DEVELOPMENT OF PCSK9 INHIBITOR TO LOWER LDL-CHOLESTEROL

Authors

  • WASSANA RIAM-AMATAKUN Department of Pharmacy, Phramongkutklao Hospital, Bangkok
  • NOPPARAT NUNTHARATANAPONG Department of Pharmacology and Toxicology, Faculty of Pharmacy, Silpakorn University, Sanamchandra Palace Campus, Nakhon Pathom

DOI:

https://doi.org/10.14456/tbps/2018.2

Keywords:

พีซีเอสเค9, ตัวรับแอลดีแอล, ยาลดคอเลสเตอรอลในเลือด, PCSK9, LDL-receptor, antihypercholesterolemia

Abstract

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.

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2018-03-15

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