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Inclisran治疗杂合性家族性高胆固醇血症患者疗效显著
作者:小柯机器人 发布时间:2020/3/29 22:56:04

南非威特沃特斯兰德大学Frederick J. Raal课题组探讨了Inclisiran治疗杂合子家族性高胆固醇血症的效果。相关论文于2020年3月18日发表在《新英格兰医学杂志》上。

家族性高胆固醇血症的特点是低密度脂蛋白(LDL)胆固醇水平升高,早发动脉粥样硬化性心血管疾病的风险增加。目前针对前蛋白转化酶枯草杆菌蛋白酶-kexin 9型(PCSK9)的单克隆抗体可使LDL胆固醇水平降低50%以上,但需要每2-4周使用一次。在一项临床2期试验中,每年注射两次Inclisiran可抑制杂合子家族性高胆固醇血症的成年人肝脏PCSK9的合成。

在这项临床3期的双盲试验中,研究组招募了482名患有杂合子家族性高胆固醇血症的成年人,将其按1:1随机分组,分别于第1、90、270和450天接受皮下注射Inclisiran钠或安慰剂。

482名患者的中位年龄为56岁,男性占47%。LDL胆固醇的平均基线水平为153 mg/dL。在第510天,Inclisiran组的LDL胆固醇水平降低了39.7%,而安慰剂组升高了8.2%,差异显著。在第90天和第540天之间,Inclisiran组LDL胆固醇水平平均降低了38.1%,而安慰剂组则升高了6.2%,差异显著。在所有基因型家族性高胆固醇血症中,LDL胆固醇水平均显著降低。两组间不良事件和严重不良事件相差不大。

综上,Inclisiran可显著降低杂合子家族性高胆固醇血症成年人的LDL胆固醇水平,且安全性可耐受。

附:英文原文

Title: Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia

Author: Frederick J. Raal, M.D., Ph.D.,, David Kallend, M.B., B.S.,, Kausik K. Ray, M.D., M.Phil.,, Traci Turner, M.D.,, Wolfgang Koenig, M.D.,, R. Scott Wright, M.D.,, Peter L.J. Wijngaard, Ph.D.,, Danielle Curcio, M.B.A.,, Mark J. Jaros, Ph.D.,, Lawrence A. Leiter, M.D.,, and John J.P. Kastelein, M.D., Ph.D.

Issue&Volume: 2020-03-18

Abstract: AbstractBackgroundFamilial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.MethodsIn this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.ResultsThe median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], 43.7 to 35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of 47.9 percentage points (95% CI, 53.5 to 42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, 41.1 to 35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of 44.3 percentage points (95% CI, 48.5 to 40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.ConclusionsAmong adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile.

DOI: 10.1056/NEJMoa1913805

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1913805

 

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home