
RIAM-AMATAKUN, W., & NUNTHARATANAPONG, N. (2018). DEVELOPMENT OF PCSK9 INHIBITOR TO LOWER LDL-CHOLESTEROL. Thai Bulletin of Pharmaceutical Sciences, 13(1), 105–123. https://doi.org/10.69598/tbps.13.1.105-123
Issue
Section
Review Articles
License
All articles published and information contained in this journal such as text, graphics, logos and images is copyrighted by and proprietary to the Thai Bulletin of Pharmaceutical Sciences, and may not be reproduced in whole or in part by persons, organizations, or corporations other than the Thai Bulletin of Pharmaceutical Sciences and the authors without prior written permission.
